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The present work aimed to investigate the induction of circadian rhythm dysfunction and dementia upon chronic exposure to light-light and its reversal by melatonin in Wistar rats. Animals underwent different light-dark conditions, viz., light/dark (LD), light/light (LL), and dark/dark (DD) in respective groups for 4 months. Melatonin 0.5 mg/kg s.c., dextromethorphan 50 μg/100 g s.c., and mifepristone 25 μg/100 g s.c. were given once a day. Chronic LL and DD conditions significantly increased brain glutamate and cortisol levels. The LL period caused a deficit in spatial memory, working memory, decision making, and exploration of novel objects, compared to LD animals. A significant ( p < 0.05) change in neuropathological observations in the hippocampus, CA1, CA2, and CA3; cortex; and cerebellum regions (40×, 100×, and 400×) was observed in the histological study. Induced oxidative stress in brain tissue was also observed by estimating tissue glutathione and TBARS levels. Dextromethorphan (NMDA antagonist), mifepristone (corticosterone antagonist), and melatonin significantly ( p < 0.05) reversed the pathological states caused due to LL. The histological features in the hippocampus, cortex, and cerebellum region revealed inflammatory cells, vacuolation, and pyknotic cells, which were significantly rescued by antagonizing NMDA or cortisol or melatonin treatment. It may be concluded that continuous exposure to light-light conditions produced an imbalance between neuronal excitation and stress hormone, leading to poor cognitive abilities and neuropathology.

Circadian rhythms are 24-hour natural rhythms regulated by the suprachiasmatic nucleus, also known as the "master clock". The retino-hypothalamic tract entrains suprachiasmatic nucleus with photic information to synchronise endogenous circadian rhythms with the Earth's light-dark cycle. However, despite the robustness of circadian rhythms, an unhealthy lifestyle and chronic photic disturbances cause circadian rhythm disruption in the suprachiasmatic nucleus's TTFL loops via affecting glutamate and γ-aminobutyric acid-mediated neurotransmission in the suprachiasmatic nucleus. Recently, considerable evidence has been shown correlating CRd with the incidence of Alzheimer's disease. The present review aims to identify the existence and signalling of endocannabinoids in CRd induced Alzheimer's disease through retino-hypothalamic tract- suprachiasmatic nucleus-cortex. Immunohistochemistry has confirmed the expression of cannabinoid receptor 1 in the suprachiasmatic nucleus to modulate the circadian phases of the master clock. Literature also suggests that cannabinoids may alter activity of suprachiasmatic nucleus by influencing the activity of their major neurotransmitter γ-aminobutyric acid or by interacting indirectly with the suprachiasmatic nucleus's two other major inputs i.e., the geniculo-hypothalamic tract-mediated release of neuropeptide Y and serotonergic inputs from the dorsal raphe nuclei. Besides, the expression of cannabinoid receptor 2 ameliorates cognitive deficits via reduction of tauopathy and microglial activation. In conclusion, endocannabinoids may be identified as a putative target for correcting CRd and decelerating Alzheimer's disease., (Copyright © 2021 Elsevier B.V. All rights reserved.)