GLIAL-CELL LINE-DERIVED NEUROTROPHIC FACTOR ATTENUATES THE EXCITOTOXIN-INDUCED BEHAVIORAL AND NEUROCHEMICAL DEFICITS IN A RODENT MODEL OF HUNTINGTONS-DISEASE

The present study determined the effects of intraventricularly adminis tered glial cell line-derived neurotrophic factor on the behavioral an d neurochemical sequelae of unilateral excitotoxic lesions of the stri atum. Distinct asymmetrical relational behavior in response to periphe ral administration of amphetamine (5 mg/kg) was noted one and two week s following injections of quinolinic acid (200 nmol) into two sites in the left striatum. In rats given a single intraventricular injection of glial cell line-derived neurotrophic factor (10-1000 mu g) 30 min b efore the toxin, amphetamine-induced rotational behavior was significa ntly attenuated. Analysis of Nissl-stained coronal sections showed mar ked neuronal loss in the striatum ipsilateral to the quinolinic acid i njections, which was al least partially prevented by glial cell line-d erived neurotrophic factor. D-1 and D-2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GAB Aergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neu rotrophic factor treatment to a similar degree, suggesting that the tw o subpopulations of GABAergic striatal output neurons are equally vuln erable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [H-3]GABA uptak e into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [H-3]choline and [H-3]dopamine uptake int o striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide leve ls of similar magnitude were evident ipsilateral to the lesion; substa nce P, met-enkephalin and dynorphin A contents in the globus pallidus and substantia nigra were significantly reduced. Striatal somatostatin and neuropeptide Y levels were not altered. All of the neurochemical deficits induced by striatal quinolinic acid lesions were attenuated b y intraventicular delivery of glial cell line-derived neurotrophic fac tor. Continuous intraventricular infusion of this trophic factor (10 m u g/day) over a two-week period did not afford notable improvement com pared to the single injection of 10 mu g. In contrast, continuous infu sion of brain-derived neurotrophic factor (10 mu g/day) directly into the striatum did not affect any of the neurochemical parameters studie d. However, neurotrophin-3 (10 mu g/day) delivery into the striatum si gnificantly increased [H-3]GABA uptake, but only modestly affected [H- 3]choline uptake. The results indicate that glial cell line-derived ne urotrophic factor counteracts neuronal damage induced by a striatal ex citotoxic insult and support its potential use as a treatment for cent ral nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease. (C) 1997 IBRO. Published by E lsevier Science Ltd.