The proposed research is designed to develop an effective treatment for Huntington's disease. The study will test the potential of GM1 gangliosides as a treatment for both the short and long-term behavioral and anatomical effects caused by intrastriatal administration of quinolinic acid, an animal model of Huntington's disease.
The specific aims will be to test whether or not pretreatment of GM1 can attenuate quinolinic acid-induced, 1) spatial learning deficits, 2) episodic barrel rolling behavior and tonic-clonic forepaw movements, 3) hyperactivity, 4) weight loss, 5) striatal atrophy, 6) ventricular dilatation, 7) gliosis, 8) neuronal death and 9) specific loss of GABA containing neurons. Two groups of rats will be given bilateral intrastriatal injections of quinolinic acid while a third group will receive injections of vehicle. Daily intraperitoneal treatments of either GM1 gangliosides or saline will be started three days prior to surgery and continued through post-operative day 14. Barrel rolling and tonic-clonic forepaw movements will be recorded during the six hours following surgery. Morris water maze testing will be conducted during post-operative days 6 to 14 for half the rats in each group, and post-operative days 62 to 70 for the other half of each group. Nocturnal locomotor activity will be assessed for a 12 hour period the day before surgery and on post-operative days five for all rats, on post-operative day fourteen for half the rats in each group and post-operative day 70 for the other half of each group. Following testing, the brain will be cut in ten micron sections and processed using cresyl violet and GABA immunocytochemistry. Area measures for gliosis, ventricular dilation and striatal atrophy, along with cell counts in the striatum, will be conducted in order to evaluate whether or not GM1 can protect against quinolinic acid-induced neuronal death and other anatomical alterations. Collectively, the behavioral and neuroanatomical results are intended to provide valuable information concerning the potential of GM1 as treatment for Huntington's disease.
|Shear, D A; Haik, K L; Dunbar, G L (2000) Creatine reduces 3-nitropropionic-acid-induced cognitive and motor abnormalities in rats. Neuroreport 11:1833-7|
|Haik, K L; Shear, D A; Schroeder, U et al. (2000) Quinolinic acid released from polymeric brain implants causes behavioral and neuroanatomical alterations in a rodent model of Huntington's disease. Exp Neurol 163:430-9|
|Shear, D A; Dong, J; Haik-Creguer, K L et al. (1998) Chronic administration of quinolinic acid in the rat striatum causes spatial learning deficits in a radial arm water maze task. Exp Neurol 150:305-11|
|Haik-Creguer, K L; Dunbar, G L; Sabel, B A et al. (1998) Small drug sample fabrication of controlled release polymers using the microextrusion method. J Neurosci Methods 80:37-40|
|Shear, D A; Dong, J; Gundy, C D et al. (1998) Comparison of intrastriatal injections of quinolinic acid and 3-nitropropionic acid for use in animal models of Huntington's disease. Prog Neuropsychopharmacol Biol Psychiatry 22:1217-40|