Glial cell line-derived neurotrophic factor attenuates the locomotor hypofunction and striatonigral neurochemical deficits induced by chronic systemic administration of the mitochondrial toxin 3-nitropropionic acid

Abstract The present study investigated whether glial cell line-derived neurotrophic factor prevents the progressive striatal degeneration induced by chronic systemic administration of the mitochondrial toxin, 3-nitropropionic acid. In addition, the effects of delayed treatment with glial cell line-derived neurotrophic factor on toxin-induced behavioural and neurochemical deficits were determined. infused with 3-nitropropionic acid (15 mg/kg/day, for four weeks) via subcutaneous osmotic minipumps was considerably reduced compared to control rats. However, in rats given a single intracerebroventricular injection of 100  μ g of glial cell line-derived neurotrophic factor, locomotor activity was significantly higher than in rats injected with the vehicle, an effect that was most pronounced at the onset of toxin infusion. Consistent with a protective or restorative effect in this model of striatal neurodegeneration, toxin-induced deficits in markers of neurotransmitter function were attenuated by glial cell line-derived neurotrophic factor. Thus, [ 3 H]GABA uptake and [ 3 H]tiagabine/GABA uptake sites in striatal target tissues (globus pallidus and substantia nigra), as well as [ 3 H]choline uptake, choline acetyltransferase activity and dopamine receptor binding in the striatum were decreased by the toxin and restored to varying degrees by glial cell line-derived neurotrophic factor administration. As with locomotor abnormalities, effects on neurochemical deficits were most prominent when glial cell line-derived neurotrophic factor was given at the start of toxin infusion, but remained significantly higher than in the vehicle-injected rats when given up to two weeks after. Substance P, dynorphin A and [Met]enkephalin levels in the striatal target tissues also were reduced by 3-nitropropionic acid. The results show that glial cell line-derived neurotrophic factor protects striatal neurons from slow excitotoxic cell death resulting from energy deprivation, secondary to mitochondrial dysfunction. Moreover, they suggest that glial cell line-derived neurotrophic factor may be a viable therapeutic agent for slowly progressive central nervous system disorders, like Huntington's disease, that may be caused by secondary excitotoxicity resulting from abnormal energy utilization.