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 Cx3cr1GFP/+ 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 twofold increase in microglia activation within 24 hours. 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.

Infiltrating Macrophages Are Key to the Development of Seizures following Virus Infection

“…Furthermore, administration of minocycline to TMEV-infected mice resulted in significantly fewer mice having seizures (16,39). However, these studies did not determine the effect of minocycline on peripheral macrophages (16,39,49). In our study, minocycline administered to TMEV-infected mice significantly reduced the number of macrophages infiltrating the brains by approximately 2-fold (Fig.…”

“…The inhibition of seizures with anti-inflammatory compounds has provided indirect experimental evidence that inflammation is important in the induction of seizures (49)(50)(51). For example, administration of minocycline prior to kainic acid (KA)-induced status epilepticus significantly decreased the number of activated microglia in the hippocampus (49).…”

“…For example, administration of minocycline prior to kainic acid (KA)-induced status epilepticus significantly decreased the number of activated microglia in the hippocampus (49). Furthermore, administration of minocycline to TMEV-infected mice resulted in significantly fewer mice having seizures (16,39).…”

Progress report on new antiepileptic drugs: A summary of the Twelfth Eilat Conference (EILAT XII)

“…Hopefully, the favourable profile of imepitoin for treatment of epilepsy in dogs will reactivate the interest in partial BZD site agonists as novel treatments for human epilepsy, too. (Abraham et al, 2012). Minocycline has also been shown to inhibit KA-SE-induced cell death via attenuation of pro-inflammatory cytokine through caspase-dependent and caspase-independent pathways (Heo et al, 2006).…”

Investigational new drugs for focal epilepsy

“…[4] Minocycline is a tetracycline-class antibiotic which is known to inhibit microglial activation and proinflammatory cytokine release in animal models and experimental data show that these immune processes may play a role in epileptogenesis. [14] In fact, preclinical studies have shown dose-dependent effects in abolishing focal seizures in the 6-Hz seizure test and in reducing after discharge duration in amygdala kindled rats. [4] At the moment, there is a Phase I dose escalation study to explore safety and efficacy in moderate and severe traumatic brain injury in humans and other studies in amyotrophic lateral sclerosis and schizophrenia.…”