The neonatal brain is different from mature brain anatomically and neurochemically, which can affect how the immature brain responds to both injury and treatment as compared to mature brain. Therefore, to find the most efficacious treatment for early childhood diseases, it is imperative to target age-specific mechanisms and test new therapies in neonatal disease models. Hypoxia-ischemia (HI) is a common cause of neonatal seizures and brain injury. Survivors of HI often experience neurological problems such as epilepsy and intellectual disability in later life. Studies suggest that seizures contribute to brain injury and affect long-term neurologic outcome. First-line drugs such as phenobarbital, which act by augmenting GABA(A) receptors, are poorly effective in treating neonatal seizures and are associated with many side effects. Potassium channels play a uniquely important role in controlling brain excitability in early life. Our recent study showed that unlike diazepam and phenobarbital, flupirtine a potassium channel opener, effectively treated chemoconvulsant- induced neonatal seizures. Flupirtine has been used clinically as an analgesic in Europe for decades with excellent safety record. Flupirtine is neuroprotective in animal models of various degenerative diseases and is currently in clinical trials as a neuroprotective therapy for multiple sclerosis. In the current proposal I hypothesize that flupirtine, with its potential neuroprotective action combined with strong efficacy to stop neonatal seizures, will treat HI-induced neonatal seizures, reduce brain injury and improve the long-term neurologic outcome. Specifically, I propose to: I. Determine whether flupirtine given after first HI-induced seizure will inhibit or reduce further HI-induced acute behavioral and electrographic seizure activity in 7 days old rats, II. Determine whether flupirtine prevents or reduces acute and chronic brain injury and identify the underlying mechanism of neuroprotection, III. Determine if treatment with flupirtine following neonatal HI alleviates behavioral deficits and inhibits epilepsy development in later life. These studies will determine if flupirtine effectively treats HI without adversely affecting development. If successful, these studies should rapidly translate into new effective treatment for neonatal HI.

Public Health Relevance

Hypoxic-ischemic encephalopathy is the single most cause of neonatal seizures and often results in long-term neurological problems. Here we propose to study the efficacy of flupirtine, a potassium channel opener that may be uniquely effective for the treatment of neonatal seizures due to the important role potassium channels play in controlling brain excitability during early-life.

Agency
National Institute of Health (NIH)
Type
Research Project (R01)
Project #
5R01HD065534-04
Application #
8663705
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Ren, Zhaoxia
Project Start
Project End
Budget Start
Budget End
Support Year
4
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Colorado Denver
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Aurora
State
CO
Country
United States
Zip Code
80045
Miller, James A; Kirkley, Kelly A; Padmanabhan, Rachel et al. (2014) Repeated exposure to low doses of kainic acid activates nuclear factor kappa B (NF-?B) prior to seizure in transgenic NF-?B/EGFP reporter mice. Neurotoxicology 44:39-47
Sampath, Dayalan; White, Andrew M; Raol, Yogendra H (2014) Characterization of neonatal seizures in an animal model of hypoxic-ischemic encephalopathy. Epilepsia 55:985-93