Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Koola, Maju Mathew

doi:10.1002/hup.2758

Cited by 16 publications

(13 citation statements)

References 233 publications

(335 reference statements)

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“…And this may possibly explain the differences observed for the effects of different doses of AMPH or LSDX evaluated here. Furthermore, lipid metabolism in SCZ might be related not just to the aberration of neural pathways, but also to disturbances in the tryptophan-kynurenine metabolic pathway [6][7][8], which may warrant future investigation.…”

Section: Discussionmentioning

confidence: 99%

“…Another pathway implicated in SCZ pathophysiology is the kynurenine pathway (KP), which involves the tryptophan metabolism [6]. The KP metabolites modulate neurotransmitters related to cognition [7]. Individuals with MDs presented lower levels of kynurenines, which may be involved in cognitive impairment [8], while conversely, SCZ patients showed increased kynurenine levels [6,8].…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, tryptophankynurenine metabolism in psychiatric disease is well established, and disturbance of the tryptophan-kynurenine metabolic pathway might be a promising target to unravel the therapeutic effects of psychoactive drugs. Additionally, the KP is also related to lipid metabolism [6,7].…”

Section: Introductionmentioning

confidence: 99%

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Effects of Psychostimulants and Antipsychotics on Serum Lipids in an Animal Model for Schizophrenia

et al. 2021

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Schizophrenia (SCZ) treatment is essentially limited to the use of typical or atypical antipsychotic drugs, which suppress the main symptoms of this mental disorder. Metabolic syndrome is often reported in patients with SCZ under long-term drug treatment, but little is known about the alteration of lipid metabolism induced by antipsychotic use. In this study, we evaluated the blood serum lipids of a validated animal model for SCZ (Spontaneously Hypertensive Rat, SHR), and a normal control rat strain (Normotensive Wistar Rat, NWR), after long-term treatment (30 days) with typical haloperidol (HAL) or atypical clozapine (CLZ) antipsychotics. Moreover, psychostimulants, amphetamine (AMPH) or lisdexamfetamine (LSDX), were administered to NWR animals aiming to mimic the human first episode of psychosis, and the effects on serum lipids were also evaluated. Discrepancies in lipids between SHR and NWR animals, which included increased total lipids and decreased phospholipids in SHR compared with NWR, were similar to the differences previously reported for SCZ patients relative to healthy controls. Administration of psychostimulants in NWR decreased omega-3, which was also decreased in the first episode of psychosis of SCZ. Moreover, choline glycerophospholipids allowed us to distinguish the effects of CLZ in SHR. Thus, changes in the lipid metabolism in SHR seem to be reversed by the long-term treatment with the atypical antipsychotic CLZ, which was under the same condition described to reverse the SCZ-like endophenotypes of this validated animal model for SCZ. These data open new insights for understanding the potential influence of the treatment with typical or atypical antipsychotics on circulating lipids. This may represent an outcome effect from metabolic pathways that regulate lipids synthesis and breakdown, which may be reflecting a cell lipids dysfunction in SCZ.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Effects of Psychostimulants and Antipsychotics on Serum Lipids in an Animal Model for Schizophrenia

et al. 2021

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“…2. The KYNA-centric hypothesis has only been published recently [61]. Additionally, KYNA as well as other KP catabolites have been extensively identified as tolerogenic molecules in the milieu of cancer pathogenesis [62][63][64][65].…”

Section: Role Of Kp Metabolites In the Pathogenesis Of Neuropsychiatric Disordersmentioning

confidence: 99%

Galantamine-Memantine Combination and Kynurenine Pathway Enzyme Inhibitors in the Treatment of Neuropsychiatric Disorders

et al. 2021

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The kynurenine pathway (KP) is a major route for L-Tryptophan (L-TRP) metabolism, yielding a variety of bioactive compounds including kynurenic acid (KYNA), 3-hydroxykynurenine (3-HK), quinolinic acid (QUIN), and picolinic acid (PIC). These tryptophan catabolites are involved in the pathogenesis of many neuropsychiatric disorders, particularly when the KP becomes dysregulated. Accordingly, the enzymes that regulate the KP such as indoleamine/tryptophan 2, 3-dioxygenase (IDO-1/TDO), kynurenine aminotransferases (KATs), and kynurenine 3-monooxygenase (KMO) represent potential drug targets, as enzymatic inhibition can favorably rebalance KP metabolite concentrations. In addition, the galantamine-memantine combination, through its modulatory effects at the alpha7 nicotinic acetylcholine receptors and N-methyl-D-aspartate receptors, may counteract the effects of KYNA. The aim of this review is to highlight the effectiveness of IDO-1, KAT II, and KMO inhibitors, as well as the galantamine-memantine combination in the modulation of different KP metabolites. KAT II inhibitors are capable of decreasing the KYNA levels in the rat brain by a maximum of 80%. KMO inhibitors effectively reduce the central nervous system (CNS) levels of 3-HK, while markedly boosting the brain concentration of KYNA. Emerging data suggest that the galantamine-memantine combination also lowers L-TRP, kynurenine, KYNA, and PIC levels in humans. Presently, there are only two pathophysiological mechanisms (cholinergic and glutamatergic) that are FDA approved for the treatment of cognitive dysfunction for which purpose the galantamine-memantine combination has been designed for clinical use against Alzheimer’s disease. The alpha7 nicotinic-NMDA hypothesis targeted by the galantamine-memantine combination has been implicated in the pathophysiology of various CNS diseases. Similarly, KYNA is well capable of modulating the neuropathophysiology of these disorders. This is known as the KYNA-centric hypothesis, which may be implicated in the management of certain neuropsychiatric conditions. In line with this hypothesis, KYNA may be considered as the “conductor of the orchestra” for the major pathophysiological mechanisms underlying CNS disorders. Therefore, there is great opportunity to further explore and compare the biological effects of these therapeutic modalities in animal models with a special focus on their effects on KP metabolites in the CNS, and with the ultimate goal of progressing to clinical trials for many neuropsychiatric diseases.

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“…The glutamatergic nervous system was proposed to be a therapeutic biomarker for mood disorders including depression [132]. Furthermore, a simultaneous intervention in the NMDA receptor and α7nAchR was suggested by novel combination for the treatment of schizophrenia [133]. Longitudinal plasma samples were studied in search of a certain plasma protein profiles as a predictive biomarker for the treatment of depression [134].…”

Section: Conclusion and Future Perspectivementioning

confidence: 99%

Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway

Török

Tanaka

Vécsei

2020

Preprint

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Neurodegenerative diseases are multifactorial, initiated by a series of the causative complex which develops into a certain clinical picture. The pathogenesis and disease course vary from patient to patient. Thus, it should be likewise to the treatment. Peripheral biomarkers are to play a central role for tailoring a personalized therapeutic plan for patients who suffered from neurodegenerative diseases such as Alzheimer’s diseases, Parkinson’s disease, and multiple sclerosis, among others. Nevertheless, the use of biomarkers in clinical practice is still underappreciated and data presented in biomarker research for clinical use is still uncompelling, compared to abundant data available for drug research and development. So is the case with kynurenines (KYNs) and the kynurenine pathway (KP) enzymes which have been associated with a wide range of diseases including cancer, autoimmune diseases, inflammatory diseases, neurologic diseases, and psychiatric disorders. This review article discusses current knowledge of the KP alteration observed in the central nervous system as well as the periphery, its involvement in pathogenesis and disease progression, and emerging evidence of roles of microbiota to the gut-brain axis, searching for practical peripheral biomarkers which ensure personalized treatment plans for neurodegenerative diseases.

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Alpha7 nicotinic‐N‐methyl‐D‐aspartate hypothesis in the treatment of schizophrenia and beyond

Cited by 16 publications

References 233 publications

Effects of Psychostimulants and Antipsychotics on Serum Lipids in an Animal Model for Schizophrenia

Effects of Psychostimulants and Antipsychotics on Serum Lipids in an Animal Model for Schizophrenia

Galantamine-Memantine Combination and Kynurenine Pathway Enzyme Inhibitors in the Treatment of Neuropsychiatric Disorders

Searching for Peripheral Biomarkers in Neurodegenerative Diseases: The Tryptophan-Kynurenine Metabolic Pathway

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