Targeting α6GABAA receptors as a novel therapy for schizophrenia: A proof-of-concept preclinical study using various animal models

Lee, Ming Tatt; Mouri, Akihiro; Kubota, Hisayoshi; Lee, Hsin‐Jung; Chang, Man‐Hsin; Wu, Chen‐Yi; Knutson, Daniel E; Mihovilovič, Marko D.; Cook, James M.; Sieghart, Werner; Nabeshima, Toshitaka; Chiou, Lih‐Chu

doi:10.1016/j.biopha.2022.113022

Cited by 11 publications

(12 citation statements)

References 65 publications

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“…A previous study also showed an increase of TH expression in the nucleus accumbens of methamphetamine‐treated mice, which are considered a model for mania, schizophrenia, and addiction, showing enhanced synaptic dopamine levels 50 . Interestingly, injection of dopaminergic toxin 6‐hydroxydopamine (6‐OHDA) antagonized the increase of TH in methamphetamine‐treated mice 50–52 . 6‐OHDA is also a neurotoxin used to produce Parkinsonism rodent models 53,54 .…”

Section: Discussionmentioning

confidence: 94%

“… 50 Interestingly, injection of dopaminergic toxin 6‐hydroxydopamine (6‐OHDA) antagonized the increase of TH in methamphetamine‐treated mice. 50 , 51 , 52 6‐OHDA is also a neurotoxin used to produce Parkinsonism rodent models. 53 , 54 Considering these previous reports and our results, the delicately balanced regulation of dopamine transmission including TH may play an important role in the drug therapy of PD, schizophrenia, and BPD.…”

Section: Discussionmentioning

confidence: 99%

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Downregulation of microRNA‐330‐5p induces manic‐like behaviors in REM sleep‐deprived rats by enhancing tyrosine hydroxylase expression

Leem

Kim

et al. 2023

CNS Neurosci Ther

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Aim In our pilot study, we found an increase in tyrosine hydroxylase (Th) mRNA expression in the prefrontal cortex of 72‐h REM sleep‐deprived (SD) rats, a mania model. Additionally, the expression levels of miR‐325‐3p, miR‐326‐3p, and miR‐330‐5p, the predicted target miRNAs on TH, were significantly decreased. Based on these results, in this study, we investigated whether miRNA‐325‐3p, miR‐326‐3p, and miR‐330‐5p modulate TH and manic‐like behaviors in SD rats. Methods Manic‐like behaviors were assessed using the open field test (OFT) and elevated plus‐maze (EPM) test. The direct binding activity of miRNAs to the 3′‐untranslated region (3′‐UTR) of the Th gene was measured in HEK‐293 cells using a luciferase reporter system. We also examined mRNA and protein expression of TH after intracerebroventricular (ICV) injection of miR‐330‐5p agomir to SD rats, along with manic‐like behaviors. Results We observed an upregulation in mRNA and protein expression of TH and downregulation in miRNA‐325‐3p, miR‐326‐3p, and miR‐330‐5p expressions in the prefrontal cortex of SD rats, together with increased manic‐like behaviors. The luciferase reporter assay showed that miR‐330‐5p could repress TH expression through direct binding to its target site in the 3′‐UTR of Th, whereas miR‐326‐3p and miR‐330‐5p could not. In addition, ICV injection of miR‐330‐5p agomir alleviated the increase in TH expression in the prefrontal cortex of SD rats and manic‐like behaviors. Conclusions TH expression regulation through miR‐330‐5p may be implicated in the pathophysiology of mania in SD rats.

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Section: Discussionmentioning

confidence: 94%

Section: Discussionmentioning

confidence: 99%

Downregulation of microRNA‐330‐5p induces manic‐like behaviors in REM sleep‐deprived rats by enhancing tyrosine hydroxylase expression

Leem

Kim

et al. 2023

CNS Neurosci Ther

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“…In addition, the identification of some pyrazoloquinolinones as the first highly selective positive modulators of α6GABA A Rs (α6-modulators), that are not able to modulate the much more abundant benzodiazepinesensitive GABA A Rs up to μM concentrations [7], changed the picture. Since that, several studies indicated that these α6modulators in animal models can reduce the symptoms of tic disorders, such as Tourette Syndrome [8,9], schizophrenia [10], and essential tremor [11], to an extent comparable with standard therapeutics used to treat these disorders. In animal models of schizophrenia these compounds not only reduced positive symptoms but also negative symptoms and cognitive impairment [10].…”

Section: α6-containing Gaba a Receptorsmentioning

confidence: 99%

Why Can Modulation of α6-Containing GABAA Receptors Reduce the Symptoms of Multiple Neuropsychiatric Disorders?

Sieghart

2024

Arch Pharmacol Ther

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α6-containing GABAA receptors (α6GABAARs) are strongly expressed in cerebellar granule cells, where they mediate a correctly timed and precise coordination of all muscle groups that execute behavior and protect the brain from information overflow. Recently, it was demonstrated that positive modulators with a high selectivity for α6GABAARs (α6-modulators) can reduce the symptoms of multiple neuropsychiatric disorders in respective animal models to an extent comparable with established clinical therapeutics. Here, these incredible findings are discussed and explained. So far, the beneficial actions of α6-modulators and their lack of side effects have only been demonstrated in animal models of the respective disorders. Preclinical studies have demonstrated their suitability for further drug development. Future human studies have to investigate their safety and possible side effects, and to clarify to which extent individual symptoms of the respective disorders can be reduced by α6-modulators in patients during acute and chronic dosing. Due to their broad therapeutic potential, α6-modulators might become a valuable new treatment option for multiple neuropsychiatric disorders.

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“…Affecting approximately 1% of the worldwide population, schizophrenia is a psychiatric disorder characterized by positive symptoms, negative symptoms, and cognitive impairment [ 166 , 167 ] with an onset of symptoms generally in the mid- to late 20s. These symptoms include visual and auditory hallucinations, delusions, depression, self-neglect, confused cognition, and memory impairments.…”

Section: Bdnf and Rs6265 In Psychiatric Disordersmentioning

confidence: 99%

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

Szarowicz

Steece‐Collier

Caulfield

2022

IJMS

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Brain-derived neurotrophic factor is an extensively studied neurotrophin implicated in the pathology of multiple neurodegenerative and psychiatric disorders including, but not limited to, Parkinson’s disease, Alzheimer’s disease, Huntington’s disease, traumatic brain injury, major de-pressive disorder, and schizophrenia. Here we provide a brief summary of current knowledge on the role of BDNF and the common human single nucleotide polymorphism, rs6265, in driving the pathogenesis and rehabilitation in these disorders, as well as the status of BDNF-targeted therapies. A common trend has emerged correlating low BDNF levels, either detected within the central nervous system or peripherally, to disease states, suggesting that BDNF replacement therapies may hold clinical promise. In addition, we introduce evidence for a distinct role of the BDNF pro-peptide as a biologically active ligand and the need for continuing studies on its neurological function outside of that as a molecular chaperone. Finally, we highlight the latest research describing the role of rs6265 expression in mechanisms of neurodegeneration as well as paradoxical advances in the understanding of this genetic variant in neuroregeneration. All of this is discussed in the context of personalized medicine, acknowledging there is no “one size fits all” therapy for neurodegenerative or psychiatric disorders and that continued study of the multiple BDNF isoforms and genetic variants represents an avenue for discovery ripe with therapeutic potential.

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Targeting α6GABAA receptors as a novel therapy for schizophrenia: A proof-of-concept preclinical study using various animal models

Cited by 11 publications

References 65 publications

Downregulation of microRNA‐330‐5p induces manic‐like behaviors in REM sleep‐deprived rats by enhancing tyrosine hydroxylase expression

Downregulation of microRNA‐330‐5p induces manic‐like behaviors in REM sleep‐deprived rats by enhancing tyrosine hydroxylase expression

Why Can Modulation of α6-Containing GABAA Receptors Reduce the Symptoms of Multiple Neuropsychiatric Disorders?

New Frontiers in Neurodegeneration and Regeneration Associated with Brain-Derived Neurotrophic Factor and the rs6265 Single Nucleotide Polymorphism

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