title: Everolimus is better than rapamycin in attenuating neuroinflammation in kainic acid-induced seizures.
abstract: Microglia is responsible for neuroinflammation, which may aggravate brain injury in diseases like epilepsy. Mammalian target of rapamycin (mTOR) kinase is related to microglial activation with subsequent neuroinflammation. In the present study, rapamycin and everolimus, both as mTOR inhibitors, were investigated in models of kainic acid (KA)-induced seizure and lipopolysaccharide (LPS)-induced neuroinflammation.
  
  
  
  In vitro, we treated BV2 cells with KA and LPS. In vivo, KA was used to induce seizures on postnatal day 25 in B6.129P-Cx3cr1tm1Litt/J mice. Rapamycin and everolimus were evaluated in their modulation of neuroinflammation detected by real-time PCR, Western blotting, and immunostaining.
  
  
  
  Everolimus was significantly more effective than rapamycin in inhibiting iNOS and mTOR signaling pathways in both models of neuroinflammation (LPS) and seizure (KA). Everolimus significantly attenuated the mRNA expression of iNOS by LPS and nitrite production by KA and LPS than that by rapamycin. Only everolimus attenuated the mRNA expression of mTOR by LPS and KA treatment. In the present study, we also found that the modulation of mTOR under LPS and KA treatment was not mediated by Akt pathway but was primarily mediated by ERK phosphorylation, which was more significantly attenuated by everolimus. This inhibition of ERK phosphorylation and microglial activation in the hippocampus by everolimus was also confirmed in KA-treated mice.
  
  
  
  Rapamycin and everolimus can block the activation of inflammation-related molecules and attenuated the microglial activation. Everolimus had better efficacy than rapamycin, possibly mediated by the inhibition of ERK phosphorylation. Taken together, mTOR inhibitor can be a potential pharmacological target of anti-inflammation and seizure treatment.
authors.affiliation: Department of Pediatrics, Far Eastern Memorial Hospital, New Taipei City, Taiwan.|Department of Chemical Engineering and Materials Science, Yuan Ze University, Taoyuan, Taiwan.
authors.forename: Ming-Tao
authors.initials: MT
authors.lastname: Yang
authors.affiliation: Department of Pediatric Neurology, National Taiwan University Children's Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan.|Graduate Institute of Brain and Mind Science, National Taiwan University, Taipei, Taiwan.
authors.forename: Yi-Chin
authors.initials: YC
authors.lastname: Lin
authors.affiliation: Department of Pediatric Neurology, National Taiwan University Children's Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan.
authors.forename: Whae-Hong
authors.initials: WH
authors.lastname: Ho
authors.affiliation: Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan.|College of Engineering, Chang Gung University, Taoyuan, Taiwan.
authors.forename: Chao-Lin
authors.initials: CL
authors.lastname: Liu
authors.affiliation: Department of Pediatric Neurology, National Taiwan University Children's Hospital, No. 7 Chung-Shan South Road, Taipei, 100, Taiwan. leeped@hotmail.com.|Graduate Institute of Brain and Mind Science, National Taiwan University, Taipei, Taiwan. leeped@hotmail.com.
authors.forename: Wang-Tso
authors.initials: WT
authors.lastname: Lee
mesh_terms: D000818:Animals; D003292:Convulsants / Q000633:toxicity; D000068338:Everolimus / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology*; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D017628:Microglia / Q000187:drug effects; D012640:Seizures / Q000139:chemically induced / Q000473:pathology*; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors*
chemical_list: D003292:Convulsants; D007166:Immunosuppressive Agents; D000068338:Everolimus; D058570:TOR Serine-Threonine Kinases; D007608:Kainic Acid; D020123:Sirolimus
keywords: ERK; Epilepsy; Everolimus; Kainic acid; Neuroinflammation; Rapamycin; mTOR