The neuroprotective effect of eugenol in aluminum chloride-induced Alzheimer's rats: Insights into the role of TLR4/MyD88/NF-kB and NLRP3 inflammasome/gasdermin D signaling pathways.

Neuroinflammation, especially involving NLRP3 inflammasome, has been recognized as a fundamental pathology in Alzheimer's disease (AD). Therefore, inhibiting the NLRP3 inflammasome activity can slow the development of AD. Eugenol, a natural phenolic compound, is known to inhibit or modulate the inflammatory response. Therefore, this study focuses on scrutinizing the potential neuroprotective effect of eugenol via the NLRP3 signaling pathway in aluminum chloride (AlCl3) elicited AD rats. Rats were split into four groups: olive oil, eugenol (50 mg/kg), AlCl3 (100 mg/kg), and eugenol + AlCl3, where rats received eugenol orally 2 weeks before and concurrently with oral induction by AlCl3 for 12 weeks. Behavioral, histopathological, and biochemical analyses were performed. Significant behavioral dysfunction, aluminum accumulation and pronounced neuronal damage were observed in AD rats. These were associated with increased hippocampal nitric oxide (NO), malondialdehyde (MDA) and amyloid beta protein 1-42 (Aβ 1-42) along with diminished serum total antioxidant capacity (TAC) levels. In addition, activation of NLRP3 inflammasome pathway components concomitant with upregulation of the pyroptotic marker; gasdermin D (GSDMD) was observed. Nevertheless, eugenol administration significantly improved rats' behavioral and histological aberrations, reduced NO, MDA, aluminum, and elevated TAC levels. Eugenol modulated toll like receptor 4 (TLR4)/myeloid differentiation primary response gene 88 (Myd88)/nuclear factor kappa B (NF-kB) signal transduction pathway, leading to inhibition of NLRP3 inflammasome pathway, inflammatory cytokines as interleukin 18 (IL-18) and interleukin 1 beta (IL-1β) as well as GSDMD. Eugenol may exert neuroprotective effects against AlCl3-induced neurodegeneration by modulating NLRP3 inflammasome, pyroptosis, and TLR4/MyD88/NF-kB signaling pathways.