Abstracts

Rationale: The current pharmacological treatments for epilepsy target only the resulting epileptiform activity, not the underlying epileptogenesis that triggers the seizures. The neuropeptide galanin displays both anticonvulsant and antiepileptigenic activity upon intraventricular injection into the brain (Mazarati, et al., J. Neurosci. 18: 23, 1998; Mazarati et al, JPET 318: 700, 2006). However, galanin displays low permeability through the blood-brain-barrier (BBB). Here we describe a modified galanin analog, NAX-5055, that exhibits central effects in rodent models of refractory epilepsy and pain when administered systemically.Methods: NAX-5055 is a rationally designed analog of truncated galanin neuropeptide that contains lipoamino acid and basic residues at the C-terminus. NAX-5055 was chemically synthesized and purified via HPLC. NAX-5055 was tested for its ability to block 6 Hz (22, 32, and 44 mA; 3 sec corneal stimulation) limbic seizures 1 hour following i.p. and s.c. administration to CF-1 mice. The antinociceptive effects of NAX-5055 were evaluated in the formalin test in both male CF-1 mice and male Sprague-Dawley rats. For formalin tests, NAX-5055 or vehicle was administered i.p. to animals at the time-to-peak effect (1 hour) before hindlimb plantar injection of 20 µl of 5% (mice) or 50 µl of 2.5% (rats). Animals were observed for flinching behavior using either the Automated Nociception Analyzer (UCSD, Dept of Anesthesiology) or visual recording of the time spent licking the injected paw. The total area under the curve (AUC) and the percent of control AUC were calculated. The ability of NAX-5055 (2 mg/kg, i.p.) to attenuate mechanical allodynia in the rat partial sciatic nerve ligation model was evaluated using the von Frey test (Seltzer et al., Pain. 43: 205, 1990).Results: In the 6 Hz test, NAX-5055 was effective at all three current intensities tested (ED50’s and 95% confidence intervals): <1.0, 0.8 (0.43-1.56), and 2.89 (1.89-4.32)mg/kg for 22, 32, and 44 mA, respectively. NAX-5055 displayed potent antinociceptive activity in the mouse and rat formalin test. At 1.5 mg/kg (mice), and 0.5 mg/kg (rats), it decreased (p < 0.01) the acute phase by 54% and 64%, respectively, and the inflammatory phase by 74% and 64%. NAX-5055 (21 mg/kg) also elevated the paw withdrawal threshold (141