The Roles of Minocycline, Rapamycin, and Everolimus in Kainic acid-induced Seizure
Date Issued
2015
Date
2015
Author(s)
Lin, Yi-Chin
Abstract
Microglia is responsible for neuroinflammation, which mediates neurodegenerative disorder and brain injury such as epilepsy. When there is brain injury, chronic microglia activation prompts pro-inflammatory factor to lead to neuroinflammatory response. Furthermore, mammalian target of rapamycin (mTOR) kinase is related to microglia activation and subsequent neuroinflammation. In order to clarify the mechanism of neuroinflammation in seizure, in vitro, we use liposaccharide (LPS) model to induce neuroinflammation in BV2 cell line. By real-time PCR and western blotting methods, we can confirm the transcriptional and translational effect of LPS on the neuroinflammation indicators: mTOR, IL-1β, and inducible nitric oxide synthase (iNOS). Minocycline, and two kinds of mTOR inhibitors, rapamycin as well as everolimus are potential to treat seizure. We find all of these three drugs are able to decrease iNOS mRNA level after LPS stimulation, and everolimus downregulates mTOR mRNA level. The three drugs decrease nitrite production after LPS stimulation. The application of kainic acid lead to similar results. Western blot results show that p-ERK is reduced by KA+everolimus, KA+rapamycin, LPS+everolimus, and LPS+minocycline. We suppose that the drugs affect inflammation and neurotoxicity through ERK pathway, and everolimus has better efficacy than rapamycin and minocycline. In vivo, we use 〖B6.129P-Cx3cr1〗^tm1Litt/J transgenic mice whose activated microglia show fluorescence to research the roles of neuroinflammation and microglial activation in seizure. We inject kainic acid (KA) twice to induce seizure on postnatal day 25 (P25) and P31(or P38). During the two KA stimulations, everolimus is applied to investigate its role in anti-inflammatory response. We assume these drugs can block microglia activation following KA injection. We suppose that drugs are able to block the activation of inflammation-related molecules to inhibit the microglia activation and neuroinflammation. Taken together, mTOR as the one of the target of anti-epileptic drug treatment may be a potential pharmacological approach to reduce neuroinflammation.
Subjects
neuroinflammation
microglia activation
kainic acid
everolimus
mTOR
seizure
Type
thesis
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