Rosiglitazone polarizes microglia and protects against pilocarpine‐induced status epilepticus

Abstract

Aims Activated microglia have been found in the forebrains and hippocampi of temporal lobe epilepsy (TLE) patients and status epileptic (SE) animal models. The peroxisome proliferator‐activated receptor γ (PPAR γ) agonist rosiglitazone has been shown to prevent microglial activation. However, its role in pilocarpine‐induced status epilepticus remains unknown. We aimed to examine the effect of the PPAR γ agonist rosiglitazone in protecting against pilocarpine‐induced status epileptic resulting from over‐activation and to explore phenotypic changes in microglia as the underlying mechanism. Methods Male C57BL/6 mice were assigned to three groups: the control group, pilocarpine‐induced (SE) group, and rosiglitazone‐treated (SE+Rosi) group. Status epileptic mice were administered 300 mg/kg pilocarpine via intraperitoneal injection. SE+Rosi mice were administered rosiglitazone (0.1 mg/kg, i.p.) after SE. Flow cytometry, immunofluorescence staining, and quantitative real‐time PCR were used to examine the activation of and phenotypic changes in microglia in the brain and to evaluate neuroinflammation. Results We found that the expression of proinflammatory CD86 and iNOS was increased and that the expression of antiinflammatory CD206 and Arg‐1 was decreased in the brains of pilocarpine‐induced SE mice compared to control mice. The mRNA levels of proinflammatory and antiinflammatory cytokines were not significantly changed in the brain. Rosiglitazone treatment significantly inhibited the proinflammatory polarization of microglia and rescued neuron loss in the temporal lobe and hippocampi of the brain after SE. Conclusion Rosiglitazone reverses microglial polarization in the brains of SE mice and also affords neuroprotection against pilocarpine‐induced status epilepticus without inducing significant changes in brain inflammation.

Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial?

“…The inflammatory response following status epilepticus causes activation of inducible nitric oxide synthase (iNOS) and iNOS-derived nitric oxide (NO) reacts with O 2 - to form the peroxynitrite and contributes the severity of oxidative stress in kainic-acid induced experimental status epilepticus in our previous studies [ 25 , 26 , 27 , 28 ]. Several studies with a various animal model of status epilepticus such as pilocarpine-induced, pentylenetetrazole-induced, diisopropylfluorophosphate, lithium-pilocarpine model, also demonstrated the critical role of NO-related pathway and neuro-inflammation contributing to neuronal damage [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ].…”

Ethyl pyruvate improves white matter remodeling in rats after traumatic brain injury

“…Influencing microglia/macrophage (please add/macrophage here) polarization to the M2 phenotype has been proposed as a possible strategy in the treatment of neurological disorders 27–31 . In this study, we found that the protective effect of EP on WMI may be associated with microglia polarization toward M2 and subsequent increase in the expression of antiinflammatory related molecules and suppression of pro‐inflammatory factors.…”

Deep brain stimulation in the medial septum attenuates temporal lobe epilepsy via entrainment of hippocampal theta rhythm

“…Moreover, we also found that HFS in the MS could exert antiseizure effect in acute seizure models, but could not drive hippocampal theta rhythm, which indicated that the other mechanisms may be involved in antiseizure effect of HFS in the MS. As HFS is generally inhibitory, we hypothesized that the antiseizure effect of HFS at MS might be mediated by the inhibition of pro‐seizure MS glutamatergic neurons 27 . Moreover, apart from the modulation of neural activities, the antiseizure effect of DBS might also be related with the neuroinflammation and microglia polarization, which has been implicated in epilepsy 54,55 . Although electrical stimulation is not cell specific compared with optogenetic intervention, DBS may be easier to have a clinical translation for epilepsy treatment.…”