Inhibitors of GABA transaminase and NKCC1 as an anticonvulsant
Inventors: Frances Jensen
Invention Types: Therapeutics
Research Areas: Neonatology/Pediatric, Neurology/Neuroscience
Keywords: PediatricFor More Information Contact: Ives, Catherine L.
This invention is the use of combination therapies: an inhibitor of gamma-amino butyric acid (GABA) transaminase as an anticonvulsant and an inhibitor of Na-K-Cl cotransporter (NKCC1). Vigabatrin (VGB) is a known anticonvulsant that acts as an irreversible inhibitor of GABA transaminase, the enzyme responsible for the catabolism of the inhibitory neurotransmitter GABA. The resultant increase in brain GABA levels is thought to be the mechanism of its anticonvulsant actions in infantile spasms and for refractory seizures.
However, VGB is associated with well-documented retinal toxicity resulting in peripheral visual field deficits and also animal models that suggest intramyelinic edema in white matter areas. In 1998 the FDA issued a ''not approvable action'' on VGB because of its high incidence (30%) of permanent vision loss.
Dr. Jensen discovered that inhibitors of NKCC1 (such as bumetanide), when coadministered with inhibitors of GABA transaminase (such as VGB) attenuate the retinal toxicity and/or the intramyelinic edema, and thereby expand the indications for VGB.
Combination treatment for:
• Neonatal seizures
• Infantile spasms
• Refractory adult seizures
• Allows for the use of VGB without the associated side effects
• Attenuates the adverse effects of VGB on the retina and on brain tissue
Key Publications: Dzhala VI, et al. NKCC1 transporter facilitates seizures in the developing brain. Nat Med. 2005 Nov;11(11):1205-13.