Pilocarpine-Induced Seizures Revisited: What Does the Model Mimic?

Abstract

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.COMMENTARY E xperimental models of seizures and epilepsy have been invaluable for understanding of the basic mechanisms underlying ictogenesis and epileptogenesis as well as for developing new therapeutic options. It is, therefore, of utmost importance to know the pathophysiological basis of the experimental model and which human pathological situations it mimics.One of the earliest and most frequently used models for evoking experimental status epilepticus and subsequent epilepsy is the systemic injection of pilocarpine in rodents (1). Treatment of rats and mice with low doses of lithium chloride (LiCl, 3 mEq/kg), followed by pilocarpine (30 mg/kg) or with a high dose of pilocarpine alone (300-350 mg/kg), results in a severe seizure-brain damage syndrome. The use of LiCl was devised to improve animal survival, because with this combination, the dose of pilocarpine can be decreased by about 10-fold. Since pilocarpine acts on muscarinic receptors (2) and its convulsant actions are evoked in the presence of the peripherally acting muscarinic antagonist, methyl-scopolamine (1), the activation of the cholinergic system by pilocarpine in the brain is believed to be the initiating factor for triggering seizures. Various studies have characterized pilocarpine-induced seizures using both EEG analysis and behavioral observations. Although there is still debate on the initiation site(s) of seizures (i.e., the hippocampus and related limbic regions vs ventral forebrain) and the involvement of brain regions in neuropathology (i.e., the hippocampus as compared to predominant neocortical damage), these initial studies nevertheless garnered a consensus among basic scientists that this model is representative of temporal lobe epilepsy precipitated by convulsive status epilepticus.Recently, novel findings raise the possibility that pilocarpine-induced seizures are not only the result of a d...

Microglia–Neuron Communication in Epilepsy

“…These models are now recognized to mimic salient histopathological and clinical features of human mesial temporal lobe epilepsy (MTLE), the most common form of epilepsy in adults. Kainic acid is a glutamate analog that preferentially activates kainate glutamate receptor subtypes (Ben‐Ari and Cossart, ) while pilocarpine is a muscarinic receptor agonist (Vezzani, ). Various kainic acid models of seizures are employed including intraperitoneal or intracerebral (such as cerebroventricular, striatal, hippocampal, and amygdala) injections.…”

Therapeutic approaches to epileptogenesis—Hope on the horizon

“…Because most of the studies have been conducted in SE models, we also pay attention to the method of induction of SE (electrical stimulation, pilocarpine, kainate), as recent studies suggest that, for example, inflammation could play different role in different preparations (Marchi et al., 2009; Vezzani, 2009). Particular attention is paid to the administration scheme of the treatment relative to the initiation and duration of SE, and on the quantification of SE.…”

“…Finally, data are accumulating indicating that all SE models are not the same. For example, in the pilocarpine model, peripheral inflammation and lymphocyte–endothelial cell adhesion play a role (Marchi et al., 2007; Fabene et al., 2008; Marchi et al., 2009), suggesting that pilocarpine might present an epileptogenic insult whereby SE is associated with systemic inflammation (see also Vezzani, 2009). Whether peripheral inflammation plays a role in other chemically induced SE models or in those triggered by electrical stimulation of the brain remains to be studied.…”

Extracellular ATP differentially affects epileptiform activity via purinergic P2X7 and adenosine A1 receptors in naive and chronic epileptic rats

“…In the present study, we investigated the involvement of ATP‐activated P2 receptors in epileptiform activity in the entorhinal cortex (EC) from naive and from pilocarpine‐treated chronic epileptic rats, a well‐accepted model of temporal lobe epilepsy (Turski et al., 1984; Vezzani, 2009).…”