Antagonism of peripheral inflammation reduces the severity of status epilepticus

Abstract

Status epilepticus (SE) is one of the most serious manifestations of epilepsy. Systemic inflammation and damage of blood-brain barrier (BBB) are etiologic cofactors in the pathogenesis of pilocarpine SE while acute osmotic disruption of the BBB is sufficient to elicit seizures. Whether an inflammatory-vascular-BBB mechanism could apply to the lithium–pilocarpine model is unknown. LiCl facilitated seizures induced by low-dose pilocarpine by activation of circulating T-lymphocytes and mononuclear cells. Serum IL-1β levels increased and BBB damage occurred concurrently to increased theta EEG activity. These events occurred prior to SE induced by cholinergic exposure. SE was elicited by lithium and pilocarpine irrespective of their sequence of administration supporting a common pathogenetic mechanism. Since IL-1β is an etiologic trigger for BBB breakdown and its serum elevation occurs before onset of SE early after LiCl and pilocarpine injections, we tested the hypothesis that intravenous administration of IL-1 receptor antagonists (IL-1ra) may prevent pilocarpine-induced seizures. Animals pre-treated with IL-1ra exhibited significant reduction of SE onset and of BBB damage. Our data support the concept of targeting systemic inflammation and BBB for the prevention of status epilepticus.

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

“…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).…”

Interleukin-1β Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice

“…The last drug administration was followed by a 3-day wash-out period during which EEG was recorded daily from 9:00 am to 11:00 am; the time required by each epileptic mouse to recover its pre-injection baseline activity after drug withdrawal (after day 4 of treatment, i.e., the eighth drug administration) was used to estimate the duration of VX-765 anticonvulsant action. At the end of the pharmacological experiments with 50 mg/kg VX-765 (including the 3 day wash-out period), the epileptic mice (Table 1, numbers [10][11][12][13][14][15] were recorded continuously between 9:00AM and 5:00PM for , and on the following day, the epileptic mice received VX-765 twice a day (at 9:00AM and 4:00PM) for 4 consecutive days, and the EEG recording was done for 2 h after each drug administration. The last drug administration was followed by a 3-day wash-out period, and each day EEG was recorded (at 9:00AM to 11:00AM) to evaluate the time required by each epileptic mouse to recover its pre-injection baseline activity after drug withdrawal.…”

“…Paracrine and autocrine activation of this signaling by the brain application of IL-1β exacerbates kainic acid-or bicuculline-induced seizures in rats and mice [5,11,13], and lowers the seizure threshold in febrile seizure models [7,8]. Conversely, IL-1 receptor antagonist (the naturally occurring competitive antagonist of IL-1R1) mediates powerful anticonvulsant effects in rodents [6,[13][14][15] and mice over-expressing IL-1 receptor antagonist in astrocytes, or lacking IL-1R1, are intrinsically less susceptible to seizures [7,13]. These data indicate the important involvement of elevated brain IL-1β levels and the activation of IL-1R1 signaling in experimental seizures.…”

The Blood-Brain Barrier and Epilepsy

“…Experimental evidence also supports a role of intravascular inflammation, often associated with BBB damage, in seizure disorders (Marchi et al, 2007a;Marchi et al, 2009;Seiffert et al, 2004;van Vliet et al, 2007). Recently, the association between circulating immune cells, their interaction with the BBB, and seizure propensity was proposed; leukocyte adhesion was shown to directly support ictogenesis in the pilocarpine model of seizures (Fabene et al, 2008).…”