Development of a rat pilocarpine model of seizure/status epilepticus that mimics chemical warfare nerve agent exposure

Abstract

We developed a rat pilocarpine seizure/status epilepticus (SE) model, which closely resembles 1.6-2.0 x LD50 soman exposure, to analyse the molecular mechanism of neuronal damage and to screen effective neuroprotectants against cholinergic agonist and chemical warfare nerve agent (CWNA) exposure. Rats implanted with radiotelemetry probes capable of recording electroencephalogram (EEG), electrocardiogram (ECG), temperature, and physical activity were treated with lithium chloride (5 mEq/kg, im), followed 24 h later by (ip) doses of pilocarpine hydrochloride. Based on radiotelemetry analysis, a dose of 240 mg/kg (ip) pilocarpine generated seizure/SE analogous to 1.6-2.0 x LD50 of soman. The model was refined by reducing the peripheral convulsions without affecting the central nervous system (CNS) by administering methylscopolamine bromide (1 mg/kg, ip), an anti-cholinergic that does not cross the blood-brain barrier. However, when methylscopolamine bromide was administered, a higher dose of pilocarpine (320 mg/kg, ip) was required to generate the equivalent seizure/SE. Histopathology data indicated that pilocarpine induces significant damage to the hippocampal region of the brain, with similar neuropathology to that of 1.6-2.0 x LD50 soman exposure. There was a reduction in body temperature after the administration of pilocarpine, as observed in organophosphate (OP) nerve agents exposure. The heart-rate of pilocarpine-treated animals increased compared to the normal range. The pilocarpine seizure/SE model was also reproducible in the absence of lithium chloride. These results support that pilocarpine seizure/SE model is useful in studying the molecular mechanisms of neuropathology and screening neuroprotectants following cholinergic agonist and CWNA exposure.

HSV Recombinant Vectors for Gene Therapy

“…In time, animals begin to display spontaneously recurrent seizures, i.e. they become truly epileptic, again reproducing the situation observed in patients [44, 45]. Paradiso and co-workers demonstrated that recombinant HSV-1-based vectors expressing a combination of two NTFs, fibroblast growth factor-2 (FGF-2) and brain-derived neurotrophic factor (BDNF), increased survival and proliferation of freshly isolated neural progenitors and favoured their differentiation into neurons in vitro .…”

The Limitations of Diazepam as a Treatment for Nerve Agent–Induced Seizures and Neuropathology in Rats: Comparison with UBP302

“…First, the efficacy of DZP decreases as the interval between the initiation of SE and the administration of DZP increases McDonough et al, 2010;Todorovic et al, 2012). This has also been documented in the lithiumpilocarpine model of SE (Walton and Treiman, 1988;Jones et al, 2002;Goodkin et al, 2003), which has many similarities to the nerve agent-induced SE, in both the mechanisms of seizure initiation and the effects it produces (Tetz et al, 2006). The development of resistance to DZP is concerning because, in a terrorist attack with nerve agents, it may not be possible for medical assistance to arrive immediately; thus, when DZP is administered, the seizures may have already become resistant to benzodiazepines.…”

Pilocarpine-Induced Convulsive Activity Is Limited by Multidrug Transporters at the Rodent Blood-Brain Barrier

“…Importantly, the model reflects many features of human TLE in terms of seizure characteristics and histopathological findings (Curia et al, 2008). Furthermore, the pilocarpine model is highly valuable for studying consequences of seizures and SE induced by cholinergic agents in chemical weapons and for developing counteractions (Tetz et al, 2006;de Araujo Furtado et al, 2012). Pilocarpine is also clinically relevant as a topical treatment of glaucoma (Lee and Higginbotham, 2005), and local or systemic treatment of dry mouth (xerostomia; Visvanathan and Nix, 2010).…”