Cilostazol and SB203580 combination: Targeting ER stress and p38MAPK signaling in Alzheimer's disease mouse model.

Endoplasmic reticulum (ER) stress and mitogen-activated protein kinase (p38MAPK) signaling contribute to neuronal inflammation, oxidative stress, and apoptosis, driving neurodegeneration in Alzheimer's disease (AD). These pathways present potential therapeutic targets. This study evaluates the neuroprotective effects of cilostazol (CLZ), a selective phosphodiesterase 3 inhibitor, and its modulation of ER stress and p38MAPK signaling in an AD mouse model induced by AlCl3 (10 mg/kg/day, i.p.) and D-galactose (150 mg/kg/day, i.p.) for 8 weeks. CLZ (30 mg/kg, p.o.), SB203580 (a p38MAPK inhibitor, 1 mg/kg, i.p.), or their combination were administered during the final 4 weeks. Results demonstrated that CLZ, alone or in combination with SB203580, mitigated cognitive decline, preserved hippocampal neurons, reduced Tau phosphorylation, and alleviated histopathological alterations. Mechanistically, CLZ suppressed ER stress by inhibiting both the IRE1α and PERK arms of ER stress. Inhibition of IRE1α inhibited p38MAPK, leading to NF-κB suppression and decreased TNF-α levels, thereby attenuating neuroinflammation. Simultaneously, PERK inhibition downregulated CHOP/GADD153, shifting the Bax/Bcl2 balance to prevent apoptosis. Additionally, CLZ reduced oxidative stress and enhanced survival signaling via p-CREB activation. Notably, combining CLZ with SB203580 further enhanced these neuroprotective effects in an additive manner. These findings underscore CLZ's potential in targeting ER stress and neuroinflammatory pathways in AD, particularly when combined with selective p38MAPK inhibition. This study highlights a promising therapeutic strategy, warranting further investigation to develop effective treatments for AD and other neurodegenerative disorders.