The risk of developing epilepsy is strongly linked to peripheral inflammatory disorders in humans. High-mobility group box protein 1 (HMGB1) has the most focus for being a suspect in this scenario. The current study aimed to detect the celecoxib effect, an anti-inflammatory drug, on decreasing seizure susceptibility and organ damage in lipopolysaccharides (LPS)/pilocarpine (PILO) pretreated Wistar rats. Rats were divided into 6 groups (8 each): group 1 (control), group 2 (PILO), group 3 (PILO+LPS), group 4 (PILO+LPS+(VPA) Valproic acid), group 5 (PILO+LPS+Celecoxib), and group 6 (PILO+LPS+VPA+Celecoxib). LPS was used to induce sepsis and PILO to induce seizures. Oxidative stress markers, pro-inflammatory cytokines, and HMGB1 levels in serum and brain homogenate were evaluated. Histopathological studies were conducted on the hippocampus, liver, lung, and kidney. Treatment with celecoxib either alone or in combination with VPA significantly reduced Racine score and delays latency to generalized tonic-clonic seizures onset with a significant decrease in hippocampal levels of pro-inflammatory cytokines, oxidative stress markers, and increase in reduced glutathione. In addition, celecoxib treatment either alone or in combination with VPA suppressed HMGB1translocation into peripheral circulation more than treatment with VPA alone. Furthermore, hippocampus, liver, lung, and kidney histopathological changes were improved in contrast to other epileptic groups. Celecoxib either alone or combined with VPA has antiepileptic and multiorgan protective effects on acute seizures and inflammatory models induced by PILO with LPS. It decreased histopathological findings, oxidative, and inflammatory effects induced by VPA and LPS. This might be due to its anti-oxidative, anti-inflammatory and anti-HMGB1 mediated effects.
Epileptogenesis is an alteration modification of the typical brain structure, yielding a brain drained by recurring seizures. Such a process is usually precipitated by neurodegeneration, disruption of blood-brain barrier (BBB), the amygdala, the glutamatergic system, oxidative stress, and epigenetic modification deoxyribonucleic acid (DNA). Since there is no efficient method yet, to modify or control this disorder's pathway due to its unclear pathology, novel therapeutic approaches are needed. The risk to develop epilepsy, aggravate the frequency of seizures have been strongly linked to peripheral inflammatory disorders in humans as well as animal studies, with the latter demonstrating a specific association between peripheral inflammatory bowel disorders and peripheral injection of the Toll‐like receptor 4 (TLR4) ligand lipopolysaccharide (LPS) and the increased seizer's frequency and their induced injuries. Understanding the exact function and role of the chemical mediators and receptors involved in the neuroinflammatory reaction could help elucidate their contribution to the pathogenesis of epilepsy. These inflammatory markers include interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha (TNF-α), which are expressed in activated microglia and astrocytes; they trigger the complement system, nuclear factor-kappa b (NF-κB), cyclooxygenase-2 (COX-2), chemokines, and acute-phase proteins. The neural tissues and the endothelial layer of the BBB neurons are involved in these inflammatory reactions. The high-mobility-group Box 1 (HMGB1) fast release from microglia, neurons, and astrocytes after exposure to pro-convulsant insult and Toll-like receptor activation (TLR) signaling in astrocytes and neurons has been proven to be significantly involved in triggering brain inflammation and reducing the seizure threshold. The current review aims to determine the effect of anti-inflammatory drugs on the epilepsy foci rather than treating the symptoms. Such understanding could be the basis of developing a new treatment that could be effective for cases refractory to the current treatment.
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