Neuroprotective Effects of Fluoxetine on Molecular Markers of Circadian Rhythm, Cognitive Deficits, Oxidative Damage, and Biomarkers of Alzheimer’s Disease-Like Pathology Induced under Chronic Constant Light Regime in Wistar Rats

Abstract

There is mounting evidence of circadian rhythm disruption in Alzheimer's disease (AD); however, the cause-and-effect relationship between them is not understood. Chronic constant light exposure effectively disrupts circadian rhythm in rats. On the basis of previous publications, we hypothesized that chronic constant light exposure might contribute significantly to development of AD-like-phenotype in rats and that fluoxetine (Flx) treatment might protect the brain against it. Adult male rats were exposed to normal light-dark cycles, constant light (LL), constant dark, and LL+Flx (5 mg/kg/day, ZT5) for four months. The expression of molecular markers of circadian rhythm: Per2 transcripts; and protein expression of peroxiredoxin-1 (PRX1) and hyperoxidized peroxiredoxins (PRX-SO 2/3 ) were significantly dysregulated in the suprachiasmatic nuclei (SCN) of LL rats, which was prevented with concomitant fluoxetine administration. The levels of glutamate and γ-aminobutyric acid were dysregulated, and oxidative damage was observed in the SCN and hippocampi of LL rats. Fluoxetine treatment conferred protection against oxidative damage in LL rats. Constant light exposure also impaired rats' performance on Y-maze, Morris maze, and novel object recognition test, which was prevented with fluoxetine administration. A significant elevation in soluble Aβ 1−42 levels, which strongly correlated with upregulation of Bace1 and Mgat3 transcripts was observed in the hippocampus of LL rats. Further, the expression of antiaging gene Sirt1 was downregulated, and neuronal damage indicator Prokr2 was upregulated in hippocampus. Fluoxetine rescued Aβ 1−42 upregulation and AD-related genes' dysregulation. Our findings show that circadian disruption by exposure to chronic constant light may contribute to progression of AD, which can be prevented with fluoxetine treatment.

Chaperone-Dependent Mechanisms as a Pharmacological Target for Neuroprotection

“…Supplementary Materials: The supporting information can be downloaded at www.mdpi.com/xxx/s1. References [127,135,157,168,[173][174][175][176][177][178][179][180][181][182][183][184][185][186][187][188][193][194][195]256,264,265,268,[270][271][272][273][274]276,324,326,327,[346][347][348]350,351,[468][469][470][471][472][473] are cited in the supplementary materials. Supplementary Materials: The supporting information can be downloaded at www.mdpi.com/xxx/s1.…”

Chronic Light-Distorted Glutamate-Cortisol Signaling, Behavioral and Histological Markers, and Induced Oxidative Stress and Dementia: An Amelioration by Melatonin

“…Photic Zeitgebers in day-to-day life may cause electrochemical excitotoxicity, and the resultant stress disrupts the coordination and homogeneity of nervous signaling across the brain regions. In our previous investigation, light–light intervention to rodent class Wistar rats for a chronic period was able to modulate the level of per2 , PRX1 , and PRX-SO2/3 gene expression, markers of CR disruption in the SCN brain region, associated with neurodegeneration, and increased the level of amyloid β, BACE1 , and Mgat3 transcript with an altered expression of Sirt1 and Prokr2 in the hippocampus region . A pathology of the AD phenotype with behavioral disturbances of dementia and cognitive disorientation was concluded .…”

“…In our previous investigation, light−light intervention to rodent class Wistar rats for a chronic period was able to modulate the level of per2, PRX1, and PRX-SO2/3 gene expression, markers of CR disruption in the SCN brain region, associated with neurodegeneration, and increased the level of amyloid β, BACE1, and Mgat3 transcript with an altered expression of Sirt1 and Prokr2 in the hippocampus region. 16 A pathology of the AD phenotype with behavioral disturbances of dementia and cognitive disorientation was concluded. 15 As an extension to previous novel findings, we aimed to investigate the role of chronic light-induced excitatory signaling caused by glutamate and cortisol and the reciprocating role of melatonin in-memory performance in Wistar rats.…”

A Growing Link between Circadian Rhythms, Type 2 Diabetes Mellitus and Alzheimer’s Disease

“…Moreover, antidepressants could also improve mood disorders and sleep quality and have favorable effects on glycemic control in T2DM [ 191 ]. A recent study reported that circadian disruption by chronic constant light led to AD progression, while fluoxetine prevented this effect [ 192 ]. Another study showed that the antidepressant agomelatine could rescue streptozotocin-induced AD pathology, including Aβ accumulation and neuroinflammation [ 193 ].…”