Elucidation of the neuroprotective mechanisms of gallic acid on pyroptosis mediated by ROS/TXNIP/NLRP3 signaling in neuroinflammation

In this thesis, the potential effects of gallic acid (GA) on the nervous system were investigated in an experimental neuroinflammation model induced by lipopolysaccharide (LPS). Neuroinflammation is a critical process characterized by an enhanced inflammatory response within the central nervous system. GA is a phenolic compound known for its strong antioxidant and anti-inflammatory properties. In this study, the effects of GA against an acute neuroinflammation model were comprehensively evaluated at histopathological, biochemical, immunohistochemical, and gene expression levels. A total of 32 male Wistar Albino rats were randomly divided into four groups of eight animals each: Control, LPS (5 mg/kg, single intraperitoneal dose), GA (100 mg/kg, single intraperitoneal dose), and LPS+GA. All animals were sacrificed six hours after LPS administration. Brain tissues were collected for histopathological and immunohistochemical examinations (tumor necrosis factor-alpha [TNF-α], caspase-3 [Cas-3], glial fibrillary acidic protein [GFAP]), biochemical analyses (total oxidant status [TOS], total antioxidant status [TAS], oxidative stress index [OSI]), and gene expression studies (thioredoxin-interacting protein [TXNIP], nucleotide-binding oligomerization domain-like receptor protein 3 [NLRP3], caspase-1 [Cas-1], interleukin-1 beta [IL-1β], interleukin-18 [IL-18], B-cell lymphoma 2 [BCL-2], and BCL-2-associated X protein [BAX]). Histopathological evaluations demonstrated that GA attenuated LPS-induced damage in the cortex, hippocampus, and cerebellum. Immunohistochemically, levels of Cas-3, TNF-α, and GFAP were significantly reduced compared to the injury group. Biochemically, GA decreased TOS levels, increased TAS levels, and thereby balanced OSI. On the molecular level, GA inhibited the TXNIP/NLRP3 pathway, leading to reduced expression of Cas-1, IL-1β, and IL-18, while regulating apoptosis through modulation of the BAX/BCL-2 ratio. All findings indicate that GA exerts potent neuroprotective effects in the LPS-induced neuroinflammation model. These results suggest that GA may protect the central nervous system by targeting key mechanisms involved in neuroinflammation such as oxidative stress, inflammation, and cell death, thus providing a foundation for future advanced preclinical studies.