THERAPEUTIC NEUROPROTECTIVE TRIALS OF TIAGABINE IN HD MOUSE MODELS Abstract Huntington's disease (HD) is a progressive and aways fatal inherited neurodegenerative disorders. There is no currently avaliable treatment which can delay the onset or slow down the progression of HD. Our long term goal is to develop effective compounds in HD models to lead further to clinical trials in human HD patients. We have done screening of NINDS library of 1040 mostly FDA-approved compounds in an inducible huntingtin expressing PC12 cell model, a compound nipecotic acid, dose-dependetly protected cell against htt toxicity and decreased inclusion formation, without changing htt expression. Since nipecotic acid can not cross the brain barrier, its lipophilic derivatives tiagabine has similar effect in our HD cell model. We now propose to conduct preclinical trials in two HD mouse models. In secific Aim 1, we will determine the dose response of tiagabine on onset and progression of disease in the fragment HD mouse model N171-82Q (line 81) mice. We will use motor behavioral function, body weight, survival, and brain pathology as our outcome measures.
In Specific Aim 2, we will investigate the effect of tiagabine on motor behavioral function and brain pathology in the full-length mutant huntingtin YAC128 mice. Tiagabine will be chronically administered to mice. Motor behavioral performance will be tested using rotarod apparatus. Brain pathology will be examined using Immunohistochemistry and Nissl staining. Since tiagabine is a FDA approved drug, the significance of proposed study is that if this compound has consistent protection in different mouse models, it might lead to therapeutic trials in human and a potential therapy for HD. THERAPEUTIC NEUROPROTECTIVE TRIALS OF TIAGABINE IN HD MOUSE MODELS Narrative: Huntington's disease (HD) is a progressive and aways fatal inherited neurodegenerative disorders. There is no currently avaliable treatment which can delay the onset or slow down the progression of HD. We propse to test a compound named Tiagabine, which was initially developed from our compound screening hit in HD cell model. The significance of proposed study is that if this compound has consistent protection in different mouse models, it might lead to therapeutic trials in human and a potential therapy for HD. ? ? ?
| Masuda, Naoki; Peng, Qi; Li, Qing et al. (2008) Tiagabine is neuroprotective in the N171-82Q and R6/2 mouse models of Huntington's disease. Neurobiol Dis 30:293-302 |
| Peng, Qi; Masuda, Naoki; Jiang, Mali et al. (2008) The antidepressant sertraline improves the phenotype, promotes neurogenesis and increases BDNF levels in the R6/2 Huntington's disease mouse model. Exp Neurol 210:154-63 |
