Glial cell line-derived neurotrophic factor attenuates the excitotoxin-induced behavioral and neurochemical deficits in a rodent model of Huntington's disease.
The present study determined the effects of intraventricularly administered glial cell line-derived neurotrophic factor on the behavioral and neurochemical sequelae of unilateral excitotoxic lesions of the striatum. Distinct asymmetrical rotational behavior in response to peripheral administration of amphetamine (5 mg/kg) was noted one and two weeks 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 micrograms) 30 min before the toxin, amphetamine-induced rotational behavior was significantly attenuated. Analysis of Nissl-stained coronal sections showed marked neuronal loss in the striatum ipsilateral to the quinolinic acid injections, which was at least partially prevented by glial cell line-derived neurotrophic factor D1 and D2 dopamine binding sites in the striatum, the majority of which are localized to subpopulations of GABAergic neurons, were decreased to a similar extent by quinolinic acid. Moreover, the reduction was attenuated by glial cell line-derived neurotrophic factor treatment to a similar degree, suggesting that the two subpopulations of GABAergic striatal output neurons are equally vulnerable to excitotoxic damage. Concomitant changes in neurotransmitter function as a result of the lesion were also observed: [3H]GABA uptake into striatal target tissues (globus pallidus and substantia nigra) was considerably reduced in the lesioned compared to the contralateral unlesioned tissues, as were [3H]choline and [3H]dopamine uptake into striatal synaptosomes. Similarly, striatal choline acetyltransferase activity was decreased by the lesion. Decrements in neuropeptide levels of similar magnitude were evident ipsilateral to the lesion; substance 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 by intraventricular delivery of glial cell line-derived neurotrophic factor. Continuous intraventricular infusion of this trophic factor (10 micrograms/day) over a two-week period did not afford notable improvement compared to the single injection of 10 micrograms. In contrast, continuous infusion of brain-derived neurotrophic factor (10 micrograms/day) directly into the striatum did not affect any of the neurochemical parameters studied. However, neurotrophin-3 (10 micrograms/day) delivery into the striatum significantly increased [3H]GABA uptake, but only modestly affected [3H]choline uptake. The results indicate that glial cell line-derived neurotrophic factor counteracts neuronal damage induced by a striatal excitotoxic insult and support its potential use as a treatment for central nervous system disorders that may be a consequence of excitotoxic processes, such as Huntington's disease.
Araujo
D M
DM
Amgen Inc., Thousand Oaks, CA 91320, USA.
Hilt
D C
DC
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology*; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D006816:Huntington Disease / Q000378:metabolism* / Q000523:psychology*; D007276:Injections, Intraventricular; D017072:Neostriatum / Q000187:drug effects / Q000201:enzymology / Q000293:injuries; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000494:pharmacology*; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018377:Neurotransmitter Agents / Q000378:metabolism; D017378:Quinolinic Acid / Q000008:administration & dosage / Q000633:toxicity; D051381:Rats; D017208:Rats, Wistar; D017447:Receptors, Dopamine D1 / Q000187:drug effects / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000187:drug effects / Q000378:metabolism; D013239:Stereotyped Behavior / Q000187:drug effects
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D018377:Neurotransmitter Agents; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D002795:Choline O-Acetyltransferase; D017378:Quinolinic Acid