Neuroprotective mechanism of hydrogen sulfide in okadaic acid-induced alzheimer-like pathology.

Abstract

Okadaic acid (OKA) is a marine biotoxin that accumulates in shellfish and is responsible for causing diarrheic shellfish poisoning. OKA is a powerful and selective inhibitor of serine/threonine phosphatases 1 and 2A, which induces hyperphosphorylation of tau in vitro and in vivo leading to Alzheimer's disease (AD)-like pathology and memory impairment. Hydrogen sulfide (H2S), a gaseous signaling molecule produced endogenously in the brain, has been demonstrated to possess neuroprotective properties in various models of neurodegeneration. The aim of this study was to investigate the potential of H₂S in reducing OKA-induced Alzheimer's disease (AD)-like pathology, focusing on its effects on the GSK3β/Tau and CaMKII/CREB signaling pathways in mice. To test this hypothesis, we used age 8-10 weeks-old male C57BL/6J wild-type mice, divided into the following experimental groups: 1. Control group: Received a single intracerebroventricular (ICV) injection of artificial cerebrospinal fluid (aCSF). 2. WT + OKA group: Received a single ICV injection of OKA (100 ng/5 µl) bilaterally to induce AD-like pathology. OKA was dissolved in artificial cerebrospinal fluid. 3. WT + OKA + GYY4137 group: Received a single ICV injection of OKA (100 ng/5 µl) bilaterally, followed by GYY4137 (30 µM/kg) via drinking water for 21 days. 4. WT + GYY4137 group: Received only GYY4137 per se (30 µM/kg) via drinking water for 21 days. After the treatment period, synaptic proteins and neurodegeneration were evaluated using Western blotting, RT-PCR, and immunohistochemistry techniques. Our results demonstrate that OKA administration results in memory impairment with decreased cerebral blood flow (CBF). OKA also caused a significant decrease in synapse proteins (PSD95, MAP-2, BDNF, CaMKIIα, and Tubulin-3β) levels, along with increased expression of Tau, PHF-1, and GSK-3β and memory-associated signaling molecules and pCREB. Interestingly, IP administration of GYY4137 (30 µM/Kg; an H2S donor) for 21 days significantly improved the level of synapse proteins and memory function in OKA-treated mice. The findings of this study determine the neuroprotective mechanism of H2S in OKA-induced AD-like pathology through the modulation of Tau, GSK3β, and pCREB signaling. Therefore, H2S ameliorates OKA-induced memory impairment by improving synapse function and forgetfulness. As a result, H2S could be used as a promising therapeutic molecule against Alzheimer's disease-like pathology.