Application of FDA-Approved Memantine and Newer NitroMemantine Derivatives to Treat Neurological Manifestations in Rodent Models of Tuberous Sclerosis Complex.

摘要

The quality of life for those afflicted by Tuberous Sclerosis Complex (TSC) is affected by intellectual and neurological disabilities mediated in part by excessive glutamatergic activity in the brain. It is important to develop rational and effective therapies for early postnatal or even embryonic treatment of these neurological manifestations. Towards this goal, we propose to investigate if administration of the FDA-approved drug, Memantine, an uncompetitive/fast off-rate antagonist of the Nmethyl-D-aspartate-type glutamate receptor, and its improved derivative, NitroMemantine, ameliorate neurological complications in mouse models of TSC. During Year 01 of the grant, we obtained favorable results for Memantine on electrophysiological and neurobehavioral tests in Tsc2+/- mice. Treatment of Tsc2+/- mice with Memantine improved long-term potentiation (LTP), an electrical correlate of learning and memory, in the CA1 region of the hippocampus. Additionally, treatment of Tsc2+/- mice with Memantine showed a trend towards restoration of the ability to locate the platform in the Morris water maze, a neurobehavioral test of hippocampal memory. In Year 02, we further validated and extended our findings with Memantine and critically tested the efficacy of NitroMemantine. We expected that NitroMemantine will offer an advantage over Memantine in TSC model mice, as we have previously demonstrated in other neurological disorders.