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Introduction
Epilepsy is a common and widespread disease of the central nervous system (CNS) (1); ~5 million individuals are diagnosed annually (2,3), >65 million are affected by epilepsy and epileptic comorbidities worldwide (4), and ~15-30% of patients with epilepsy experience epilepsy-related comorbidities (5). Neuronal injury and neuroinflammation caused by long-term recurrent seizures are characteristics of epilepsy that further result in behavioral disorders (6,7). Anti-epileptic drug (AED) therapy remains the preferred treatment for epilepsy, and although 30 types of AEDs with diverse molecular targets are available, numerous challenges are associated with their use (8), among which AED resistance and side effects are the primary issues (9,10). In addition, ~30% of patients with epilepsy fail to respond to AEDs, and long-term use affects cognitive function and causes psychological impairments (8,11). Therefore, research into novel AEDs with greater effectiveness and fewer side effects is urgently required.
Previous studies have suggested that neuroinflammatory processes play a key role in epileptogenesis. Seizures cause neuroinflammation, which in turn aggravates epilepsy (12,13). The NLRP3 inflammasome results from the assembly of NLR family pyrin domain containing 3 (NLRP3), apoptosis-associated speck-like protein (ASC) and caspase-1 (14), and promotes the secretion of inflammatory cytokines, influencing the pathophysiology of epilepsy (14). Additionally, in animal and clinical epilepsy-related research, increased levels of the NLRP3 inflammasome and neuroinflammatory cytokines have been detected in hippocampal tissues (15,16), suggesting their close association with epileptogenesis. Moreover, numerous studies have reported that inhibiting NLRP3 activation and inflammatory cytokine secretion decreases to occurrence of epileptic seizures and ameliorates cognitive dysfunction (17,18). These findings suggest that inhibition of NLRP3 inflammasome activity and the associated cascade reactions may be a promising approach for adjuvant treatment of epilepsy.
Initially, glucagon like peptide-1 (GLP-1) was widely regarded as a peripheral incretin hormone. Natural GLP-1 has a short half-life and is quickly degraded by proteases, which promotes GLP-1 analogue generation (19). Originally, GLP-1 analogues were used as second-line hypoglycemic drugs, and further research has demonstrated that GLP-1 exerts anti-inflammatory and neuroprotective effects, as well as the ability to ameliorate cognitive dysfunction (20). Numerous studies have also demonstrated that GLP-1 analogues reduce tissue apoptosis by suppressing NLRP3 inflammasome activation and downstream inflammatory cytokine secretion (21,22). In the brain, preproglucagon neurons synthesize GLP-1; subsequently, GLP-1 is distributed in the nucleus...