Abstracts

Rationale: Galanin is an endogenous neuropeptide upregulated and released during seizure activity in hippocampus (Wasterlain et al., Epilepsia, 43: S5, 2002). Galanin also has demonstrated anticonvulsant activity when injected directly into the brain in a rat model of status epilepticus (Mazarati et al., J Neurosci. 18: 23, 1998). A major obstacle in the development of neuropeptides as potential antiepileptic drugs (AED) is their limited central nervous system (CNS) bioavailability. The peptide NAX-5055 is a ‘first-in-class’ galanin analog targeting galanin receptors in both the central and peripheral nervous systems. It is metabolically stable and proof-of-principal studies in acute seizure models demonstrate systemic activity. The goal of the present investigation was to determine the disease modifying potential of systemically administered NAX-5055 in the mouse corneal kindling model.Methods: Male CF-1 mice (~25g) were given an intraperitoneal (i.p.) injection of either NAX-5055 (4mg/kg, n=8) or 0.9% NaCl (n=8) b.i.d. One hour post-injection (time of peak effect), mice were stimulated via corneal electrodes with a subconvulsive current (50 Hz, 3mA, 3 sec). Seizure score was determined based on the Racine scale (Racine, Electroencephalogr Clin Neurophysiol 32:3, 1972). Dosing and stimulations were continued until vehicle treated animals displayed 5 consecutive stage 4/5 seizures (acquisition phase). Following the acquisition phase, mice were given one week treatment- and stimulation-free (washout). After washout, mice were re-challenged with the same stimulation in the absence of peptide and subsequent seizure severities were recorded.Results: The acquisition of kindling did not differ significantly between NAX-5055 treated and vehicle treated mice. However, a close analysis of the data demonstrated that NAX-5055 treated mice segregated into two populations; those that exhibited stage 5 seizures (NAX-5055 unprotected, n=5) and those that did not (NAX-5055 protected, n=3). NAX-5055 protected animals required a significantly greater number of stimulations to induce partial seizure activity (stages 1/2) compared to both vehicle treated and NAX-5055 unprotected animals. Additionally, on re-challenge NAX-5055 protected animals required a significantly greater number of stimulations to reach fully generalized seizure activity (stage 4/5) seizures compared to vehicle-treated mice. Significance was defined as p < 0.05 when compared by one-way ANOVA.Conclusions: The delay of corneal kindling acquisition in a subpopulation of NAX-5055 treated mice (37.5%) support the hypothesis that NAX-5055 may possess disease-modifying properties. Ongoing dose-response studies are evaluating the dose dependency of this protection. Our present findings demonstrate that NAX-5055 penetrates the BBB at an efficacious concentration, supporting the further evaluation of this novel ‘first-in-class’ therapeutic for the treatment of experimental epilepsy. (Epilepsy Foundation of America (GB & HSW) and University of Utah VIP Award (GB & HSW))