Peroxisome proliferator‐activated receptor gamma agonist, rosiglitazone, suppresses CD40 expression and attenuates inflammatory responses after lithium pilocarpine‐induced status epilepticus in rats

Abstract

Inflammatory responses in the brain are involved in the etiopathogenesis and sequelae of seizures. Ligation of microglial CD40 plays a role in the development of inflammatory responses in the central nervous system (CNS). Our study showed that there was an increased CD40 expression on activated microglia in the brain injury after lithium pilocarpine-induced status epilepticus (SE) in rats. Since peroxisome proliferator-activated receptor gamma (PPARgamma) acts as a regulator of CNS inflammation and a powerful pharmacological target for counteracting CNS diseases, we investigated the role of the PPARgamma agonist, rosiglitazone, in the modulation of CD40 expression and in the pathological processes of inflammation after SE. We found that rosiglitazone inhibited the expression of CD40, tumor necrosis factor (TNF-alpha), and microglial activation in different regions of hippocampus. The results were indicated by immunohistochemistry, Western blot, and ELISA, respectively. Rosiglitazone also prevented neuronal loss in the CA1 area after SE observed by Nissl-staining. These protective effects were significantly reversed by the co-treatment with T0070907, a selective antagonist of the PPARgamma, which clearly demonstrated a PPARgamma-dependent mechanism. Our data provide evidence that rosiglitazone considerably attenuates inflammatory responses after SE by suppressing CD40 expression and microglial activation. Our data also support the idea that rosiglitazone might be a potential neuroprotective agent in epilepsy.

The PPARγ agonist rosiglitazone prevents cognitive impairment by inhibiting astrocyte activation and oxidative stress following pilocarpine-induced status epilepticus

“…These data suggest a role for oxidative stress and astrocyte activation in cognitive impairment in epilepsy, and are consistent with our previous study demonstrating that the neuroprotective effect of rosiglitazone involved inhibition of microglia-mediated inflammation and oxidative stress in the hippocampus after SE [16,17]. We further extended these data to show that rosiglitazone may be a promising therapeutic agent for the treatment of epilepsy.…”

“…*P \ 0.01 and # P [ 0.05 versus vehicle-treated SE group; P [ 0.05 versus control group (n = 4 per group, ANOVA with Dunnett's post test). Scale bar c 100 lm model of epilepsy, and that the PPARc antagonist T0070907 down-regulated PPARc expression [16,17]. Taken together, these data suggest that the protective action rosiglitazone after SE is mediated via PPARc activation, via a PPARc-dependent mechanism.…”

“…The detailed procedure was performed as previously described [16]. Lithium chloride (127 mg/kg, i.p., Sigma) was injected 24 h prior to the administration of pilocarpine.…”

“…Activation of PPARc can also regulate inflammatory responses and oxidative stress in the CNS [14], and PPARc agonists can ameliorate a variety of inflammatory reactions. For example, troglitazone inhibits both post-glutamate and low-potassium induced neurotoxicity in cerebellar granule neurons [15], while we previously reported that the PPARc agonist rosiglitazone suppressed CD40 expression and microglial activation and attenuated seizure-induced neuronal loss in the hippocampus [16,17]. However, the effects of PPARc on reactive astrocytosis observed in epilepsy are unknown.…”

The Potential of Antiseizure Drugs and Agents that Act on Novel Molecular Targets as Antiepileptogenic Treatments

“…Fenofibrate displayed anticonvulsant effects in the lithium-pilocarpine SE model and against pentylentetrazol-induced seizures [124]. Another PPARγ agonist, rosiglitazone, consistently displayed significant neuroprotective effects and attenuated inflammatory responses after induction of SE [125][126][127]. Importantly, intracerebroventricular rosiglitazone administered prior to the administration of lithium-pilocarpine also decreased the number of spontaneous recurrent seizures in the chronic phase beginning 2 weeks after SE, although it did not affect the severity of SE in the acute phase; some of its protective effects were indirectly mediated by TrkB signaling [128].…”