Abstracts

Rationale: Neuropeptides and their receptors provide novel therapeutic targets that may benefit a substantial number of patients with pharmacoresistant epilepsy. Neuropeptide-Y (NPY) and neurotensin (NT) are involved in controlling neuronal excitability, and direct administration of these neuropeptides into the brain has shown that they possess anticonvulsant activity in rodent seizure models. In previous studies we employed a proprietary combination of cationization and lipidization modifications to produce galanin-based analogs that display increased metabolic stability, penetrate the blood-brain-barrier, and are potently active in the 6 Hz model of refractory epilepsy following systemic administration (Bulaj, et al., J. Med. Chem., 51(24), 2008: 8038-47; White, et al., Neurotherapeutics, 6(2), 2009: 372-80). Here we apply the same chemical modifications to NPY and NT, and evaluated two prototype analogs for antiepileptic activity following systemic administration. Methods: Native NPY and NT peptides, NAX 208-1 and NAX 1007-5 (two modified analogs of NPY and NT, respectively), were evaluated in the 6 Hz psychomotor seizure model (transcorneal electrical stimulation at 6 Hz, 32 mA, 3.0 s). Following intraperitoneal (i.p.) administration in CF-1 mice each compound was evaluated in the 6 Hz test at time-points ranging from 15 min to 4 h and the ED₅₀ value was determined at the time of peak activity. NAX 208-1 was further evaluated in the maximal electroshock (MES) and subcutaneous pentylenetetrazol (scPTZ) tests. Results: Both NAX 208-1 and NAX 1007-5 demonstrated potent activity in the 6 Hz model with peak protection observed at 1 hour following i.p. administration. The ED₅₀ values for NAX 208-1 and NAX 1007-5 were 2.7 mg/kg and 2.9 mg/kg, respectively. The native NPY and NT peptides, when administered i.p., were not active in the 6 Hz seizure test. In contrast to the 6 Hz results, NAX 208-1 was not active in either the MES or scPTZ tests at any of the time-points evaluated at doses of 8 and 4 mg/kg i.p., respectively. Conclusions: These results further demonstrate that NPY and NT play a role in controlling neuronal excitability and we continue to evaluate systemically active analogs of these neuropeptides for the treatment of epilepsy and pain. In addition, these studies provide proof-of-principle that the proprietary modifications previously established with galanin may be broadly amenable to other small peptides for the treatment of neurological conditions. Supported in part by grants from the Epilepsy Therapy Project and the Epilepsy Research Foundation and by NIH grant R21-NS059669. GB and HSW are scientific co-founders of NeuroAdjuvants, Inc.