期刊
INTERNATIONAL IMMUNOPHARMACOLOGY
卷 109, 期 -, 页码 -出版社
ELSEVIER
DOI: 10.1016/j.intimp.2022.108860
关键词
Alzheimer ?s disease; Coagulansin-A; Amyloid-beta (A ?) peptide aggregation; Oxidative stress; Neuro-inflammation; Neurodegeneration
资金
- Higher Education Commission (HEC) , Pakistan under indigenous fellowship [17-5 (Ph-II) /2MD4-051/HEC/IS/2017]
The present study investigated the therapeutic effects of Coagulansin-A (Coag-A) against Alzheimer's disease (AD) by inhibiting amyloid beta (Aβ) aggregation and reducing oxidative stress. Coag-A showed neuroprotective effects and attenuated cognitive decline in a mouse model of AD. It also exhibited anti-inflammatory, antioxidant, and anti-apoptotic effects by regulating the expression of nuclear factor erythroid-2-related factor (Nrf-2) and nuclear factor kappa B (NF-κB).
The present study was designed to investigate the underlying molecular signaling of Coagulansin-A (Coag-A) as a therapeutic agent against Alzheimer's disease (AD). Preliminarily, it exhibited a neuroprotective effect against H2O2-induced oxidative stress in HT-22 cells. The in vivo studies were performed by administering Coag-A (0.1, 1, and 10 mg/kg) intraperitoneally to 5xFAD transgenic (Tg) mouse model. Coag-A (10 mg/kg) significantly attenuated the cognitive decline compared to Tg mice group in the shallow water maze (SWM) and Y-maze test paradigms. The anti-aggregation potential of Coag-A was determined by performing Fourier transform-infrared (FT-IR) spectroscopy and differential scanning calorimeter (DSC) analysis in the prefrontal cortex (PFC) and hippocampal (HC) regions of mice brain. The FT-IR spectra demonstrated the inhibition of amyloid beta (A beta) through a decrease in beta-sheet aggregation, along with the inhibition of changes in the lipids, proteins, and phospholipids. The DSC analysis displayed a low-temperature exotherm associated with the reversible process of aggregation of soluble protein fractions prior to denaturation. Furthermore, Coag-A treatment displayed a regular density of granule cells in H&E stained sections, along with a reduced amyloid load and PAS-positive granules in all the regions of interest in mice brain. The real-time polymerase chain reaction (q-PCR), western blot and immunohistochemical (IHC) analysis demonstrated antioxidant, anti-inflammatory, and anti-apoptotic effect of Coag-A by enhancing the expression of nuclear factor erythroid-2-related factor (Nrf-2) and reducing nuclear factor kappa B (NF-kappa B) and Bax protein expression. In addition, Coag-A significantly increased the antioxidant enzymes and proteins level, along with a reduced pro-inflammatory cytokines production.
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