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Pharmaceuticals
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Repurposing Drug Strategies for CNS Disorders
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Repurposing Drug Strategies for CNS Disorders

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (19 November 2021) | Viewed by 21778

Special Issue Editor

Dr. Roberto Frau

E-Mail Website
Guest Editor
Department of Biomedical Sciences, Section of Neuroscience and Clinical Pharmacology, University of Cagliari, 09124 Cagliari, CA, Italy
Interests: neurosteroids; neuroactive steroids; cannabinoids; neuropsychiatric disorders; schizophrenia; bipolar disorders; sleep deprivation; Parkinson’s disease
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Despite huge advances in translational research and technology, the development of brand-new drugs has not undergone the acceleration that we hoped it would. The transfer of a drug from bench to bedside still remains an extremely expensive and time-consuming process, with no guarantee of success. It has been estimated that the journey of new chemical entities, from their discovery to the marketplace, takes at least 10 years and requires a cost of over 1 billion dollars. Furthermore, it is estimated that less than 10% of newly developed drugs that enter into the clinical phase effectively reach the market and become available for patients.

In this scenario, it is crucial to find complementary strategies able to reduce the escalating costs and lengths of time length required for R&D, and, more importantly, improve success rates. An approach to overcome the bottleneck process that accompanies drug development is provided by drug repurposing. Drug repurposing (or repositioning) is the process of finding new therapeutic uses for existing drugs, outside their original indications. These repurposed drugs have been subjected to extensive investigations, in terms of efficacy, toxicity, and safety, and therefore are ready to enter into experimental clinical trials. CNS appears to fit very well for drug reprofiling, as recent advances in techniques used across the field of neuroscience have opened the door to new and unexpected biological targets that can be targeted by ‘old molecules’ already present in the clinical setting for other disorders.

This Special Issue welcomes submissions of original research articles and reviews focused on the use of repurposing drugs for the treatment of brain neurodevelopmental, neurodegenerative and neuropsychiatric disorders. The scope of this Special Issue is to collect findings from different fields of neuroscience, pharmacology and pharmaceuticals to highlight how drugs already approved for other indications with multiple mechanisms of action may offer interesting options compared to benchmark prescription drugs, often characterized by non-negligible side effects.

Dr. Roberto Frau
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Pharmaceuticals is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

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Published Papers (5 papers)

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Research

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14 pages, 3026 KiB  
Article
Combined Antagonism of 5-HT2 and NMDA Receptors Reduces the Aggression of Monoamine Oxidase a Knockout Mice
by Roberto Frau, Alessandra Pardu, Sean Godar, Valentina Bini and Marco Bortolato
Pharmaceuticals 2022, 15(2), 213; https://doi.org/10.3390/ph15020213 - 10 Feb 2022
Cited by 8 | Viewed by 2323
Abstract
The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient [...] Read more.
The enzyme monoamine oxidase A (MAOA) catalyzes the degradation of several neurotransmitters, including serotonin. A large body of evidence has shown that genetic MAOA deficiency predisposes humans and mice to aggression and antisocial behavior. We previously documented that the aggression of male MAOA-deficient mice is contributed by serotonin 5-HT2 and glutamate N-methyl-D-aspartate (NMDA) receptors in the prefrontal cortex (PFC). Indeed, blocking either receptor reduces the aggression of MAOA knockout (KO) mice; however, 5-HT2 receptor antagonists, such as ketanserin (KET), reduce locomotor activity, while NMDA receptor blockers are typically associated with psychotomimetic properties. To verify whether NMDA receptor blockers induce psychotomimetic effects in MAOA KO mice, here we tested the effects of these compounds on prepulse inhibition (PPI) of the acoustic startle reflex. We found that male MAOA KO mice are hypersensitive to the PPI-disrupting properties of NMDA receptor antagonists, including the non-competitive antagonist dizocilpine (DIZ; 0.1, 0.3 mg/kg, IP) and the NR2B subunit-specific blocker Ro-256981 (5, 10 mg/kg, IP). Since KET has been previously shown to counter the PPI deficits caused by NMDA receptor antagonists, we tested the behavioral effects of the combination of KET (2 mg/kg, IP) and these drugs. Our results show that the combination of KET and DIZ potently reduces aggression in MAOA KO mice without any PPI deficits and sedative effects. While the PPI-ameliorative properties of KET were also observed after infusion in the medial PFC (0.05 μg/side), KET did not counter the PPI-disruptive effects of Ro-256981 in MAOA KO mice. Taken together, these results point to the combination of non-subunit-selective NMDA and 5-HT2 receptor antagonists as a potential therapeutic approach for aggression and antisocial behavior with a better safety and tolerability profile than each monotherapy. Full article
(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)
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19 pages, 4555 KiB  
Article
Combinatorial Regimen of Carbamazepine and Imipramine Exhibits Synergism against Grandmal Epilepsy in Rats: Inhibition of Pro-Inflammatory Cytokines and PI3K/Akt/mTOR Signaling Pathway
by Faheem Hyder Pottoo, Mohammed Salahuddin, Firdos Alam Khan, Marwa Abdullah AL Dhamen, Walaa Jafar Alsaeed, Mohamed S. Gomaa, Chittibabu Vatte and Mohammad N. Alomary
Pharmaceuticals 2021, 14(11), 1204; https://doi.org/10.3390/ph14111204 - 22 Nov 2021
Cited by 9 | Viewed by 3140
Abstract
Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a [...] Read more.
Epilepsy is a neurodegenerative disorder that causes recurring seizures. Thirty-five percent of patients remain refractory, with a higher prevalence of depression. We investigated the anticonvulsant efficacy of carbamazepine (CBZ; 20 and 50 mg/kg), imipramine (IMI; 10 and 20 mg/kg) alone, and as a low dose combination. This preclinical investigation included dosing of rats for 14 days followed by elicitation of electroshock on the last day of treatment. Along with behavioral monitoring, the rat hippocampus was processed for quantification of mTOR, IL-1β, IL-6 and TNF-α levels. The histopathological analysis of rat hippocampus was performed to ascertain neuroprotection. In vitro studies and in silico studies were also conducted. We found that the low dose combinatorial therapy of CBZ (20 mg/kg) + IMI (10 mg/kg) exhibits synergism (p < 0.001) in abrogation of maximal electroshock (MES) induced convulsions/tonic hind limb extension (THLE), by reducing levels of pro-inflammatory cytokines, and weakening of the PI3K/Akt/mTOR signal. The combination also exhibits cooperative binding at the Akt. As far as neuroprotection is concerned, the said combination increased cell viability by 166.37% compared to Pentylenetetrazol (PTZ) treated HEK-293 cells. Thus, the combination of CBZ (20 mg/kg) + IMI (10 mg/kg) is a fruitful combination therapy to elevate seizure threshold and provide neuroprotection. Full article
(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)
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12 pages, 2173 KiB  
Communication
The Effects of N-Acetylcysteine on the Rat Mesocorticolimbic Pathway: Role of mGluR5 Receptors and Interaction with Ethanol
by Sandra Fernández-Rodríguez, Claudia Esposito-Zapero, Teodoro Zornoza, Ana Polache, Luis Granero and María José Cano-Cebrián
Pharmaceuticals 2021, 14(6), 593; https://doi.org/10.3390/ph14060593 - 20 Jun 2021
Cited by 3 | Viewed by 2931
Abstract
N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol [...] Read more.
N-acetylcysteine (NAC) is a prodrug that is marketed as a mucolytic agent and used for the treatment of acetaminophen overdose. Over the last few decades, evidence has been gathered that suggests the potential use of NAC as a new pharmacotherapy for alcohol use disorder (AUD), although its mechanism of action is already being debated. In this paper, we set out to assess both the potential involvement of the glutamate metabotropic receptors (mGluR) in the possible dual effect of NAC administered at two different doses and NAC’s effect on ethanol-induced activation. To this aim, 30 or 120 mg/kg of NAC was intraperitoneally administered to rats with the presence or absence of the negative allosteric modulator of mGluR5 (MTEP 0.1 mg/kg). Thereafter, the cFOS IR-cell expression was analyzed. Secondly, we explored the effect of 120 mg/kg of NAC on the neurochemical and behavioral activation induced by intra-VTA ethanol administration (150 nmol). Our results showed that the high NAC dose stimulated cFOS expression in the NAcc, and that this effect was suppressed in the presence of MTEP, thus suggesting the implication of mGluR5. Additionally, high doses could attenuate the ethanol-induced increase in cFOS-expression in the NAcc, probably due to a phenomenon based on the long-term depression of the MSNs. Additional experiments are required to corroborate our hypothesis. Full article
(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)
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13 pages, 3029 KiB  
Article
EEG and Sleep Effects of Tramadol Suggest Potential Antidepressant Effects with Different Mechanisms of Action
by Szabolcs Koncz, Noémi Papp, Noémi Menczelesz, Dóra Pothorszki and György Bagdy
Pharmaceuticals 2021, 14(5), 431; https://doi.org/10.3390/ph14050431 - 4 May 2021
Cited by 8 | Viewed by 8294
Abstract
Tramadol is a widely used, centrally acting, opioid analgesic compound, with additional inhibitory effects on the synaptic reuptake of serotonin and noradrenaline, as well as on the 5-HT2 and NMDA receptors. Preclinical and clinical evidence also suggests its therapeutic potential in the [...] Read more.
Tramadol is a widely used, centrally acting, opioid analgesic compound, with additional inhibitory effects on the synaptic reuptake of serotonin and noradrenaline, as well as on the 5-HT2 and NMDA receptors. Preclinical and clinical evidence also suggests its therapeutic potential in the treatment of depression and anxiety. The effects of most widely used antidepressants on sleep and quantitative electroencephalogram (qEEG) are well characterized; however, such studies of tramadol are scarce. Our aim was to characterize the effects of tramadol on sleep architecture and qEEG in different sleep–wake stages. EEG-equipped Wistar rats were treated with tramadol (0, 5, 15 and 45 mg/kg) at the beginning of the passive phase, and EEG, electromyogram and motor activity were recorded. Tramadol dose-dependently reduced the time spent in rapid eye movement (REM) sleep and increased the REM onset latency. Lower doses of tramadol had wake-promoting effects in the first hours, while 45 mg/kg of tramadol promoted sleep first, but induced wakefulness thereafter. During non-REM sleep, tramadol (15 and 45 mg/kg) increased delta and decreased alpha power, while all doses increased gamma power. In conclusion, the sleep-related and qEEG effects of tramadol suggest antidepressant-like properties, including specific beneficial effects in selected patient groups, and raise the possibility of a faster acting antidepressant action. Full article
(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)
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Review

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17 pages, 364 KiB  
Review
Repurposing Peroxisome Proliferator-Activated Receptor Agonists in Neurological and Psychiatric Disorders
by Claudia Sagheddu, Miriam Melis, Anna Lisa Muntoni and Marco Pistis
Pharmaceuticals 2021, 14(10), 1025; https://doi.org/10.3390/ph14101025 - 8 Oct 2021
Cited by 19 | Viewed by 3871
Abstract
Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors [...] Read more.
Common pathophysiological mechanisms have emerged for different neurological and neuropsychiatric conditions. In particular, mechanisms of oxidative stress, immuno-inflammation, and altered metabolic pathways converge and cause neuronal and non-neuronal maladaptative phenomena, which underlie multifaceted brain disorders. The peroxisome proliferator-activated receptors (PPARs) are nuclear receptors modulating, among others, anti-inflammatory and neuroprotective genes in diverse tissues. Both endogenous and synthetic PPAR agonists are approved treatments for metabolic and systemic disorders, such as diabetes, fatty liver disease, and dyslipidemia(s), showing high tolerability and safety profiles. Considering that some PPAR-acting drugs permeate through the blood–brain barrier, the possibility to extend their scope from the periphery to central nervous system has gained interest in recent years. Here, we review preclinical and clinical evidence that PPARs possibly exert a neuroprotective role, thereby providing a rationale for repurposing PPAR-targeting drugs to counteract several diseases affecting the central nervous system. Full article
(This article belongs to the Special Issue Repurposing Drug Strategies for CNS Disorders)
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