Abstract
BackgroundEpilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Inflammation is considered to be a critical factor in the pathophysiology of epilepsy. Sinomenine (SN), a bioactive alkaloid with anti-inflammatory effect, exerts neuroprotective activity in many nervous system diseases. However, little is known about the effect of SN on epilepsy.MethodsThe chronic epilepsy model was established by pentylenetetrazole (PTZ) kindling. Morris water maze (MWM) was used to test spatial learning and memory ability. H.E. staining and Hoechst 33258 staining were used to evaluate hippocampal neuronal damage. The expression of nucleotide oligomerization domain (NOD)-like receptor protein 1 (NLRP1) inflammasome complexes and the level of inflammatory cytokines were determined by western blot, quantitative real-time PCR and enzyme-linked immunosorbent assay (ELISA) kits.ResultsSN (20, 40, and 80 mg/kg) dose-dependently disrupts the kindling acquisition process, which decreases the seizure scores and the incidence of fully kindling. SN also increases the latency of seizure and decreases the duration of seizure in fully kindled rats. In addition, different doses of SN block the hippocampal neuronal damage and minimize the impairment of spatial learning and memory in PTZ kindled rats. Finally, PTZ kindling increases the expression of NLRP1 inflammasome complexes and the levels of inflammatory cytokines IL-1β, IL-18, IL-6, and TNF-α, which are all attenuated by SN in a dose- dependent manner.ConclusionsSN exerts anticonvulsant and neuroprotective activity in PTZ kindling model of epilepsy. Disrupting the kindling acquisition, which inhibits NLRP1 inflammasome-mediated inflammatory process, might be involved in its effects.
Highlights
Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs)
Inflammasomes are multi-protein complexes that consist of a cytosolic pattern-recognition receptor (a member of nucleotide oligomerization domain (NOD)-like receptor (NLR) family or HIN domain-containing (PYHIN) family), an adaptor known as apoptosis-associated speck-like protein containing a caspase-activating recruitment domain (ASC) and pro-caspase-1 [15]
Increasing evidence has shown that inflammatory processes within brain may be a crucial mechanism in the pathophysiology of epilepsy and inflammation is considered as a biomarker of epileptogenesis [42, 43]
Summary
Epilepsy is a common neurological disorder and is not well controlled by available antiepileptic drugs (AEDs). Epilepsy is one of the most common neurological disorders characterized by recurrent epileptic seizures and cognitive and behavior impairment [1, 2]. The expression of pro-inflammatory cytokines, such as IL-1β, IL-6, and TNF-α, is increased in brains of epileptic animals [9, 10]. Recent study shows that NLRP1 inflammasome contributes to seizure-induced degenerative process in patients and in the animals with temporal lobe epilepsy (TLE) [27]. These indicate that NLRP1 inflammasome-mediated inflammatory processes might be a critical mediator in the physiopathology of epilepsy
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