Possible modulatory effect of some antidiabetic drugs in lipopolysaccharide-induced neuroinflammation and cognitive impairment in mice / Nesma Ahmed Abdelrahman Mohamed ; Supervised Nesrine Salaheldine Elsayed , Lamiaa Ahmed Ahmed , Ayman Elsayed Elsahar

Thesis (Ph.D.) - Cairo University - Faculty of Pharmacy - Department of Pharmacology and Toxicology

Neuroinflammation plays a crucial role in the pathogenesis and progression of various neurodegenerative diseases such as Alzheimer{u2019}s disease (AD). A growing body of evidence supports that antidiabetic drugs such as metformin and dipeptidylpeptidase-4 inhibitors possess various neuroprotective effects that can improve learning and memory impairments in AD models. Thus, the present study aimed to investigate the possible neuroprotective effects of metformin and alogliptin each alone or in combination against intracerebroventricular (ICV) lipopolysaccharide (LPS)-induced neuroinflammation and cognitive impairment in mice as well as the potential mechanisms underlying these effects. Mice were treated with metformin (200 mg/kg/d; p.o.) and alogliptin (20 mg/kg/d; p.o.) alone or in combination for 14 days, starting 1 day prior to ICV LPS injection (8 og/oL in 3 oL). Both metformin and alogliptin alleviated LPSinduced cognitive impairment as assessed by Morris water maze and novel object recognition tests. Moreover, the treatment regimens reversed LPS-induced increases in toll-like receptor 4 (TLR4) and myeloid differentiation primary response protein 88 (MYD88) protein expression as well as nuclear factor-mB (NF-mB) p65 content. The tested regimens also abrogated the LPSinduced increase in microRNA-155 (miRNA-155) and decrease in suppressor of cytokine signaling-1 (SOCS-1) gene expression. Importantly, they rescued LPS-induced decrease in phosphorylated cyclic adenosine monophosphate response element binding protein (pCREB) protein expression in the brain. Consequently, the tested regimens ameliorated the measured inflammatory markers (tumor necrosis factor-Ü and interleukin-6 contents as well as ionized calcium-binding adaptor molecule-1 and glial fibrillary acid protein), amyloidogenic biomarkers (amyloid Ý (1-42) content and Ý-secretase activity) and apoptotic markers (Bax and Bcl-2). In conclusion, the present study sheds light on the potential neuroprotective effects of metformin and alogliptin alone or in combination against ICV LPS-induced neuroinflammation and its associated amyloidogenesis, apoptosis, and memory impairment via inhibition of TLR4/MyD88/NF-mB signaling, modulation of microRNA-155/SOCS-1 expression, and enhancement of pCREB expression in the brain

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