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The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Applied Chemistry".

Deadline for manuscript submissions: 31 December 2024 | Viewed by 7858

Special Issue Editor

Prof. Dr. Nikolaos Pitsikas

E-Mail Website
Guest Editor
Department of Pharmacology, School of Medicine, Faculty of Health Sciences, University of Thessaly, Larisa, Greece
Interests: behavioral pharmacology; neuroscience; psychopharmacology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The search of novel molecules in therapy is a hot issue. The gaseous neurotransmitter nitric oxide is intensively studied for its implication in a wide range of neuropsychiatric and neurodegenerative diseases, including anxiety, depression, schizophrenia, dementia, Parkinson disease, Alzheimer’s disease, etc.

This Special Issue of Molecules aims to assess new advances of the therapeutic action of nitric oxide and its modulators targeting different pathologies. In this context, we intend to highlight and emphasize their pharmacological activity.

We cordially invite researchers working in the field to contribute original research articles, as well as critical review articles, that unravel the therapeutic potential of nitric oxide and its modulators.

We look forward to receiving your contributions.

Prof. Dr. Nikolaos Pitsikas
Guest Editor

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Keywords

  • nitric oxide
  • biological targets
  • pharmacology
  • neuropsychiatric disorders
  • neurodegenerative disorders

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Published Papers (5 papers)

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Research

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26 pages, 14555 KiB  
Article
The Effect of Chronic Treatment with the Inhibitor of Phosphodiesterase 5 (PDE5), Sildenafil, in Combination with L-DOPA on Asymmetric Behavior and Monoamine Catabolism in the Striatum and Substantia Nigra of Unilaterally 6-OHDA-Lesioned Rats
by Elżbieta Lorenc-Koci, Kinga Kamińska, Tomasz Lenda and Jolanta Konieczny
Molecules 2024, 29(18), 4318; https://doi.org/10.3390/molecules29184318 - 11 Sep 2024
Viewed by 829
Abstract
The use of phosphodiesterase inhibitors in the treatment of Parkinson’s disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 [...] Read more.
The use of phosphodiesterase inhibitors in the treatment of Parkinson’s disease is currently widely discussed. The study aimed to investigate the impact of acute and chronic treatment with the phosphodiesterase 5 inhibitor, sildenafil, at low and moderate doses of 2 mg/kg and 6 mg/kg, and L-DOPA (12.5 mg/kg), alone or in combination, on asymmetric behavior and dopamine (DA) and serotonin metabolism in the striatum and substantia nigra of unilaterally 6-OHDA-lesioned rats. Acute administration of sildenafil at both tested doses jointly with L-DOPA significantly increased the number of contralateral rotations during a 2 h measurement compared to L-DOPA alone. The effect of a lower dose of sildenafil combined with L-DOPA was much greater in the second hour of measurement. However, the acute combined administration of a higher dose of sildenafil with L-DOPA resulted in an immediate and much stronger increase in the number of contralateral rotations compared to L-DOPA alone, already visible in the first hour of measurement. Interestingly, the chronic combined administration of 2 mg/kg of sildenafil and L-DOPA significantly reduced the number of contralateral rotations, especially during the first hour of measurement, compared to the long-term treatment with L-DOPA alone. Such an effect was not observed after the long-term combined treatment of a higher dose of sildenafil and L-DOPA compared to L-DOPA alone. The concentration of DA in the ipsilateral striatum and substantia nigra after the last combined chronic dose of sildenafil (2 or 6 mg/kg) and L-DOPA (12.5 mg/kg) was significantly higher than after L-DOPA alone. In spite of much stronger increases in the DA concentration in the ipsilateral striatum and substantia nigra, the number of contralateral rotations was reduced in the group of rats treated with the combination of 2 mg/kg sildenafil and L-DOPA compared to the group receiving L-DOPA alone. Moreover, the combined treatment with a low dose of sildenafil and L-DOPA had an opposite effect on DA catabolism, as assessed by DOPAC/DA and HVA/DA indexes, and these indexes were reduced in the ipsilateral striatum but increased in the contralateral striatum and substantia nigra compared to the treatment with L-DOPA alone. The results of the present study show that the addition of a low dose of a PDE5 inhibitor to the standard L-DOPA therapy differently modulates rotational behavior, the tissue DA concentration and its catabolism in the striatum and substantia nigra. Full article
(This article belongs to the Special Issue The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders)
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20 pages, 3277 KiB  
Article
The Impact of LY487379 or CDPPB on eNOS Expression in the Mouse Brain and the Effect of Joint Administration of Compounds with NO• Releasers on MK-801- or Scopolamine-Driven Cognitive Dysfunction in Mice
by Agata Płoska, Anna Siekierzycka, Paulina Cieślik, Lawrence W. Dobrucki, Leszek Kalinowski and Joanna M. Wierońska
Molecules 2024, 29(3), 627; https://doi.org/10.3390/molecules29030627 - 29 Jan 2024
Viewed by 1208
Abstract
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer’s disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were [...] Read more.
The role of endothelial nitric oxide synthase (eNOS) in the regulation of a variety of biological processes is well established, and its dysfunction contributes to brain pathologies, including schizophrenia or Alzheimer’s disease (AD). Positive allosteric modulators (PAMs) of metabotropic glutamate (mGlu) receptors were shown to be effective procognitive compounds, but little is known about their impact on eNOS expression and stability. Here, we investigated the influence of the acute and chronic administration of LY487379 or CDPPB (mGlu2 and mGlu5 PAMs), on eNOS expression in the mouse brain and the effect of the joint administration of the ligands with nitric oxide (NO) releasers, spermineNONOate or DETANONOate, in different combinations of doses, on MK-801- or scopolamine-induced amnesia in the novel object recognition (NOR) test. Our results indicate that both compounds provoked eNOS monomer formation, and CDPPB at a dose of 5 mg/kg exaggerated the effect of MK-801 or scopolamine. The coadministration of spermineNONOate or DETANONOate enhanced the antiamnesic effect of CDPPB or LY487379. The best activity was observed for ineffective or moderate dose combinations. The results indicate that treatment with mGluR2 and mGluR5 PAMs may be burdened with the risk of promoting eNOS uncoupling through the induction of dimer dissociation. Administration of the lowest possible doses of the compounds with NO• donors, which themselves have procognitive efficacy, may be proposed for the treatment of schizophrenia or AD. Full article
(This article belongs to the Special Issue The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders)
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15 pages, 1968 KiB  
Article
The Nitric Oxide (NO) Donor Molsidomine Attenuates Memory Impairments Induced by the D1/D2 Dopaminergic Receptor Agonist Apomorphine in the Rat
by Foteini Vartzoka, Elif Ozenoglu and Nikolaos Pitsikas
Molecules 2023, 28(19), 6861; https://doi.org/10.3390/molecules28196861 - 28 Sep 2023
Cited by 3 | Viewed by 1157
Abstract
Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It [...] Read more.
Several lines of evidence suggest that scarcity of the gaseous molecule nitric oxide (NO) is associated with the pathogenesis of schizophrenia. Therefore, compounds, such as NO donors, that can normalize NO levels might be of utility for the treatment of this pathology. It has been previously shown that the NO donor molsidomine attenuated schizophrenia-like behavioral deficits caused by glutamate hypofunction in rats. The aim of the current study was to investigate the efficacy of molsidomine and that of the joint administration of this NO donor with sub-effective doses of the non-typical antipsychotics clozapine and risperidone to counteract memory deficits associated with dysregulation of the brain dopaminergic system in rats. Molsidomine (2 and 4 mg/kg) attenuated spatial recognition and emotional memory deficits induced by the mixed dopamine (DA) D1/D2 receptor agonist apomorphine (0.5 mg/kg). Further, the joint administration of sub-effective doses of molsidomine (1 mg/kg) with those of clozapine (0.1 mg/kg) or risperidone (0.03 mg/kg) counteracted non-spatial recognition memory impairments caused by apomorphine. The present findings propose that molsidomine is sensitive to DA dysregulation since it attenuates memory deficits induced by apomorphine. Further, the current findings reinforce the potential of molsidomine as a complementary molecule for the treatment of schizophrenia. Full article
(This article belongs to the Special Issue The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders)
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Review

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35 pages, 2532 KiB  
Review
“NO” Time in Fear Response: Possible Implication of Nitric-Oxide-Related Mechanisms in PTSD
by Mariana G. Fronza, Bruna F. Ferreira, Isabela Pavan-Silva, Francisco S. Guimarães and Sabrina F. Lisboa
Molecules 2024, 29(1), 89; https://doi.org/10.3390/molecules29010089 - 22 Dec 2023
Cited by 1 | Viewed by 1941
Abstract
Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by persistent fear responses and altered neurotransmitter functioning due to traumatic experiences. Stress predominantly affects glutamate, a neurotransmitter crucial for synaptic plasticity and memory formation. Activation of the N-Methyl-D-Aspartate glutamate receptors (NMDAR) can trigger [...] Read more.
Post-traumatic stress disorder (PTSD) is a psychiatric condition characterized by persistent fear responses and altered neurotransmitter functioning due to traumatic experiences. Stress predominantly affects glutamate, a neurotransmitter crucial for synaptic plasticity and memory formation. Activation of the N-Methyl-D-Aspartate glutamate receptors (NMDAR) can trigger the formation of a complex comprising postsynaptic density protein-95 (PSD95), the neuronal nitric oxide synthase (nNOS), and its adaptor protein (NOS1AP). This complex is pivotal in activating nNOS and nitric oxide (NO) production, which, in turn, activates downstream pathways that modulate neuronal signaling, including synaptic plasticity/transmission, inflammation, and cell death. The involvement of nNOS and NOS1AP in the susceptibility of PTSD and its comorbidities has been widely shown. Therefore, understanding the interplay between stress, fear, and NO is essential for comprehending the maintenance and progression of PTSD, since NO is involved in fear acquisition and extinction processes. Moreover, NO induces post-translational modifications (PTMs), including S-nitrosylation and nitration, which alter protein function and structure for intracellular signaling. Although evidence suggests that NO influences synaptic plasticity and memory processing, the specific role of PTMs in the pathophysiology of PTSD remains unclear. This review highlights pathways modulated by NO that could be relevant to stress and PTSD. Full article
(This article belongs to the Special Issue The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders)
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14 pages, 2949 KiB  
Review
Neuronal Nitric Oxide Synthase and Post-Translational Modifications in the Development of Central Nervous System Diseases: Implications and Regulation
by Cristina Maccallini and Rosa Amoroso
Molecules 2023, 28(18), 6691; https://doi.org/10.3390/molecules28186691 - 19 Sep 2023
Cited by 4 | Viewed by 2206
Abstract
In the Central Nervous System (CNS), Nitric Oxide (NO) is mainly biosynthesized by neuronal Nitric Oxide Synthase (nNOS). The dysregulated activation of nNOS in neurons is critical in the development of different conditions affecting the CNS. The excessive production of NO by nNOS [...] Read more.
In the Central Nervous System (CNS), Nitric Oxide (NO) is mainly biosynthesized by neuronal Nitric Oxide Synthase (nNOS). The dysregulated activation of nNOS in neurons is critical in the development of different conditions affecting the CNS. The excessive production of NO by nNOS is responsible for a number of proteins’ post-translational modifications (PTMs), which can lead to aberrant biochemical pathways, impairing CNS functions. In this review, we briefly revise the main implications of dysregulated nNOS in the progression of the most prevalent CNS neurodegenerative disorders, i.e., Alzheimer’s disease (AD) and Parkinson’s disease, as well as in the development of neuronal disorders. Moreover, a specific focus on compounds able to modulate nNOS activity as promising therapeutics to tackle different neuronal diseases is presented. Full article
(This article belongs to the Special Issue The Gaseous Neurotransmitter Nitric Oxide: A Potential Therapeutic Target for Neuropsychiatric and Neurodegenerative Disorders)
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