Clin Exp Pharmacol Physiol. 2021 Apr 26. doi: 10.1111/1440-1681.13508. Online ahead of print.
ABSTRACT
Epilepsy is a chronic widely prevalent neurologic disorder, affecting brain functions with broad spectrum of deleterious consequences. High-mobility group box1 (HMGB1) is a nuclear non-histone protein that targets vital cell receptor of toll like receptor 4 (TLR4) and advanced glycation end products (RAGE). HMGB1 mediated TLR4/RAGE cascade has been scored as a key culprit in neuro-inflammatory signaling that critically evokes development of impaired cognition and epilepsy. The current study aimed to investigate the neuroprotective effect of pentoxifylline (PTX) on pentylenetetrazol (PTZ)-Kindling rats by its anti-inflammatory/antioxidant capacity besides its impact on memory and cognition were investigated, too. PTZ was intraperitoneally injected 35 mg/kg, every (48) hours, for 14 doses, to evoke kindling model. Phenytoin (30 mg/kg, i.p.) and PTX (60 mg/kg, i.p.) or their combination were given once daily for 27 days. PTX treatment showed a statistically significant effect on behavioral, histopathological and neurochemical analysis. PTX protected the PTZ kindling rats from epileptic seizures and improved memory and cognitive impairment through Morris water maze (MWM) test. Furthermore, PTX reversed PTZ hippocampal neuronal loss by decreasing protein expression of amyloid-β peptide (Aβ), Tau and β site-amyloid precursor protein-cleavage enzyme 1 (BACE1), associated with a marked reduction in expression of inflammatory mediators such as HMGB1, TL4, and RAGE proteins. Furthermore, PTX inhibited hippocampal apoptotic caspase 1 protein, total reactive oxygen species (TROS) along with upregulated erythroid 2-related factor 2 (Nrf2) content. In conclusion, PTX or its combination with phenytoin represent a promising drug to inhibit the epilepsy progression via targeting HMGB1/TLR4/RAGE signaling pathway.
PMID:33899956 | DOI:10.1111/1440-1681.13508
