title: Minocycline attenuates microglia activation and blocks the long-term epileptogenic effects of early-life seizures.
abstract: Innate immunity mediated by microglia appears to play a crucial role in initiating and propagating seizure-induced inflammatory responses. To address the role of activated microglia in the pathogenesis of childhood epilepsy, we first examined the time course of microglia activation following kainic acid-induced status epilepticus (KA-SE) in Cx3cr1(GFP/+) transgenic mice whose microglia are fluorescently labeled. We then determined whether this seizure-induced microglia activation primes the central immune response to overreact and to increase the susceptibility to a second seizure later in life. We used an inhibitor of microglia activation, minocycline, to block the seizure-induced inflammation to determine whether innate immunity plays a causal role in mediating the long-term epileptogenic effects of early-life seizure. First status epilepticus was induced at postnatal day (P) 25 and a second status at P39. KA-SE at P25 caused nearly a two-fold increase in microglia activation within 24h. Significant seizure-induced activation persisted for 7 days and returned to baseline by 14 days. P39 animals with prior exposure to KA-SE not only responded with greater microglial activation in response to "second hit" of KA, but shorter latency to express seizures. Inhibition of seizure-induced inflammation by 7 day minocycline post-treatment abrogated both the exaggerated microglia activation and the increased susceptibility to the second seizure later in life. The priming effect of early-life seizures is accompanied by modified and rapidly reactivated microglia. Our results suggest that anti-inflammatory therapy after SE may be useful to block the epileptogenic process and mitigate the long-term damaging effects of early-life seizures.
authors.affiliation: Department of Pediatrics, Children's Memorial Hospital, Division of Neurobiology, Children's Memorial Research Center, IL, USA.
authors.forename: Jayne
authors.initials: J
authors.lastname: Abraham
authors.forename: Patrick D
authors.initials: PD
authors.lastname: Fox
authors.forename: Carlo
authors.initials: C
authors.lastname: Condello
authors.forename: Alyssa
authors.initials: A
authors.lastname: Bartolini
authors.forename: Sookyong
authors.initials: S
authors.lastname: Koh
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000187:drug effects* / Q000378:metabolism*; D008911:Minocycline / Q000494:pharmacology / Q000627:therapeutic use*; D009433:Neural Inhibition / Q000187:drug effects* / Q000502:physiology; D012640:Seizures / Q000503:physiopathology* / Q000517:prevention & control*; D013997:Time Factors
chemical_list: D008911:Minocycline