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Review

Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic

by
Songhyun Lim
1 and
Sanghee Lee
1,2,*
1
Creative Research Center for Brain Science, Brain Science Institute, Korea Institute of Science and Technology, Seoul 02792, Korea
2
Department of HY-KIST Bio-Convergence, Hanyang University, Seoul 04763, Korea
*
Author to whom correspondence should be addressed.
Molecules 2022, 27(16), 5088; https://doi.org/10.3390/molecules27165088
Submission received: 12 July 2022 / Revised: 5 August 2022 / Accepted: 9 August 2022 / Published: 10 August 2022
(This article belongs to the Special Issue Young Scholars’ Developments in Chemical Biology)
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Abstract

:
Autism spectrum disorders (ASD) are neurodevelopmental disorders characterized by diverse behavioral symptoms such as repetitive behaviors, social deficits, anxiety, hyperactivity, and irritability. Despite their increasing incidence, the specific pathological mechanisms of ASD are still unknown, and the degree and types of symptoms that vary from patient to patient make it difficult to develop drugs that target the core symptoms of ASD. Although various atypical antipsychotics and antidepressants have been applied to regulate ASD symptoms, these drugs can only alleviate the symptoms and do not target the major causes. Therefore, development of novel drugs targeting factors directly related to the onset of ASD is required. Among the various factors related to the onset of ASD, several chemical modulators to treat ASD, focused on serotonin (5-hydroxytryptamine, 5-HT) and glutamate receptors, microbial metabolites, and inflammatory cytokines, are explored in this study. In particular, we focus on the chemical drugs that have improved various aspects of ASD symptoms in animal models and in clinical trials for various ages of patients with ASD.

Graphical Abstract

1. Introduction

Autism spectrum disorders (ASD) are a part of neurodevelopmental disorders and reveals a broad range of symptoms primarily characterized by repetitive behaviors, irritability, delayed development of language skills, and restricted social interactions [1,2,3,4]. It is known that abnormal brain developmental processes in ASD affect cognition, emotion, learning, and memory, thereby linking to abnormal behaviors [3]. Current study estimated that about 1 in 100 children around the world are diagnosed with ASD, and the prevalence is increasing over time [5]. According to the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders from the American Psychiatric Association, ASD includes Asperger’s disorder and pervasive developmental disorder not otherwise specified (PPD-NOS) [4,6]. Despite the large number of patients, only limited cases of patients that have a recognized etiology and the pathological mechanism of ASD is still unknown in detail. [2,7]. Since there is no clear biomarker to objectively diagnose ASD, various diagnostic criteria and discrimination of the diversity of disorders are mainly based on monitoring behavioral features [2,8]. Moreover, ASD patients have a wide range of disabilities from a patient with a minimal effect on living to a patient where active support is needed. All these features of ASD such as ambiguous cause, no specific biomarkers, and broad range of patient spectrum make difficult to target core symptoms of ASD in drug discovery.
To find a therapeutic agent, an early drug discovery process accompanied by target identification and target validation, followed by assay development with specific biomarkers, leads to a drug development strategy [9]. However, the general early drug discovery process is very limited in ASD due to the lack of biomarkers and the unclear pathological mechanisms. Therefore, to date, there are no medications approved for use in treating the core symptoms of ASD [10]. Previously known drugs are primarily used to alleviate the behavioral symptoms of ASD, including irritability, repetitive behaviors, agitation, aggression, self-injury, anxiety, hyperactivity, insomnia, impulsivity, and inattention [3,10,11]. Several studies have reported the benefit of atypical antipsychotics including risperidone, aripiprazole, and lurasidone for behavioral improvement in certain symptoms of ASD such as aggression, hyperactivity, repetitive behavior, self-injury, irritability, and impulsivity [3,10,11,12,13,14,15,16,17,18,19,20,21,22,23]. Moreover, typical antipsychotics, antidepressants, and mood stabilizers are commonly used to regulate the behavioral symptoms of ASD in patients [10,11,14,15]. Along with various types of pharmaceuticals, behavioral interventions are also applied to control the symptoms of ASD [10,24,25,26].
Lack of exact pathological mechanisms, clinical targets, and specific biomarkers are considered characteristic features of ASD. These characteristics make it difficult to approach ASD from the perspective of chemical modulators. Moreover, drug repurposing with conventional drugs which have been developed to treat other neurological disorders validated their therapeutic effect for alleviating behavioral symptoms of ASD. Recently, the original targets of repurposing drugs have been found to have a function related to ASD. Therefore, in this review, we have summarized and discussed several types of chemical modulators by focusing on recent studies of drug candidates targeting ASD from their mode-of-action to proof-of concept (POC) in the preclinical stage and the therapeutic effects in clinical trials. We investigated a series of chemical modulators based on biochemical regulations including serotonin (5-hydroxytryptamine, 5-HT) and glutamate targeting core symptoms in ASD. For environmental regulations, the study of microbial metabolites targeting ASD was discussed. Finally, immune regulation associated with proinflammatory cytokines was investigated, as cytokine modulation could be a potential target for the treatment of ASD.

2. Pathophysiology of ASD

It is suggested that genetic, epigenetic, and environmental factors are involved in the process of the development and deepening of ASD (Figure 1). As various factors are involved in ASD, the genetic variation among individuals and the resulting variation of ASD symptoms appear widely. Although the exact pathological mechanism of ASD is unknown, genetic factors are strongly implicated to be involved in ASD pathophysiology. Sibling studies, twin studies, and the male-to-female ratio in ASD indicate the role of genetic components in the etiology of ASD [27,28,29,30,31]. Moreover, gene polymorphisms such as point mutation, translocation, and de novo copy number variations are possible risk factors in the development of ASD [3,32,33]. Several studies have mentioned the important role of de novo copy number variations in neurodevelopmental pathway of ASD [30,33,34,35,36,37].
Epigenetic modifications regulate chromatin structure and gene expression without the change in DNA sequence. Factors such as DNA methylation, histone modification, and microRNA regulate chromatin structure and gene expression, which plays a role in regulating brain development and can cause neurodevelopmental disorders including ASD [33].
Environmental factors, mostly in the prenatal period, are also an important cause of ASD. Viral infections, parental age and health, zinc and copper deficiency, toxic chemical exposures, various fetal environments, and perinatal/natal risk factors are involved [38,39]. Along with genetic and environmental factors, various central neurotransmitter systems involved in initial brain development, serotonin (5-hydroxytryptamine, 5-HT), gamma-aminobutyric acid (GABA), dopamine, glutamate, histamine, and acetylcholine are suggested to play a significant role in onset and development of ASD [3,32].

3. Classification of Chemical Modulators

3.1. Neurotransmitters

3.1.1. 5-HT Receptors (5-HTRs)

Among various neurotransmitters, 5-HT is especially important in brain development and ASD symptoms including aggression, anxiety, insomnia, and social behavior as it regulates cell division, differentiation, and synaptogenesis [40,41]. Elevated 5-HT levels in plasma and platelets (hyperserotonemia) have been detected in more than 25% of children with autism at the early stage of ASD development, which is often observed in people with developmental disorders [3,41,42]. Moreover, changes in 5-HT synthesis and 5-HTR density with age are highly related to ASD development and progress [40]. Several studies have indicated that targeting 5-HTRs could be effective in treating the core symptoms of ASD [43].
Various types of compounds including atypical antipsychotic drugs, antidepressants, and selective serotonin reuptake inhibitors (SSRIs) have been applied to target seven families of 5-HTRs in ASD treatments (Table 1). First, several types of atypical antipsychotic drugs were prescribed for ASD patients in clinical settings. Aripiprazole, the United States Food and Drug Administration (FDA)-approved antipsychotic, was demonstrated as both an agonist and antagonist for several 5-HTR types and has been used to alleviate irritability in ASD [3,16,44,45,46]. Comparably, other pharmaceuticals such as risperidone and lurasidone showed antagonistic activity against various types of 5-HTR as well as dopamine receptors, and these drugs were effective against irritability, aggression, temper outburst, and the self-injurious behavior of children with autism [2,3,47,48,49,50,51]. Antidepressant agents targeting the 5-HT level have been used to manage not only anxiety and obsessive–compulsive symptoms but also other complex autistic symptoms. Vortioxetine, another antidepressant, 5-HT transporter, and 5-HT1A/5-HT1B activator, reduced repetitive behavior but showed little effect on enhancing sociability in the rodent model of ASD [52]. Clomipramine, a tricyclic antidepressant and a potent SSRI, has been FDA-approved for treating patients with obsessive–compulsive disorder, which is strongly related to ASD symptoms [11,14]. Clomipramine was effective in reducing abnormal social interaction, compulsive symptoms, and stereotypic ASD behaviors in the treated group compared to the placebo group in a double-blind study [53]. Other SSRIs, fluoxetine, fluvoxamine, and sertraline, showed an improvement of symptoms associated with ASD including repetitive behavior, aggression, language usage, abnormal social interactions, cognition, anxiety, irritability, and agitation [54,55,56,57,58,59]. All these applications of known drugs indicated 5-HTR engagement to alleviate ASD symptoms and to address the unmet needs for the specific regulation of 5-HTR. For this purpose, several studies for the development of a specific chemical modulator for 5-HTR in ASD treatment have been reported. (+)-5-FPT, a 5-HT1AR/5-HT2CR agonist and 5-HT7R antagonist, was developed and studied in a mouse model to reduce repetitive behavior through 5-HT1AR agonism and audiogenic seizure through 5-HT2CR agonism [60,61]. The administration of 8-OH DPAT, a 5-HT1AR/5-HT7R agonist, to a valproate-induced rat ASD model improved social interaction and reduced anxiety and hyperactivity [62]. A recent study designed and synthesized a compound 2c, which acts as an antagonist against 5-HT7R [63]. In a transgenic mouse model of ASD, 2c reduced the level of repetitive behaviors to a level similar to the wildtype mice. These results demonstrated that investigation of a 5-HTR modulator could potentially lead to the development of effective drugs for ASD stereotypes.

3.1.2. Glutamate Receptors (GluRs)

Glutamate, the primary excitatory neurotransmitter in the brain, plays a role in neuronal developmental processes such as learning and memory formation [2,64,65]. The disruption of the glutamate system is involved in ASD development, because ASD may be caused by a disruption of the balance between exhibition and inhibition in the brain [2]. An increased glutamate level in the blood and platelets of individuals with autism has been reported [65,66,67,68]. This evidence suggests that abnormalities in the glutamatergic signaling pathways occur in ASD [65]. A previous study identified that in a valproic acid (VPA)-induced ASD rat model, a substantial increase in the expression of genes encoding subunits of the ionotropic GluRs was detected [69]. Therefore, GluRs could be a plausible target for treatment of ASD symptoms, and various preclinical and clinical cases have been reported (Table 2).
There are two types of GluRs, ionotropic and metabotropic, and three subtypes of ionotropic glutamate receptors including kainite, α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and N-methyl-D-aspartate (NMDA) [2,64]. Glutamate ionotropic receptor kainite type subunit 2 (GRIK2), which encodes for GluR6, is a strong candidate gene for ASD treatment [2,65,70,71,72]. GRIK2 is localized in the autism-specific region on chromosome 6q21, and its encoded protein GluR6 is involved with ASD symptoms such as anxiety, learning, and memory [70,71]. Unfortunately, to date, there is no preclinical drug development targeting abnormal GluR6 activity to treat ASD. Meanwhile, previous studies reported that modulation of AMPA reduced social impairments in animal models of ASD [73,74]. In particular, ampakine Cx546, an AMPA receptor positive allosteric modulator, improved social interaction in genetic mouse models of ASD [75]. These results indicate that the mechanism for enhancement of excitatory synaptic transmission would be a novel candidate to treat ASD symptoms.
Another therapeutic target in ASD is the glutamate hyperfunction at NMDA receptors [2,70]. A representative NMDA antagonist, memantine, has been widely studied for treatment of people with ASD symptoms. An open-label add-on therapy of memantine offered to patients with ASD or PPD-NOS over a 21-month period showed improvements in language function, social behavior, and self-stimulatory behaviors [76]. Another study of a randomized single-blind clinical trial for children under 14 with ASD introduced memantine as a new adjunct drug with applied behavior analysis (ABA), which resulted in the improvement of ASD symptoms, compared to the ABA-only group [77]. As well as children, an open-label trial of memantine for adults with ASD showed a significant improvement in ADHD and anxiety after a 12-week intervention [78]. A randomized controlled trial of memantine for the treatment of social impairment in adolescents with ASD is currently underway (ClinicalTrials.gov: NCT01972074). D-cycloserine, a partial agonist at NMDA receptors, has shown positive effects on the social behavior of ASD in animal models [79,80]. Based on the therapeutic effects of D-cycloserine on the ASD animal models, several clinical trials were conducted to validate a reduction in the social deficit in people with ASD. A single-blind placebo lead-in phase study for 2 weeks to examine the effects of D-cycloserine on age 5 and older subjects showed a significant improvement in social impairment in ASD [81]. A double-blind randomized 10-week trial on older adolescents and young adults with ASD showed that D-cycloserine caused a clinically and statistically significant improvement in social deficits, a major impairment in ASD [82]. A 10-week double-blind placebo-controlled trial on children ages 5–11 years showed an adjunctive effect on increasing the sustained benefit from short-term social skills intervention [83].
Metabotropic GluRs are expressed at presynaptic sites and glial cells, thereby regulating neurotransmitter release, and play critical roles in neuroprotection, glial-neuron communication, and glutamate release, implicating their regulation in neuronal development and neurological disorders [84,85]. Various agonists or antagonists of metabotropic GluR subtypes have been considered as alleviators of ASD symptoms. A previous study investigated the potential effect of the metabotropic GluR5 antagonist, fenobam, and the GluR1 antagonist, JNJ16259685 [86]. Deletion of the eukaryotic initiation factor 4E-binding protein 2 (4E-BP2) gene in mouse showed an imbalance in excitatory and inhibitory neurotransmission and ASD-like behaviors. Treatment of fenobam and JNJ16259685 in 4E-BP2-deleted mice led to a reduction in repetitive behaviors and improved social behaviors. Moreover, 2-methyl-6-phenylethynyl-pyridine (MPEP), an antagonist of the metabotropic GluR5, reduced the repetitive behavior of various ASD mouse models in previous studies [87,88]. Acamprosate, a weak NMDA receptor antagonist and also a metabotropic GluR5 antagonist, was administered to children with ASD for an 8-week open-label trial [89]. Although the scale of the trial was relatively small, the results showed positive effects of acamprosate on verbalization, attention, social behavior, and hyperactivity. As for current trial results to look forward to, a phase 1 double-blind placebo-controlled study of acamprosate in ASD is ongoing (ClinicalTrials.gov: NCT01813318).
Table
Table 2. Glutamate-related pharmacological agents and their potential effects on treating ASD symptoms. AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA: N-methyl-D-aspartate, GluR: Glutamate receptor, MPEP: 2-methyl-6-phenylethynyl-pyridine.
Table 2. Glutamate-related pharmacological agents and their potential effects on treating ASD symptoms. AMPA: α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid, NMDA: N-methyl-D-aspartate, GluR: Glutamate receptor, MPEP: 2-methyl-6-phenylethynyl-pyridine.
CompoundsStructuresTargetsStageEffects
Cx546 Molecules 27 05088 i012AMPA receptor positive allosteric modulatorPreclinicalImproved social interaction [75]
Memantine/Memantine hydrochloride (Namenda) Molecules 27 05088 i013NMDA antagonistClinicalImprovements in language function, social behavior, ADHD, anxiety and self-stimulatory behaviors [76,77,78]
D-cycloserine Molecules 27 05088 i014Partial agonist at NMDA receptorsPreclinicalPositive effects on social behavior [79,80]
ClinicalPositive effects on social behavior [81,82], increasing the sustained benefit from short-term social skills intervention [83]
Fenobam Molecules 27 05088 i015Metabotropic GluR5 antagonistPreclinicalReduction of repetitive behaviors, improved social behaviors [86]
JNJ16259685 Molecules 27 05088 i016GluR1 antagonistPreclinicalReduction of repetitive behaviors, improved social behaviors [86]
MPEP Molecules 27 05088 i017Metabotropic GluR5 antagonistPreclinicalImproved repetitive behavior [87,88]
Acamprosate Molecules 27 05088 i018A weak NMDA receptor antagonist, metabotropic GluR5 antagonistClinicalPositive effects on verbalization, attention, social behavior and hyperactivity [89]

3.2. Microbial Metabolites

Recent studies have uncovered the important role of the gut–brain axis and microbiota in brain physiology–pathology and various neurological disorders (Figure 2) [90,91]. One of the environmental factors underlying the etiology of ASD is viral infection and consequent changes in the gut microbiome [92]. The result of reinducing or treating gut microbial ecology in various mouse models with ASD-like symptoms showed improved social behavior [92,93,94]. Furthermore, the regulation of neuroactive microbial metabolites and crosstalk with the immune system are attracting growing attention as a therapeutic approach for ASD. This approach avoids crossing the blood–brain barrier in drug discovery. Recently, an open-label phase 1b/2a trial was conducted to remove increased levels of toxic microbial metabolites, which are related to ASD-associated behaviors [8]. 4-ethylphenyl sulfate (4EPS), one of the gut microbial metabolites, is eventually produced by 4-ethylphenol through various intermediates starting from tyrosine, a precursor of various mammalian neurotransmitters (Figure 3) [95]. 4EPS is initially produced in gut microbiota and then circulates through the whole body by blood. 4EPS is highly observed in the plasma of individuals with ASD symptoms [95,96]. AB-2004, also known as AST-120, is an oral gastrointestinal-restricted adsorbent, which has an affinity for small aromatic/phenolic molecules, especially uremic toxins including those of gut bacteriological origin. In other words, AB-2004 works as a toxin scavenger generated in the microbiome. Treatment of AB-2004 reduced the level of 4EPS in mice and reduced anxiety and behavioral deficits [8]. Furthermore, the administration of AB-2004 for an adolescent ASD population in a phase 1 clinical trial for 8 weeks confirmed the decreased level of gut microbiological metabolites in plasma and urine, improved gastrointestinal health, and decreased symptoms of anxiety and irritability (ClinicalTrials.gov: NCT04895215).

3.3. Inflammatory Cytokines

The central nervous system is closely correlated with the immune system. Neuropeptides, which are formed by neurons, act as chemoattractants to recruit immune cells, and various effects of immune factors on neuronal migration and neurochemical receptors are related to the genetic risk of ASD [97,98]. In particular, the abnormalities of the immune system and consequent generation of autoantibodies and cytokine alternations/imbalance are closely connected with the ASD phenotype [99,100,101]. The formation of maternal autoantibodies is one of the most important aspects of ASD symptomatology in the prenatal period. Indirect evidence shows that the parents of a child with ASD, especially mothers, have a higher incidence of autoimmune disease [97]. In addition, abnormal brain enlargement in children with ASD was only observed in the case where the mother had the maternal autoantibodies for fetal brain protein [102].
The risk of developing ASD symptoms in children increased when the mothers were exposed to maternal inflammation during pregnancy [103,104,105]. A maternal immune activation (MIA) model was generated by administration of a viral mimetic polyinosinic-polycytidylic acid (poly(I:C)) to activate the maternal immune system of pregnant mice, and the MIA-induced offspring showed representative symptoms of ASD such as impaired sociability and reactive behavior [106]. Over the last half-decade, subsequent experimental evidence has revealed that maternal inflammation and the subsequent changes in gut microbiota affect neurobehavior in the MIA model, and these results suggest the significant role of MIA in ASD [93,107,108].
In line with the outcome of increased ASD risk in offspring by MIA, maternal infection leads to maternal proinflammatory cytokine release and Th17 cell activation, which can heighten the risk for ASD in offspring, combined with the fetus’ immune state and genetic predisposition [109]. When MIA was induced in two types of mice with different microbiota compositions, ASD symptoms were observed only in the mice with higher interleukin (IL)-17a production [110]. The result proved the significant role of IL-17a regulated by the prenatal microbiota composition, which closely relates to the onset of ASD by affecting the immune profiles.
As well as IL-17a, various cytokines play an important role in neurodevelopment by modulating brain function and neural activity [111]. For example, proinflammatory cytokines such as tumor necrosis factor α (TNFα), IL-6, and IL-1β are known to cross the blood–brain barrier and affect the hypothalamus [97,112]. As one of the effects of the immune system in the prenatal period, elevated levels of IL-1β and IL-4 are associated with childhood ASD development [101,113]. Cytokines are also closely related to the pathogenesis and maintenance of ASD in the postnatal period. A previous study reported that the plasma levels of IL-1β, IL-1 receptor antagonist, IL-5, IL-8, IL-12(p70), IL-13, IL-17, and growth-related oncogene-α in male children with ASD were elevated compared to healthy male subjects [114]. Moreover, several studies have confirmed the elevated level of cytokines in ASD patients in various age ranges [111,115,116,117,118,119,120]. Thus, it is considered that an altered profile of cytokines or cytokine overproduction is involved in ASD pathophysiology.
Recently, new treatments by immunomodulation have been introduced through several studies along with mounting evidence of the link between the immune response and ASD pathophysiology (Table 3). In particular, increased proinflammatory cytokines along with JAK (Janus tyrosine kinase)/STAT (signal transducer and activator of transcription) signaling have been identified in children with ASD; therefore, targeting JAK/STAT signaling has therapeutic potential for ASD. Luteolin, known as an antioxidant and a citrus bioflavonoid, is an inhibitor of neuronal IL-6-induced JAK2/STAT3 phosphorylation [4,121]. A case series administering NeuroProtek, which mainly contains luteolin, to children with ASD aged 4–14 years was published [122]. The study reported significant improvement in eye contact and attention to directions in about half the patients and social interactions in 30–50% of patients. Another open-label pilot study for children with ASD provided them with a luteolin formulation for 26 weeks. The results showed significant improvement in adaptive functioning and overall ASD behavior with no major adverse effects [123]. Diosmin, a structural analog of luteolin, is also an inhibitor of the JAK2/STAT3 signaling pathway. A study that orally administered diosmin in a MIA mouse model showed significantly reduced abnormal behavior and neuropathological abnormalities in the offspring [121]. Tyrphostin AG126, a protein tyrosine kinase inhibitor, is known to play a role in neuroprotection and neuroinflammation [124,125]. The effects of tyrphostin AG126 have been demonstrated in two animal studies using a BTBR mouse model of ASD. Treatment of tyrphostin AG126 resulted in an improvement of repetitive and social behavior, as well as the downregulation of IL-21/IL-21R and IL-17A cytokine levels and the JAK/STAT pathway [126,127]. Resveratrol is another drug attenuating proinflammatory cytokines such as IL-17A, IL-6, interferon (IFN)-γ, and TNF-α and activation of the JAK1/STAT3 pathway [4,128]. Several studies have demonstrated the behavioral effects of resveratrol using animal models of ASD. Core ASD symptoms such as repetitive behavior and social deficits were prevented by resveratrol [129,130,131,132,133]. Based on the positive results for ASD in animal studies, a double-blind and placebo-controlled randomized trial was conducted with children with ASD [134]. Although there was no significant improvement in the primary outcome, add-on pharmacotherapy with resveratrol showed an improvement in hyperactivity at the end of the study.
In addition, several compounds that inhibit proinflammatory cytokines have been applied to clinical trials for children with ASD. Celecoxib, an inhibitor against cyclooxygenase-2, has been reported as significantly effective for ASD symptoms [135]. A randomized double-blind placebo-controlled trial, which used celecoxib adjunctively with risperidone, demonstrated positive effects on social deficit, stereotyped activity, and irritability in children with ASD [136]. Another proinflammatory cytokine inhibitor, pentoxifylline, was also applied as an adjunctive treatment to risperidone to control the behavioral aspects of ASD [137]. A double-blind placebo-controlled clinical trial with children diagnosed with ASD demonstrated improvements in social withdrawal/lethargy, stereotyped behavior, irritability, hyperactivity/noncompliance, and inappropriate speech.
The normalization of increased IL-6 by purinoceptor suggested a therapeutic effect on ASD. Suramin is a P2-purinoceptor antagonist [138]. A recent study demonstrated that blocking the purinergic receptor with suramin increased the survival of postnatal neural progenitor cells [139]. Based on the significant role of neural progenitor cells in brain development, the effect of suramin was addressed in various mouse models of ASD. A study with a VPA-induced ASD mouse model showed restored sociability and decreased anxiety after treatment with suramin [140]. Moreover, suramin induced the normalization of an elevated level of IL-6 in ASD mice. In other studies, using MIA mouse models exposed to poly(I:C), suramin resulted in reversed social abnormalities [141,142]. A double-blind placebo-controlled randomized clinical trial was conducted with ten male subjects with ASD ages 5–14 years. A single intravenous treatment of suramin led to improvements in social interaction and language and reduced repetitive/restricted behaviors [143].
Table
Table 3. Immune regulation agents and their potential effects on treating ASD symptoms. IL: interleukin, JAK/STAT: janus tyrosine kinase/signal transducer and activator of transcription, IFN: interferon, TNF: tumor necrosis factor.
Table 3. Immune regulation agents and their potential effects on treating ASD symptoms. IL: interleukin, JAK/STAT: janus tyrosine kinase/signal transducer and activator of transcription, IFN: interferon, TNF: tumor necrosis factor.
CompoundsStructuresTargetsStageEffects
Luteolin Molecules 27 05088 i019Inhibitor of neuronal IL-6-induced JAK3/STAT3 phosphorylationClinicalImproved eye contact, attention to directions, social interactions [122], improvement in adaptive functioning and overall ASD behavior [123]
Diosmin Molecules 27 05088 i020Inhibitor of neuronal IL-6-induced JAK3/STAT3 phosphorylationPreclinicalOpposed abnormal behavior and neuropathological abnormalities [121]
Tyrphostin AG126 Molecules 27 05088 i021Protein tyrosine kinase inhibitor, IL-21/IL-21R, IL-17A, JAK/STAT downregulatorPreclinicalImprovement of repetitive and social behavior [126,127]
Resveratrol Molecules 27 05088 i022IL-17A, IL-6, IFN-γ, TNF-α, and JAK1/STAT3 downregulatorPreclinicalImprovement in repetitive behavior, social deficits [129,130,131,132,133]
ClinicalImprovement in hyperactivity [134]
Celecoxib Molecules 27 05088 i023Cyclooxygenase-2 inhibitorClinicalImprovement in social deficit, stereotyped activity, and irritability [136]
Pentoxifylline Molecules 27 05088 i024Pro-inflammatory cytokine inhibitorClinicalImproved social withdrawal/lethargy, stereotyped behavior, irritability, hyperactivity/noncompliance, and inappropriate speech [137]
Suramin Molecules 27 05088 i025P2-purinoceptor antagonist, leads to IL-6 decreasePreclinicalImprovement in sociability [140,141,142] and anxiety [140]
ClinicalImprovement in sociability, language, and repetitive/restricted behaviors [143]

4. Challenges and Future Perspectives

The challenging part of developing chemical modulators to cure ASD is that the pathological mechanism of ASD is not clear and the degree of symptoms varies greatly from patient to patient. The most challenging part is the lack of a therapeutic target for ASD. Nevertheless, the continuous effort to elucidate biological targets for ASD has progressed. The strategies discussed in this study, such as regulation for neurotransmitters, microbial metabolites, and pro-inflammatory cytokines, have been elucidated based on clinically observed features in ASD patients.
Successful drug development for ASD requires the development of appropriate biomarkers and animal models that target the core symptoms of ASD, and POC for alleviating ASD symptoms must be validated in connection with clinical evidence. Based on the validated POC, it is also necessary to expand potential seed compounds. For these purposes, various immunomodulators for regulating cytokines or microbiome metabolites would be a novel approach for the identification of potential candidates.

5. Conclusions

In this review, we focused on chemical modulators, which can be potential drugs for the treatment of ASD. We especially focused on pharmacological agents that are known to target 5-HT and glutamate receptors, microbial metabolites, and inflammatory cytokines. Based on the analysis of 50 publications and clinical trial information on ClinicalTrials.gov, we investigated the therapeutic effect of 25 chemical modulators for ASD.
Antipsychotics and antidepressants once applied to several neurological diseases have been reported as agonists or antagonists to various types of 5-HTR. Moreover, other compounds such as (+)-5-FPT, 8-OH DPAT, and 2c act as agonists or antagonists to the 5-HTR family, especially to 5-HT7R. These drugs have been effective for a reduction in repetitive behavior and the improvement in social behavior and other symptoms related to ASD. In addition, the effects of the selective serotonin reuptake inhibitor on ASD symptoms fully demonstrated that 5-HT is a potential target for the treatment of ASD. Moreover, there are two types of receptors for glutamate, ionotropic and metabotropic. Drugs acting as an allosteric modulator, antagonist, or agonist for two types of glutamate receptors showed positive results for ASD symptoms. In particular, memantine, D-cycloserine, and acamprosate, which are agonists/antagonists for the NMDA receptor, a type of ionotropic receptor, showed a significant improvement in the behavioral symptoms of ASD in clinical trials for patients of various ages. Microbial metabolites and inflammatory cytokine levels are environmental factors that are known to be associated with the expression of ASD symptoms. AB-2004, a drug that removes 4EPS, one of the toxic microbial metabolites, showed alleviation of anxiety and other behavioral deficits in an ASD mouse model and a subsequent clinical trial. This suggests the effect of the gut–brain axis system centered on the systemic circulation of gut microbial metabolites on the occurrence and deterioration of ASD. Meanwhile, an MIA model has been widely used as an experimental ASD model based on the fact that maternal infection and proinflammatory cytokines increase the risk of ASD development in offspring. In conjunction with these characteristics, inhibitors/downregulators for proinflammatory cytokines such as IL-6 and IL-17 and subsequently activated pathways were applied to patients with ASD symptoms. In particular, tyrphostin AG126, resveratrol, and suramin showed positive effects on reducing repetitive behavior and improving social interaction, core symptoms of ASD. Overall, various chemical modulators are being developed for the treatment of the core symptoms of ASD focused on neurotransmitters, harmful microbial metabolites, proinflammatory cytokines, and immune system regulation.

Author Contributions

Conceptualization: S.L. (Songhyun Lim) and S.L. (Sanghee Lee), Writing—original draft preparation: S.L. (Songhyun Lim), Writing—review and editing: S.L. (Sanghee Lee), supervision: S.L. (Sanghee Lee), Funding acquisition: S.L. (Sanghee Lee). All authors have read and agreed to the published version of the manuscript.

Funding

This research was funded by the KIST Institutional Program, 2E31512 and 2E31524. This research was also supported by the Korea Foundation for Women In Science, Engineering and Technology (WISET), 2022-279.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Nightingale, S. Autism Spectrum Disorders. Nat. Rev. Drug Discov. 2012, 11, 745–746. [Google Scholar] [CrossRef] [PubMed]
  2. Chadman, K.K.; Guariglia, S.R.; Yoo, J.H. New directions in the treatment of autism spectrum disorders from animal model research. Expert Opin. Drug Discov. 2012, 7, 407–416. [Google Scholar] [CrossRef] [PubMed]
  3. Lee, J.; Avramets, D.; Jeon, B.; Choo, H. Modulation of Serotonin Receptors in Neurodevelopmental Disorders: Focus on 5-HT7 Receptor. Molecules 2021, 26, 3348. [Google Scholar] [CrossRef] [PubMed]
  4. Baranova, J.; Dragunas, G.; Botellho, M.C.S.; Ayub, A.L.P.; Bueno-Alves, R.; Alencar, R.R.; Papaiz, D.D.; Sogayar, M.C.; Ulrich, H.; Correa, R.G. Autism Spectrum Disorder: Signaling Pathways and Prospective Therapeutic Targets. Cell. Mol. Neurobiol. 2021, 41, 619–649. [Google Scholar] [CrossRef]
  5. Zeidan, J.; Fombonne, E.; Scorah, J.; Ibrahim, A.; Durkin, M.S.; Saxena, S.; Yusuf, A.; Shih, A.; Elsabbagh, M. Global prevalence of autism: A systematic review update. Autism Res. 2022, 15, 778–790. [Google Scholar] [CrossRef] [PubMed]
  6. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders (Dsm-5®); American Psychiatric Publishing: Washington, DC, USA, 2019; pp. 50–59. [Google Scholar]
  7. Barton, M.; Volkmar, F. How Commonly Are Known Medical Conditions Associated with Autism? J. Autism Dev. Disord. 1998, 28, 273–278. [Google Scholar] [CrossRef] [PubMed]
  8. Campbell, A.S.; Needham, B.D.; Meyer, C.R.; Tan, J.; Conrad, M.; Preston, G.M.; Bolognani, F.; Rao, S.G.; Heussler, H.; Griffith, R.; et al. Safety and target engagement of an oral small-molecule sequestrant in adolescents with autism spectrum disorder: An open-label phase 1b/2a trial. Nat. Med. 2022, 28, 528–534. [Google Scholar] [CrossRef]
  9. Hughes, J.P.; Rees, S.; Kalindjian, S.B.; Philpott, K.L. Principles of Early Drug Discovery. Br. J. Pharmacol. 2011, 162, 1239–1249. [Google Scholar] [CrossRef] [Green Version]
  10. DeFilippis, M.; Wagner, K.D. Treatment of Autism Spectrum Disorder in Children and Adolescents. Psychopharmacol. Bull. 2016, 46, 18–41. [Google Scholar]
  11. Posey, D.J.; McDougle, C.J. Pharmacotherapeutic management of autism. Expert Opin. Pharmacother. 2001, 2, 587–600. [Google Scholar] [CrossRef] [PubMed]
  12. Oswald, D.P.; Sonenklar, N.A. Medication Use Among Children with Autism Spectrum Disorders. J. Child Adolesc. Psychopharmacol. 2007, 17, 348–355. [Google Scholar] [CrossRef] [PubMed]
  13. Barnard, L.; Young, A.H.; Pearson, J.; Geddes, J.; O’Brien, G. A systematic review of the use of atypical antipsychotics in autism. J. Psychopharmacol. 2002, 16, 93–101. [Google Scholar] [CrossRef]
  14. Doyle, C.A.; McDougle, C.J. Pharmacotherapy to control behavioral symptoms in children with autism. Expert Opin. Pharmacother. 2012, 13, 1615–1629. [Google Scholar] [CrossRef] [PubMed]
  15. McDougle, C.J.; Stigler, K.A.; Erickson, C.A.; Posey, D.J. Pharmacology of Autism. Clin. Neurosci. Res. 2006, 6, 179–188. [Google Scholar] [CrossRef]
  16. Marcus, R.N.; Owen, R.; Kamen, L.; Manos, G.; McQuade, R.D.; Carson, W.H.; Aman, M.G. A Placebo-Controlled, Fixed-Dose Study of Aripiprazole in Children and Adolescents with Irritability Associated With Autistic Disorder. J. Am. Acad. Child Adolesc. Psychiatry 2009, 48, 1110–1119. [Google Scholar] [CrossRef]
  17. McCracken, J.T.; McGough, J.; Shah, B.; Cronin, P.; Hong, D.; Aman, M.G.; Arnold, L.E.; Lindsay, R.; Nash, P.; Hollway, J.; et al. Risperidone in Children with Autism and Serious Behavioral Problems. N. Engl. J. Med. 2002, 347, 314–321. [Google Scholar] [CrossRef]
  18. Nicolson, R.; Awad, D.; Sloman, L. An Open Trial of Risperidone in Young Autistic Children. J. Am. Acad. Child Adolesc. Psychiatry 1998, 37, 372–376. [Google Scholar] [CrossRef] [PubMed]
  19. Findling, R.L.; Maxwell, K.; Wiznitzer, M. An Open Clinical Trial of Risperidone Monotherapy in Young Children with Autistic Disorder. Psychopharmacol Bull. 1997, 33, 155–159. [Google Scholar] [PubMed]
  20. Mcdougle, C.J.; Holmes, J.P.; Bronson, M.R.; Anderson, G.M.; Volkmar, F.R.; Price, L.H.; Cohen, D.J. Risperidone Treatment of Children and Adolescents with Pervasive Developmental Disorders: A Prospective, Open-Label Study. J. Am. Acad. Child Adolesc. Psychiatry 1997, 36, 685–693. [Google Scholar] [CrossRef]
  21. Mukaddes, N.M.; Abali, O.; Gurkan, K. Short-Term Efficacy and Safety of Risperidone in Young Children with Autistic Disorder (AD). World J. Biol. Psychiatry 2004, 5, 211–214. [Google Scholar] [CrossRef]
  22. Diler, R.S.; Firat, S.; Avci, A. An open-label trial of risperidone in children with autism. Curr. Ther. Res. 2002, 63, 91–102. [Google Scholar] [CrossRef]
  23. Hardan, A.; Johnson, K.; Johnson, C.; Hrecznyj, B. Case Study: Risperidone Treatment of Children and Adolescents with Developmental Disorders. J. Am. Acad. Child Adolesc. Psychiatry 1996, 35, 1551–1556. [Google Scholar] [CrossRef]
  24. Danial, J.T.; Wood, J.J. Cognitive Behavioral Therapy for Children with Autism: Review and Considerations for Future Research. J. Dev. Behav. Pediatr. 2013, 34, 702–715. [Google Scholar] [CrossRef]
  25. Roane, H.S.; Fisher, W.W.; Carr, J.E. Applied Behavior Analysis as Treatment for Autism Spectrum Disorder. J. Pediatr. 2016, 175, 27–32. [Google Scholar] [CrossRef] [PubMed]
  26. Lei, J.; Ventola, P. Pivotal response treatment for autism spectrum disorder: Current perspectives. Neuropsychiatr. Dis. Treat. 2017, 13, 1613–1626. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Bailey, A.; Le Couteur, A.; Gottesman, I.; Bolton, P.; Simonoff, E.; Yuzda, E.; Rutter, M. Autism as a strongly genetic disorder: Evidence from a British twin study. Psychol. Med. 1995, 25, 63–77. [Google Scholar] [CrossRef] [PubMed]
  28. Lauritsen, M.B.; Ewald, H. The Genetics of Autism. Acta Psychiatr. Scand. 2001, 103, 411–427. [Google Scholar] [CrossRef] [PubMed]
  29. Sandin, S.; Lichtenstein, P.; Kuja-Halkola, R.; Larsson, H.; Hultman, C.M.; Reichenberg, A. The Familial Risk of Autism. JAMA 2014, 311, 1770–1777. [Google Scholar] [CrossRef]
  30. Samsam, M.; Ahangari, R.; Naser, S.A. Pathophysiology of autism spectrum disorders: Revisiting gastrointestinal involvement and immune imbalance. World J. Gastroenterol. 2014, 20, 9942–9951. [Google Scholar] [CrossRef]
  31. Masini, E.; Loi, E.; Vega-Benedetti, A.F.; Carta, M.; Doneddu, G.; Fadda, R.; Zavattari, P. An Overview of the Main Genetic, Epigenetic and Environmental Factors Involved in Autism Spectrum Disorder Focusing on Synaptic Activity. Int. J. Mol. Sci. 2020, 21, 8290. [Google Scholar] [CrossRef]
  32. Eissa, N.; Al-Houqani, M.; Sadeq, A.; Ojha, S.K.; Sasse, A.; Sadek, B. Current Enlightenment About Etiology and Pharmacological Treatment of Autism Spectrum Disorder. Front. Neurosci. 2018, 12, 304. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  33. Yoon, S.H.; Choi, J.; Lee, W.J.; Do, J.T. Genetic and Epigenetic Etiology Underlying Autism Spectrum Disorder. J. Clin. Med. 2020, 9, 966. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  34. Sebat, J.; Lakshmi, B.; Malhotra, D.; Troge, J.; Lese-Martin, C.; Walsh, T.; Yamrom, B.; Yoon, S.; Krasnitz, A.; Kendall, J.; et al. Strong Association of De Novo Copy Number Mutations with Autism. Science 2007, 316, 445–449. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  35. Mikhail, F.M.; Lose, E.J.; Robin, N.H.; Descartes, M.D.; Rutledge, K.D.; Rutledge, S.L.; Korf, B.R.; Carroll, A.J. Clinically Relevant Single Gene or Intragenic Deletions Encompassing Critical Neurodevelopmental Genes in Patients with Developmental Delay, Mental Retardation, and/or Autism Spectrum Disorders. Am. J. Med. Genet. A 2011, 155A, 2386–2396. [Google Scholar] [CrossRef] [PubMed]
  36. Iossifov, I.; Ronemus, M.; Levy, D.; Wang, Z.; Hakker, I.; Rosenbaum, J.; Yamrom, B.; Lee, Y.-H.; Narzisi, G.; Leotta, A.; et al. De Novo Gene Disruptions in Children on the Autistic Spectrum. Neuron 2012, 74, 285–299. [Google Scholar] [CrossRef] [Green Version]
  37. Iossifov, I.; O’Roak, B.J.; Sanders, S.J.; Ronemus, M.; Krumm, N.; Levy, D.; Stessman, H.A.; Witherspoon, K.T.; Vives, L.; Patterson, K.E.; et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature 2014, 515, 216–221. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  38. Bölte, S.; Girdler, S.; Marschik, P.B. The contribution of environmental exposure to the etiology of autism spectrum disorder. Cell. Mol. Life Sci. 2019, 76, 1275–1297. [Google Scholar] [CrossRef] [Green Version]
  39. Karimi, P.; Kamali, E.; Mousavi, S.M.; Karahmadi, M. Environmental factors influencing the risk of autism. J. Res. Med. Sci. 2017, 22, 27. [Google Scholar] [CrossRef] [PubMed]
  40. Chugani, D.C. Role of altered brain serotonin mechanisms in autism. Mol. Psychiatry 2002, 7, S16–S17. [Google Scholar] [CrossRef] [Green Version]
  41. Cook, E.H.; Leventhal, B.L. The serotonin system in autism. Curr. Opin. Pediatr. 1996, 8, 348–354. [Google Scholar] [CrossRef]
  42. Muller, C.L.; Anacker, A.M.J.; Veenstra-VanderWeele, J. The serotonin system in autism spectrum disorder: From biomarker to animal models. Neuroscience 2016, 321, 24–41. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Lacivita, E.; Niso, M.; Mastromarino, M.; Silva, A.G.; Resch, C.; Zeug, A.; Loza, M.I.; Castro, M.; Ponimaskin, E.; Leopoldo, M. Knowledge-Based Design of Long-Chain Arylpiperazine Derivatives Targeting Multiple Serotonin Receptors as Potential Candidates for Treatment of Autism Spectrum Disorder. ACS Chem. Neurosci. 2021, 12, 1313–1327. [Google Scholar] [CrossRef]
  44. Blankenship, K.; Erickson, C.A.; Stigler, K.A.; Posey, D.J.; McDougle, C.J. Aripiprazole for irritability associated with autistic disorder in children and adolescents aged 6–17 years. Pediatr. Health 2010, 4, 375–381. [Google Scholar] [CrossRef]
  45. Cookson, J.; Pimm, J. Partial Agonists of Dopamine Receptors: Mechanisms and Clinical Effects of Aripiprazole, Brexpiprazole and Cariprazine. BJPsych Adv. 2021, 1–6. [Google Scholar] [CrossRef]
  46. Owen, R.; Sikich, L.; Marcus, R.N.; Corey-Lisle, P.; Manos, G.; McQuade, R.D.; Carson, W.H.; Findling, R.L. Aripiprazole in the Treatment of Irritability in Children and Adolescents with Autistic Disorder. Pediatrics 2009, 124, 1533–1540. [Google Scholar] [CrossRef] [Green Version]
  47. Risperidone Treatment of Autistic Disorder: Longer-Term Benefits and Blinded Discontinuation after 6 Months. Am. J. Psychiatry 2005, 162, 1361–1369. [CrossRef] [PubMed] [Green Version]
  48. Kent, J.M.; Kushner, S.; Ning, X.; Karcher, K.; Ness, S.; Aman, M.; Singh, J.; Hough, D. Risperidone Dosing in Children and Adolescents with Autistic Disorder: A Double-Blind, Placebo-Controlled Study. J. Autism Dev. Disord. 2013, 43, 1773–1783. [Google Scholar] [CrossRef]
  49. Malone, R.P.; Maislin, G.; Choudhury, M.S.; Gifford, C.; Delaney, M.A. Risperidone Treatment in Children and Adolescents with Autism: Short- and Long-Term Safety and Effectiveness. J. Am. Acad. Child Adolesc. Psychiatry 2002, 41, 140–147. [Google Scholar] [CrossRef]
  50. Canitano, R. Self injurious behavior in autism: Clinical aspects and treatment with risperidone. J. Neural Transm. 2006, 113, 425–431. [Google Scholar] [CrossRef]
  51. Loebel, A.; Brams, M.; Goldman, R.S.; Silva, R.; Hernandez, D.; Deng, L.; Mankoski, R.; Findling, R.L. Lurasidone for the Treatment of Irritability Associated with Autistic Disorder. J. Autism Dev. Disord. 2016, 46, 1153–1163. [Google Scholar] [CrossRef] [Green Version]
  52. Witt, N.A.; Lee, B.; Ghent, K.; Zhang, W.Q.; Pehrson, A.L.; Sánchez, C.; Gould, G.G. Vortioxetine Reduces Marble Burying but Only Transiently Enhances Social Interaction Preference in Adult Male BTBR T+Itpr3tf/J Mice. ACS Chem. Neurosci. 2019, 10, 4319–4327. [Google Scholar] [CrossRef]
  53. Gordon, C.T.; State, R.C.; Nelson, J.E.; Hamburger, S.D.; Rapoport, J.L. A Double-blind Comparison of Clomipramine, Desipramine, and Placebo in the Treatment of Autistic Disorder. Arch. Gen. Psychiatry 1993, 50, 441–447. [Google Scholar] [CrossRef]
  54. Hollander, E.; Phillips, A.; Chaplin, W.; Zagursky, K.; Novotny, S.; Wasserman, S.; Iyengar, R. A Placebo Controlled Crossover Trial of Liquid Fluoxetine on Repetitive Behaviors in Childhood and Adolescent Autism. Neuropsychopharmacology 2005, 30, 582–589. [Google Scholar] [CrossRef] [Green Version]
  55. McDougle, C.J.; Naylor, S.T.; Cohen, D.J.; Volkmar, F.R.; Heninger, G.R.; Price, L.H. A Double-blind, Placebo-Controlled Study of Fluvoxamine in Adults with Autistic Disorder. Arch. Gen. Psychiatry 1996, 53, 1001–1008. [Google Scholar] [CrossRef]
  56. Delong, G.R.; Teague, L.A.; Kamran, M.M. Effects of fluoxetine treatment in young children with idiopathic autism. Dev. Med. Child Neurol. 2008, 40, 551–562. [Google Scholar] [CrossRef] [Green Version]
  57. McDougle, C.J.; Brodkin, E.S.; Naylor, S.T.; Carlson, D.C.; Cohen, D.J.; Price, L.H. Sertraline in Adults with Pervasive Developmental Disorders: A Prospective Open-Label Investigation. J. Clin. Psychopharmacol. 1998, 18, 62–66. [Google Scholar] [CrossRef]
  58. Steingard, R.J.; Zimnitzky, B.; DeMaso, D.R.; Bauman, M.L.; Bucci, J.P. Sertraline Treatment of Transition-Associated Anxiety and Agitation in Children with Autistic Disorder. J. Child Adolesc. Psychopharmacol. 1997, 7, 9–15. [Google Scholar] [CrossRef]
  59. Sugie, Y.; Sugie, H.; Fukuda, T.; Ito, M.; Sasada, Y.; Nakabayashi, M.; Fukashiro, K.; Ohzeki, T. Clinical Efficacy of Fluvoxamine and Functional Polymorphism in a Serotonin Transporter Gene on Childhood Autism. J. Autism Dev. Disord. 2005, 35, 377–385. [Google Scholar] [CrossRef]
  60. Canal, C.E.; Felsing, D.E.; Liu, Y.; Zhu, W.; Wood, J.T.; Perry, C.K.; Vemula, R.; Booth, R.G. An Orally Active Phenylaminotetralin-Chemotype Serotonin 5-Ht7 and 5-Ht1a Receptor Partial Agonist That Corrects Motor Stereotypy in Mouse Models. ACS Chem. Neurosci. 2015, 6, 1259–1270. [Google Scholar] [CrossRef]
  61. Armstrong, J.L.; Casey, A.B.; Saraf, T.S.; Mukherjee, M.; Booth, R.G.; Canal, C.E. (S)-5-(2′-Fluorophenyl)-N,N-Dimethyl-1,2,3,4-Tetrahydronaphthalen-2-Amine, a Serotonin Receptor Modulator, Possesses Anticonvulsant, Prosocial, and Anxiolytic-Like Properties in an Fmr1 Knockout Mouse Model of Fragile X Syndrome and Autism Spectrum Disorder. ACS Pharmacol. Transl. Sci. 2020, 3, 509–523. [Google Scholar]
  62. Wu, H.-F.; Chen, Y.-J.; Chu, M.-C.; Hsu, Y.-T.; Lu, T.-Y.; Chen, I.-T.; Chen, P.S.; Lin, H.-C. Deep Brain Stimulation Modified Autism-Like Deficits via the Serotonin System in a Valproic Acid-Induced Rat Model. Int. J. Mol. Sci. 2018, 19, 2840. [Google Scholar] [CrossRef] [Green Version]
  63. Kwag, R.; Lee, J.; Kim, D.; Lee, H.; Yeom, M.; Woo, J.; Cho, Y.; Kim, H.J.; Kim, J.; Keum, G.; et al. Discovery of G Protein-Biased Antagonists against 5-HT7R. J. Med. Chem. 2021, 64, 13766–13779. [Google Scholar] [CrossRef]
  64. Nisar, S.; Bhat, A.A.; Masoodi, T.; Hashem, S.; Akhtar, S.; Ali, T.A.; Amjad, S.; Chawla, S.; Bagga, P.; Frenneaux, M.P.; et al. Genetics of glutamate and its receptors in autism spectrum disorder. Mol. Psychiatry 2022, 27, 2380–2392. [Google Scholar] [CrossRef]
  65. Choudhury, P.R.; Lahiri, S.; Rajamma, U. Glutamate mediated signaling in the pathophysiology of autism spectrum disorders. Pharmacol. Biochem. Behav. 2012, 100, 841–849. [Google Scholar] [CrossRef]
  66. Aldred, S.; Moore, K.M.; Fitzgerald, M.; Waring, R.H. Plasma amino acid levels in children with autism and their families. J. Autism Dev. Disord. 2003, 33, 93–97. [Google Scholar] [CrossRef]
  67. Shinohe, A.; Hashimoto, K.; Nakamura, K.; Tsujii, M.; Iwata, Y.; Tsuchiya, K.J.; Sekine, Y.; Suda, S.; Suzuki, K.; Sugihara, G.-I.; et al. Increased Serum Levels of Glutamate in Adult Patients with Autism. Prog. Neuropsychopharmacol. Biol. Psychiatry 2006, 30, 1472–1477. [Google Scholar] [CrossRef] [Green Version]
  68. Rojas, D.C. The role of glutamate and its receptors in autism and the use of glutamate receptor antagonists in treatment. J. Neural Transm. 2014, 121, 891–905. [Google Scholar] [CrossRef] [Green Version]
  69. Lenart, J.; Augustyniak, J.; Lazarewicz, J.W.; Zieminska, E. Altered expression of glutamatergic and GABAergic genes in the valproic acid-induced rat model of autism: A screening test. Toxicology 2020, 440, 152500. [Google Scholar] [CrossRef]
  70. Carlson, G.C. Glutamate receptor dysfunction and drug targets across models of autism spectrum disorders. Pharmacol. Biochem. Behav. 2012, 100, 850–854. [Google Scholar] [CrossRef] [Green Version]
  71. Xie, X.; Hou, F.; Li, L.; Chen, Y.; Liu, L.; Luo, X.; Gu, H.; Li, X.; Zhang, J.; Gong, J.; et al. Polymorphisms of Ionotropic Glutamate Receptor-Related Genes and the Risk of Autism Spectrum Disorder in a Chinese Population. Psychiatry Investig. 2019, 16, 379–385. [Google Scholar] [CrossRef]
  72. Jamain, S.; Betancur, C.; Quach, H.; Philippe, A.; Fellous, M.; Giros, B.; Gillberg, C.; Leboyer, M.; Bourgeron, T.; The Paris Autism Research International Sibpair (PARIS) Study. Linkage and association of the glutamate receptor 6 gene with autism. Mol. Psychiatry 2002, 7, 302–310. [Google Scholar] [CrossRef] [Green Version]
  73. Kim, J.-W.; Park, K.; Kang, R.J.; Gonzales, E.L.T.; Kim, D.G.; Oh, H.A.; Seung, H.; Ko, M.J.; Kwon, K.J.; Kim, K.C.; et al. Pharmacological modulation of AMPA receptor rescues social impairments in animal models of autism. Neuropsychopharmacology 2019, 44, 314–323. [Google Scholar] [CrossRef] [Green Version]
  74. Silverman, J.L.; Oliver, C.F.; Karras, M.N.; Gastrell, P.T.; Crawley, J.N. AMPAKINE enhancement of social interaction in the BTBR mouse model of autism. Neuropharmacology 2013, 64, 268–282. [Google Scholar] [CrossRef] [Green Version]
  75. Sacai, H.; Sakoori, K.; Konno, K.; Nagahama, K.; Suzuki, H.; Watanabe, T.; Watanabe, M.; Uesaka, N.; Kano, M. Autism spectrum disorder-like behavior caused by reduced excitatory synaptic transmission in pyramidal neurons of mouse prefrontal cortex. Nat. Commun. 2020, 11, 5140. [Google Scholar] [CrossRef]
  76. Chez, M.G.; Burton, Q.; Dowling, T.; Chang, M.; Khanna, P.; Kramer, C. Memantine as Adjunctive Therapy in Children Diagnosed with Autistic Spectrum Disorders: An Observation of Initial Clinical Response and Maintenance Tolerability. J. Child Neurol. 2007, 22, 574–579. [Google Scholar] [CrossRef]
  77. Karahmadi, M.; Tarrahi, M.J.; Ardestani, S.S.V.; Omranifard, V.; Farzaneh, B. Efficacy of Memantine as Adjunct Therapy for Autism Spectrum Disorder in Children Aged < 14 Years. Adv. Biomed. Res. 2018, 7, 131. [Google Scholar] [CrossRef]
  78. Joshi, G.; Wozniak, J.; Faraone, S.V.; Fried, R.; Chan, J.; Furtak, S.; Grimsley, E.; Conroy, K.; Kilcullen, J.R.; Woodworth, K.Y.; et al. A Prospective Open-Label Trial of Memantine Hydrochloride for the Treatment of Social Deficits in Intellectually Capable Adults with Autism Spectrum Disorder. J. Clin. Psychopharmacol. 2016, 36, 262–271. [Google Scholar] [CrossRef]
  79. Deutsch, S.I.; Pepe, G.J.; Burket, J.A.; Winebarger, E.E.; Herndon, A.L.; Benson, A.D. D-cycloserine improves sociability and spontaneous stereotypic behaviors in 4-week old mice. Brain Res. 2012, 1439, 96–107. [Google Scholar] [CrossRef]
  80. Modi, M.E.; Young, L.J. D-Cycloserine Facilitates Socially Reinforced Learning in an Animal Model Relevant to Autism Spectrum Disorders. Biol. Psychiatry 2011, 70, 298–304. [Google Scholar] [CrossRef] [Green Version]
  81. Posey, D.J.; Kem, D.L.; Swiezy, N.B.; Sweeten, T.L.; Wiegand, R.E.; McDougle, C.J. A Pilot Study of d-Cycloserine in Subjects with Autistic Disorder. Am. J. Psychiatry 2004, 161, 2115–2117. [Google Scholar] [CrossRef]
  82. Urbano, M.; Okwara, L.; Manser, P.; Hartmann, K.; Herndon, A.; Deutsch, S.I. A Trial of D-Cycloserine to Treat Stereotypies in Older Adolescents and Young Adults with Autism Spectrum Disorder. Clin. Neuropharmacol. 2014, 37, 69–72. [Google Scholar] [CrossRef] [Green Version]
  83. Wink, L.K.; Minshawi, N.F.; Shaffer, R.C.; Plawecki, M.H.; Posey, D.J.; Horn, P.S.; Adams, R.; Pedapati, E.V.; Schaefer, T.L.; McDougle, C.J.; et al. D-Cycloserine enhances durability of social skills training in autism spectrum disorder. Mol. Autism 2017, 8, 2. [Google Scholar] [CrossRef] [Green Version]
  84. Zoicas, I.; Kornhuber, J. The Role of Metabotropic Glutamate Receptors in Social Behavior in Rodents. Int. J. Mol. Sci. 2019, 20, 1412. [Google Scholar] [CrossRef] [Green Version]
  85. Kim, C.H.; Lee, J.; Lee, J.-Y.; Roche, K.W. Metabotropic glutamate receptors: Phosphorylation and receptor signaling. J. Neurosci. Res. 2007, 86, 1–10. [Google Scholar] [CrossRef]
  86. Aguilar-Valles, A.; Matta-Camacho, E.; Khoutorsky, A.; Gkogkas, C.; Nader, K.; Lacaille, J.-C.; Sonenberg, N. Inhibition of Group I Metabotropic Glutamate Receptors Reverses Autistic-Like Phenotypes Caused by Deficiency of the Translation Repressor eIF4E Binding Protein 2. J. Neurosci. 2015, 35, 11125–11132. [Google Scholar] [CrossRef] [Green Version]
  87. Silverman, J.L.; Tolu, S.S.; Barkan, C.L.; Crawley, J.N. Repetitive Self-Grooming Behavior in the BTBR Mouse Model of Autism is Blocked by the mGluR5 Antagonist MPEP. Neuropsychopharmacology 2010, 35, 976–989. [Google Scholar] [CrossRef]
  88. Mehta, M.V.; Gandal, M.J.; Siegel, S.J. Mglur5-Antagonist Mediated Reversal of Elevated Stereotyped, Repetitive Behaviors in the Vpa Model of Autism. PLoS ONE 2011, 6, e26077. [Google Scholar] [CrossRef] [Green Version]
  89. Erickson, C.A.; Early, M.; Stigler, K.A.; Wink, L.K.; Mullett, J.E.; McDougle, C.J. An Open-Label Naturalistic Pilot Study of Acamprosate in Youth with Autistic Disorder. J. Child. Adolesc. Psychopharmacol. 2011, 21, 565–569. [Google Scholar] [CrossRef] [Green Version]
  90. Rutsch, A.; Kantsjö, J.B.; Ronchi, F. The Gut-Brain Axis: How Microbiota and Host Inflammasome Influence Brain Physiology and Pathology. Front. Immunol. 2020, 11, 604179. [Google Scholar] [CrossRef]
  91. Cryan, J.F.; O’Riordan, K.J.; Cowan, C.S.M.; Sandhu, K.V.; Bastiaanssen, T.F.S.; Boehme, M.; Codagnone, M.G.; Cussotto, S.; Fulling, C.; Golubeva, A.V.; et al. The Microbiota-Gut-Brain Axis. Physiol. Rev. 2019, 99, 1877–2013. [Google Scholar] [CrossRef]
  92. Ho, L.K.H.; Tong, V.J.W.; Syn, N.; Nagarajan, N.; Tham, E.H.; Tay, S.K.; Shorey, S.; Tambyah, P.A.; Law, E.C.N. Gut microbiota changes in children with autism spectrum disorder: A systematic review. Gut Pathog. 2020, 12, 6. [Google Scholar] [CrossRef] [Green Version]
  93. Buffington, S.A.; Di Prisco, G.V.; Auchtung, T.A.; Ajami, N.J.; Petrosino, J.F.; Costa-Mattioli, M. Microbial Reconstitution Reverses Maternal Diet-Induced Social and Synaptic Deficits in Offspring. Cell 2016, 165, 1762–1775. [Google Scholar] [CrossRef] [Green Version]
  94. Luk, B.; Veeraragavan, S.; Engevik, M.; Balderas, M.; Major, A.; Runge, J.; Luna, R.A.; Versalovic, J. Postnatal colonization with human “infant-type” Bifidobacterium species alters behavior of adult gnotobiotic mice. PLoS ONE 2018, 13, e0196510. [Google Scholar] [CrossRef]
  95. Zheng, Y.; Bek, M.K.; Prince, N.Z.; Marzal, L.N.P.; Garssen, J.; Pardo, P.P.; Kraneveld, A.D. The Role of Bacterial-Derived Aromatic Amino Acids Metabolites Relevant in Autism Spectrum Disorders: A Comprehensive Review. Front. Neurosci. 2021, 15, 738220. [Google Scholar] [CrossRef]
  96. Needham, B.D.; Adame, M.D.; Serena, G.; Rose, D.R.; Preston, G.M.; Conrad, M.C.; Campbell, A.S.; Donabedian, D.H.; Fasano, A.; Ashwood, P.; et al. Plasma and Fecal Metabolite Profiles in Autism Spectrum Disorder. Biol. Psychiatry 2020, 89, 451–462. [Google Scholar] [CrossRef]
  97. Mead, J.; Ashwood, P. Evidence supporting an altered immune response in ASD. Immunol. Lett. 2015, 163, 49–55. [Google Scholar] [CrossRef]
  98. Chez, M.G.; Guido-Estrada, N. Immune therapy in autism: Historical experience and future directions with immunomodulatory therapy. Neurotherapeutics 2010, 7, 293–301. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  99. Masi, A.; Quintana, D.S.; Glozier, N.; Lloyd, A.R.; Hickie, I.B.; Guastella, A.J. Cytokine aberrations in autism spectrum disorder: A systematic review and meta-analysis. Mol. Psychiatry 2015, 20, 440–446. [Google Scholar] [CrossRef] [PubMed]
  100. Marchezan, J.; Dos Santos, E.G.A.W.; Deckmann, I.; Riesgo, R.S. Immunological Dysfunction in Autism Spectrum Disorder: A Potential Target for Therapy. Neuroimmunomodulation 2018, 25, 300–319. [Google Scholar] [CrossRef] [PubMed]
  101. Masi, A.; Glozier, N.; Dale, R.; Guastella, A.J. The Immune System, Cytokines, and Biomarkers in Autism Spectrum Disorder. Neurosci. Bull. 2017, 33, 194–204. [Google Scholar] [CrossRef] [Green Version]
  102. Nordahl, C.W.; Braunschweig, D.; Iosif, A.-M.; Lee, A.; Rogers, S.; Ashwood, P.; Amaral, D.G.; Van de Water, J. Maternal autoantibodies are associated with abnormal brain enlargement in a subgroup of children with autism spectrum disorder. Brain Behav. Immun. 2013, 30, 61–65. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  103. Parker-Athill, E.C.; Tan, J. Maternal Immune Activation and Autism Spectrum Disorder: Interleukin-6 Signaling as a Key Mechanistic Pathway. Neurosignals 2010, 18, 113–128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  104. Atladóttir, H.Ó.; Thorsen, P.; Østergaard, L.; Schendel, D.E.; Lemcke, S.; Abdallah, M.; Partner, E.T. Maternal Infection Requiring Hospitalization During Pregnancy and Autism Spectrum Disorders. J. Autism Dev. Disord. 2010, 40, 1423–1430. [Google Scholar] [CrossRef]
  105. Brown, A.S.; Sourander, A.; Hinkka-Yli-Salomäki, S.; McKeague, I.W.; Sundvall, J.; Surcel, H.-M. Elevated maternal C-reactive protein and autism in a national birth cohort. Mol. Psychiatry 2014, 19, 259–264. [Google Scholar] [CrossRef] [PubMed]
  106. Lammert, C.R.; Lukens, J.R. Modeling Autism-Related Disorders in Mice with Maternal Immune Activation (MIA). Methods Mol. Biol. 2019, 1960, 227–236. [Google Scholar] [CrossRef]
  107. Yim, Y.S.; Park, A.; Berrios, J.; Lafourcade, M.; Pascual, L.M.; Soares, N.; Kim, J.Y.; Kim, S.; Kim, H.; Waisman, A.; et al. Reversing behavioural abnormalities in mice exposed to maternal inflammation. Nature 2017, 549, 482–487. [Google Scholar] [CrossRef] [Green Version]
  108. Kim, S.; Kim, H.; Yim, Y.S.; Ha, S.; Atarashi, K.; Tan, T.G.; Longman, R.S.; Honda, K.; Littman, D.R.; Choi, G.B.; et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring. Nature 2017, 549, 528–532. [Google Scholar] [CrossRef] [Green Version]
  109. Estes, M.L.; McAllister, A.K. Maternal Immune Activation: Implications for Neuropsychiatric Disorders. Science 2016, 353, 772–777. [Google Scholar] [CrossRef] [Green Version]
  110. Lammert, C.R.; Frost, E.L.; Bolte, A.C.; Paysour, M.J.; Shaw, M.E.; Bellinger, C.E.; Weigel, T.K.; Zunder, E.R.; Lukens, J.R. Cutting Edge: Critical Roles for Microbiota-Mediated Regulation of the Immune System in a Prenatal Immune Activation Model of Autism. J. Immunol. 2018, 201, 845–850. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  111. Egottfried, C.; Bambini-Junior, V.; Francis, F.; Riesgo, R.; Savino, W. The Impact of Neuroimmune Alterations in Autism Spectrum Disorder. Front. Psychiatry 2015, 6, 121. [Google Scholar] [CrossRef] [Green Version]
  112. Dantzer, R. Cytokine-Induced Sickness Behavior: Where Do We Stand? Brain Behav. Immun. 2001, 15, 7–24. [Google Scholar] [CrossRef] [Green Version]
  113. Krakowiak, P.; Goines, P.E.; Tancredi, D.J.; Ashwood, P.; Hansen, R.L.; Hertz-Picciotto, I.; Van de Water, J. Neonatal Cytokine Profiles Associated with Autism Spectrum Disorder. Biol. Psychiatry 2015, 81, 442–451. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  114. Suzuki, K.; Matsuzaki, H.; Iwata, K.; Kameno, Y.; Shimmura, C.; Kawai, S.; Yoshihara, Y.; Wakuda, T.; Takebayashi, K.; Takagai, S.; et al. Plasma Cytokine Profiles in Subjects with High-Functioning Autism Spectrum Disorders. PLoS ONE 2011, 6, e20470. [Google Scholar] [CrossRef]
  115. Ashwood, P.; Krakowiak, P.; Hertz-Picciotto, I.; Hansen, R.; Pessah, I.; Van de Water, J. Elevated plasma cytokines in autism spectrum disorders provide evidence of immune dysfunction and are associated with impaired behavioral outcome. Brain Behav. Immun. 2011, 25, 40–45. [Google Scholar] [CrossRef] [Green Version]
  116. Jácome, M.C.I.; Chacòn, L.M.M.; Cuesta, H.V.; Rizo, C.M.; Santiesteban, M.W.; Hernandez, L.R.; García, E.N.; Fraguela, M.E.G.; Verdecia, C.I.F.; Hurtado, Y.V.; et al. Peripheral Inflammatory Markers Contributing to Comorbidities in Autism. Behav. Sci. 2016, 6, 29. [Google Scholar] [CrossRef] [Green Version]
  117. Xie, J.; Huang, L.; Li, X.; Li, H.; Zhou, Y.; Zhu, H.; Pan, T.; Kendrick, K.M.; Xu, W. Immunological cytokine profiling identifies TNF-α as a key molecule dysregulated in autistic children. Oncotarget 2017, 8, 82390–82398. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  118. Al-Ayadhi, L.Y.; Mostafa, G.A. Elevated serum levels of interleukin-17A in children with autism. J. Neuroinflammation 2012, 9, 158. [Google Scholar] [CrossRef] [Green Version]
  119. Hu, C.-C.; Xu, X.; Xiong, G.-L.; Xu, Q.; Zhou, B.-R.; Li, C.-Y.; Qin, Q.; Liu, C.-X.; Li, H.-P.; Sun, Y.-J.; et al. Alterations in plasma cytokine levels in chinese children with autism spectrum disorder. Autism Res. 2018, 11, 989–999. [Google Scholar] [CrossRef]
  120. Emanuele, E.; Orsi, P.; Boso, M.; Broglia, D.; Brondino, N.; Barale, F.; di Nemi, S.U.; Politi, P. Low-grade endotoxemia in patients with severe autism. Neurosci. Lett. 2010, 471, 162–165. [Google Scholar] [CrossRef] [PubMed]
  121. Parker-Athill, E.; Luo, D.; Bailey, A.; Giunta, B.; Tian, J.; Shytle, R.D.; Murphy, T.; Legradi, G.; Tan, J. Flavonoids, a Prenatal Prophylaxis Via Targeting Jak2/Stat3 Signaling to Oppose Il-6/Mia Associated Autism. J. Neuroimmunol. 2009, 217, 20–27. [Google Scholar] [CrossRef] [Green Version]
  122. Theoharides, T.C.; Asadi, S.; Panagiotidou, S. A Case Series of a Luteolin Formulation (Neuroprotek®) in Children with Autism Spectrum Disorders. Int. J. Immunopathol. Pharmacol. 2012, 25, 317–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Taliou, A.; Zintzaras, E.; Lykouras, L.; Francis, K. An Open-Label Pilot Study of a Formulation Containing the Anti-Inflammatory Flavonoid Luteolin and Its Effects on Behavior in Children with Autism Spectrum Disorders. Clin. Ther. 2013, 35, 592–602. [Google Scholar] [CrossRef] [PubMed]
  124. Kann, O.; Hoffmann, A.; Schumann, R.R.; Weber, J.R.; Kettenmann, H.; Hanisch, U.-K. The tyrosine kinase inhibitor AG126 restores receptor signaling and blocks release functions in activated microglia (brain macrophages) by preventing a chronic rise in the intracellular calcium level. J. Neurochem. 2004, 90, 513–525. [Google Scholar] [CrossRef]
  125. Menzfeld, C.; John, M.; Van Rossum, D.; Regen, T.; Scheffel, J.; Janova, H.; Götz, A.; Ribes, S.; Nau, R.; Borisch, A.; et al. Tyrphostin AG126 exerts neuroprotection in CNS inflammation by a dual mechanism. Glia 2015, 63, 1083–1099. [Google Scholar] [CrossRef] [Green Version]
  126. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Bakheet, S.A.; Alsanea, S.; Al-Hosaini, K.A.; Mohammad, H.M.; Alzahrani, M.Z.; Attia, S.M. Inhibition of Tyrosine Kinase Signaling by Tyrphostin Ag126 Downregulates the Il-21/Il-21r and Jak/Stat Pathway in the Btbr Mouse Model of Autism. NeuroToxicology 2020, 77, 1–11. [Google Scholar] [CrossRef]
  127. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Bakheet, S.A.; Alshammari, M.A.; Attia, S.A. Protection by Tyrosine Kinase Inhibitor, Tyrphostin Ag126, through the Suppression of Il-17a, Rorγt, and T-Bet Signaling, in the Btbr Mouse Model of Autism. Brain Res. Bull. 2018, 142, 328–337. [Google Scholar] [CrossRef]
  128. Ahmad, S.F.; Ansari, M.A.; Nadeem, A.; Bakheet, S.A.; Alzahrani, M.Z.; Alshammari, M.A.; Alanazi, W.A.; Alasmari, A.F.; Attia, S.M. Resveratrol attenuates pro-inflammatory cytokines and activation of JAK1-STAT3 in BTBR T + Itpr3 tf /J autistic mice. Eur. J. Pharmacol. 2018, 829, 70–78. [Google Scholar] [CrossRef]
  129. Bakheet, S.A.; Alzahrani, M.Z.; Nadeem, A.; Ansari, M.A.; Zoheir, K.M.A.; Attia, S.M.; Al-Ayadhi, L.Y.; Ahmad, S.F. Resveratrol treatment attenuates chemokine receptor expression in the BTBR T + tf/J mouse model of autism. Mol. Cell. Neurosci. 2016, 77, 1–10. [Google Scholar] [CrossRef]
  130. Bambini-Junior, V.; Zanatta, G.; Nunes, G.D.F.; de Melo, G.M.; Michels, M.; Fontes-Dutra, M.; Freire, V.N.; Riesgo, R.; Gottfried, C. Resveratrol prevents social deficits in animal model of autism induced by valproic acid. Neurosci. Lett. 2014, 583, 176–181. [Google Scholar] [CrossRef]
  131. Bakheet, S.A.; Alzahrani, M.Z.; Ansari, M.A.; Nadeem, A.; Zoheir, K.M.A.; Attia, S.M.; Al-Ayadhi, L.Y.; Ahmad, S.F. Resveratrol Ameliorates Dysregulation of Th1, Th2, Th17, and T Regulatory Cell-Related Transcription Factor Signaling in a BTBR T + tf/J Mouse Model of Autism. Mol. Neurobiol. 2017, 54, 5201–5212. [Google Scholar] [CrossRef]
  132. Hidema, S.; Kikuchi, S.; Takata, R.; Yanai, T.; Shimomura, K.; Horie, K.; Nishimori, K. Single administration of resveratrol improves social behavior in adult mouse models of autism spectrum disorder. Biosci. Biotechnol. Biochem. 2020, 84, 2207–2214. [Google Scholar] [CrossRef]
  133. Malaguarnera, M.; Khan, H.; Cauli, O. Resveratrol in Autism Spectrum Disorders: Behavioral and Molecular Effects. Antioxidants 2020, 9, 188. [Google Scholar] [CrossRef] [Green Version]
  134. Hendouei, F.; Moghaddam, H.S.; Mohammadi, M.R.; Taslimi, N.; Rezaei, F.; Akhondzadeh, S. Resveratrol as adjunctive therapy in treatment of irritability in children with autism: A double-blind and placebo-controlled randomized trial. J. Clin. Pharm. Ther. 2020, 45, 324–334. [Google Scholar] [CrossRef]
  135. McDougle, C.J.; Landino, S.M.; Vahabzadeh, A.; O’Rourke, J.; Zurcher, N.R.; Finger, B.C.; Palumbo, M.L.; Helt, J.; Mullett, J.E.; Hooker, J.M.; et al. Toward an Immune-Mediated Subtype of Autism Spectrum Disorder. Brain Res. 2015, 1617, 72–92. [Google Scholar] [CrossRef]
  136. Asadabadi, M.; Mohammadi, M.-R.; Ghanizadeh, A.; Modabbernia, A.; Ashrafi, M.; Hassanzadeh, E.; Forghani, S.; Akhondzadeh, S. Celecoxib as Adjunctive Treatment to Risperidone in Children with Autistic Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial. Psychopharmacology 2013, 225, 51–59. [Google Scholar] [CrossRef]
  137. Akhondzadeh, S.; Fallah, J.; Mohammadi, M.-R.; Imani, R.; Mohammadi, M.; Salehi, B.; Ghanizadeh, A.; Raznahan, M.; Mohebbi-Rasa, S.; Rezazadeh, S.-A.; et al. Double-blind placebo-controlled trial of pentoxifylline added to risperidone: Effects on aberrant behavior in children with autism. Prog. Neuro-Psychopharmacol. Biol. Psychiatry 2010, 34, 32–36. [Google Scholar] [CrossRef]
  138. Dunn, P.M.; Blakeley, A.G.H. Suramin: A reversible P2-purinoceptor antagonist in the mouse vas deferens. Br. J. Pharmacol. 1988, 93, 243–245. [Google Scholar] [CrossRef] [Green Version]
  139. Herrera, A.; Morcuende, S.; Talaverón, R.; Benítez-Temiño, B.; Pastor, A.M.; Matarredona, E.R. Purinergic Receptor Blockade with Suramin Increases Survival of Postnatal Neural Progenitor Cells In Vitro. Int. J. Mol. Sci. 2021, 22, 713. [Google Scholar] [CrossRef]
  140. Hirsch, M.M.; Deckmann, I.; Santos-Terra, J.; Staevie, G.Z.; Fontes-Dutra, M.; Carello-Collar, G.; Körbes-Rockenbach, M.; Schwingel, G.B.; Bauer-Negrini, G.; Rabelo, B.; et al. Effects of single-dose antipurinergic therapy on behavioral and molecular alterations in the valproic acid-induced animal model of autism. Neuropharmacology 2020, 167, 107930. [Google Scholar] [CrossRef]
  141. Naviaux, J.C.; Schuchbauer, M.A.; Li, K.; Wang, L.; Risbrough, V.B.; Powell, S.B.; Naviaux, R.K. Reversal of autism-like behaviors and metabolism in adult mice with single-dose antipurinergic therapy. Transl. Psychiatry 2014, 4, e400. [Google Scholar] [CrossRef]
  142. Naviaux, R.K.; Zolkipli, Z.; Wang, L.; Nakayama, T.; Naviaux, J.C.; Le, T.P.; Schuchbauer, M.A.; Rogac, M.; Tang, Q.; Dugan, L.L.; et al. Antipurinergic Therapy Corrects the Autism-Like Features in the Poly(IC) Mouse Model. PLoS ONE 2013, 8, e57380. [Google Scholar] [CrossRef] [PubMed]
  143. Naviaux, R.K.; Curtis, B.; Li, K.; Naviaux, J.C.; Bright, A.T.; Reiner, G.E.; Westerfield, M.; Goh, S.; Alaynick, W.A.; Wang, L.; et al. Low-Dose Suramin in Autism Spectrum Disorder: A Small, Phase I/Ii, Randomized Clinical Trial. Ann. Clin. Transl. Neurol. 2017, 4, 491–505. [Google Scholar] [CrossRef] [PubMed]
Molecules 27 05088 g001 550
Figure 1. Factors involved in the development of autism spectrum disorder (ASD).
Figure 1. Factors involved in the development of autism spectrum disorder (ASD).
Molecules 27 05088 g001
Molecules 27 05088 g002 550
Figure 2. Microbiota gut–brain axis mechanisms focused on microbial metabolites and their influences on the brain. (Brain image from BioRender.com).
Figure 2. Microbiota gut–brain axis mechanisms focused on microbial metabolites and their influences on the brain. (Brain image from BioRender.com).
Molecules 27 05088 g002
Molecules 27 05088 g003 550
Figure 3. Formation of 4-ethylphenyl sulfate (4EPS) from tyrosine. Solid arrows show established reactions, and dotted arrows represent expected reactions.
Figure 3. Formation of 4-ethylphenyl sulfate (4EPS) from tyrosine. Solid arrows show established reactions, and dotted arrows represent expected reactions.
Molecules 27 05088 g003
Table
Table 1. 5-HT-related pharmacological agents and their potential effects on treating ASD symptoms. 5-HT: serotonin (5-hydroxytryptamine), 5-HTRs: 5-HT receptors. SSRI: selective serotonin reuptake inhibitor.
Table 1. 5-HT-related pharmacological agents and their potential effects on treating ASD symptoms. 5-HT: serotonin (5-hydroxytryptamine), 5-HTRs: 5-HT receptors. SSRI: selective serotonin reuptake inhibitor.
CompoundsStructuresTargetsStageEffects
Aripiprazole Molecules 27 05088 i001Partial 5-HT1AR/5-HT2CR, agonist, 5-HT1BR/5-HT1DR/5-HT2AR/5-HT2CR/5-HT3AR/5-HT6R/5-HT7R antagonistClinicalAlleviating irritability [16,44,46]
Risperidone Molecules 27 05088 i0025-HT1AR/5-HT1DR/5-HT2AR/5-HT2CR/5-HT7R antagonistClinicalEffective in irritability, aggression, temper-outburst and self-injurious behavior [47,48,49]
Lurasidone Molecules 27 05088 i0035-HT2AR/5-HT7R antagonist, 5-HT1AR partial agonistClinicalAlleviating irritability [51]
Clomipramine Molecules 27 05088 i004Potent SSRIClinicalAlleviating obsessive-compulsive disorder and abnormal social interaction [53]
Vortioxetine Molecules 27 05088 i0055-HT transporter, 5-HT1A/5-HT1B activatorPreclinicalReduced repetitive behavior [52]
Fluoxetine Molecules 27 05088 i006SSRIClinicalImprovement in repetitive behavior, social interactions, language and cognition [54,56]
Fluvoxamine Molecules 27 05088 i007SSRIClinicalImprovement in repetitive behavior, maladaptive behavior, aggression, social interaction and language usage [55,59]
Sertraline Molecules 27 05088 i008SSRIClinicalImprovement in repetitive behavior, aggression, anxiety, irritability and agitation [57,58]
(+)-5-FPT Molecules 27 05088 i0095-HT1AR/5-HT2CR agonist, 5-HT7R antagonistPreclinicalReduced repetitive behavior [60,61]
8-OH DPAT Molecules 27 05088 i0105-HT1AR/5-HT7R agonistPreclinicalImprovement in social interaction, anxiety and hyperactivity [62]
2c Molecules 27 05088 i0115-HT7R antagonistPreclinicalReduced repetitive behavior [63]
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Lim, S.; Lee, S. Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic. Molecules 2022, 27, 5088. https://doi.org/10.3390/molecules27165088

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Lim S, Lee S. Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic. Molecules. 2022; 27(16):5088. https://doi.org/10.3390/molecules27165088

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Lim, Songhyun, and Sanghee Lee. 2022. "Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic" Molecules 27, no. 16: 5088. https://doi.org/10.3390/molecules27165088

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Lim, S., & Lee, S. (2022). Chemical Modulators for Targeting Autism Spectrum Disorders: From Bench to Clinic. Molecules, 27(16), 5088. https://doi.org/10.3390/molecules27165088

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