Investigation for novel pharmacological target for dementia of Alzheimer s type

Abstract

newline x newlineABSTRACT newlineCircadian rhythm disruption is prevalent in contemporary society where light-noise, newlinejet-lag, and shift-work are commonplace, and its comorbidity with Alzheimer s newlinedisease (AD) is well documented, but the cause and effect relationship between the newlinetwo is not fully understood. Here, we investigated the effect of circadian rhythm newlinedisruption caused by constant light on rats memory performance and newlineneurobiochemistry. Adult male Wistar rats were exposed to different light conditions newlineviz. normal light-dark cycles (LD), constant light (LL), and constant dark (DD) for newlinetwo months. Significant cognitive impairment and oxidative stress were observed in newlineLL animals without a significant elevation in the soluble Aand#946;1-42 levels. Next, we newlineexamined whether long-term exposure to constant light may accelerate dementia in a newlinesub-pathological Aand#946; model of rats. Normal control rats received ACSF, AD rats newlinereceived 440pmol, and sub-pathological Aand#946; rats (Aand#946;(s)) received 220pmol of human newlineAand#946;42 peptide in a single unilateral ICV administration. Sub-pathological Aand#946; rats newlineexposed to constant light (LL + Aand#946;(s)) show significant memory deficits and oxidative newlinedamage, although not significantly different from LL rats. Additionally, constant light newlinepromoted aggregation of exogenous Aand#946;42 in LL + Aand#946;(s) rats shown by the presence of newlinecongophilic plaques. Furthermore, chronic fluoxetine treatment (5 mg/kg/day) rescued newlinerats from the behavioral deficits, oxidative damage and amyloid aggregation. newlineWhereas, rifampicin treatment (20 mg/kg/day) did not reverse the behavioral deficits newlineor oxidative stress but rescued rats from amyloid plaque formation. newlineFurthermore, we investigated the effect of circadian rhythm disruption caused by newlineconstant light exposure for four months on rats memory performance and newlineneurobiochemistry. The estimation of circadian rhythm biomarkers revealed: Per2 newlinewas significantly upregulated at zeitgeber time (ZT0); PRX1 was significantly newlineupregulated at ZT12; and PRX-SO2/3 was significantly upregulated at both ZT0 and newlineZT12 in the suprachiasmatic nuclei (SCN) of LL rats. Furthermore, glutamate levels newlinewere significantly reduced and GABA levels were significantly elevated at ZT0. newlineFinally, the levels of malondialdehyde were significantly elevated; and the levels of newlinereduced glutathione and Na+K+ATPase activity were significantly reduced in the SCN newlineof LL rats. The neuronal dysregulation in the SCN was paralleled by oxidative newlinedamage in the hippocampus and memory deficits. LL rats show significant newlineimpairment in memory performance on Y-maze, Morris maze and novel object newlinexi newlinerecognition test compared to LD. The levels of oxidative stress markers newlinemalondialdehyde and PRX-SO2/3 were significantly elevated; whereas the levels of newlinereduced glutathione were significantly reduced in the hippocampi of LL rats. newlineFurthermore, the expression of antioxidant gene Sirt1 was downregulated as opposed newlineto the upregulated expression of neuronal damage indicator Prokr2. AD-likephenotype newlinewas confirmed by significantly elevation in the levels of Aand#946;1-42, which newlinestrongly correlated with upregulation of Bace1 and Mgat3 transcripts in the newlinehippocampi of LL rats, which were normalized by daily fluoxetine (5mg/kg/day) newlineadministration. Fluoxetine also ameliorated memory deficits and oxidative damage in newlinerats exposed to constant light. The results demonstrate that constant light profoundly newlineaffects memory performance, brain metabolism, and exert immense oxidative stress newlinethat induces an AD-like-phenotype in Wistar rats, which can be rescued by fluoxetine newlinetreatment. newlineKeywords: Alzheimer s disease; Amyloid beta; Bace1; Fluoxetine; Hippocampus; newlineMgat3; Oxidative stress; Per2; Peroxiredoxin; Rat behavior; Rifampicin; newlineSuprachiasmatic nuclei