Huntington’s disease (HD) causes progressive movement disorders and cognitive deficits. Besides, sleep disturbances and emotional distress are prominent clinical signatures of HD. The experimental subjects and HD human brains display altered regenerative plasticity resulting from aberrant neurogenic and nonneurogenic areas. Sleep disorders, emotional disruption, and cognitive deficits have been linked to impaired cell cycle events of neural stem cells (NSC) in neurodegenerative disorders. In a physiological state, circadian clock gene pathways play important roles in the regulation of the proliferation and differentiation of NSC, whereas the irregular circadian clock pathway is attributed to impairment in the neurogenic process. The recent advancement of chemogenetic-based approaches represents a potential scientific tool to rectify the abnormal circadian clock which may aid in mitigating neurogenic failure in the brain. Notably, GABAergic vasoactive intestinal peptide (VIP)-expressing neurons in the brain plays a key role in the regulation of neuroplasticity and circadian rhythm. Thus, this conceptual review article addresses the potential link between sleep disorder and aberrant neurogenic events in HD and proposes chemogenetic kindling of vasoactive intestinal peptide (VIP) -expressing GABAergic neurons in the brain as a therapeutic strategy for reprogramming the clock gene pathways in mitigating the neurodegenerative failure in HD.
Elevated levels of histamine cause over-secretion of gastric hydrochloric acid (HCl), leading to gastrointestinal (GI) disorders and anxiety. Ranitidine is an antihistamine drug widely used in the management of GI disorders, as it works by blocking the histamine−2 receptors in parietal cells, thereby reducing the production of HCl in the stomach. While some reports indicate the neuroprotective effects of ranitidine, its role against GI disorder-related anxiety remains unclear. Therefore, we investigated the effect of ranitidine against anxiety-related behaviors in association with changes in neuronal density in the hippocampal cornu ammonis (CA)–3 region of cysteamine hydrochloride-induced mouse model of GI disorder. Results obtained from the open field test (OFT), light and dark box test (LDBT), and elevated plus maze (EPM) test revealed that ranitidine treatment reduces anxiety-like behaviors in experimental animals. Nissl staining and immunohistochemical assessment of ionized calcium-binding adapter molecule (Iba)-1 positive microglia in cryosectioned brains indicated enhanced density of pyramidal neurons and reduced activation of microglia in the hippocampal CA–3 region of brains of ranitidine-treated experimental mice. Therefore, this study suggests that ranitidine mediates anxiolytic effects, which can be translated to establish a pharmacological regime to ameliorate anxiety-related symptoms in humans.
Huntington’s disease (HD) is a progressive neurodegenerative disorder characterized by abnormal progressive involuntary movements, cognitive deficits, sleep disturbances, and psychiatric symptoms. The onset and progression of the clinical symptoms have been linked to impaired adult neurogenesis in the brains of subjects with HD, due to the reduced neurogenic potential of neural stem cells (NSCs). Among various pathogenic determinants, an altered clock pathway appears to induce the dysregulation of neurogenesis in neurodegenerative disorders. Notably, gamma-aminobutyric acid (GABA)-ergic neurons that express the vasoactive intestinal peptide (VIP) in the brain play a key role in the regulation of circadian rhythm and neuroplasticity. While an abnormal clock gene pathway has been associated with the inactivation of GABAergic VIP neurons, recent studies suggest the activation of this neuronal population in the brain positively contributes to neuroplasticity. Thus, the activation of GABAergic VIP neurons in the brain might help rectify the irregular circadian rhythm in HD. Chemogenetics refers to the incorporation of genetically engineered receptors or ion channels into a specific cell population followed by its activation using desired chemical ligands. The recent advancement of chemogenetic-based approaches represents a potential scientific tool to rectify the aberrant circadian clock pathways. Considering the facts, the defects in the circadian rhythm can be rectified by the activation of VIP-expressing GABAergic neurons using chemogenetics approaches. Thus, the chemogenetic-based rectification of an abnormal circadian rhythm may facilitate the neurogenic potentials of NSCs to restore the neuroregenerative plasticity in HD. Eventually, the increased neurogenesis in the brain can be expected to mitigate neuronal loss and functional deficits.
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