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.
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. Locomotor activity in rats 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 micrograms 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, [3H]GABA uptake and [3H]tiagabine/GABA uptake sites in striatal target tissues (globus pallidus and substantia nigra), as well as [3H]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.
Araujo
D M
DM
Department of Clinical Development, Amgen Inc., Thousand Oaks, CA 91320, USA. DArcatz@aol.com
Hilt
D C
DC
D000818:Animals; D001345:Autoradiography; D002795:Choline O-Acetyltransferase / Q000378:metabolism; D005260:Female; D051100:Glial Cell Line-Derived Neurotrophic Factor; D007276:Injections, Intraventricular; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D009043:Motor Activity / Q000187:drug effects*; D017072:Neostriatum / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D009479:Neuropeptides / Q000494:pharmacology; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000494:pharmacology*; D009498:Neurotoxins / Q000633:toxicity*; D009557:Nipecotic Acids / Q000378:metabolism; D009574:Nitro Compounds; D011422:Propionates / 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; D018079:Receptors, GABA / Q000187:drug effects / Q000378:metabolism; D013378:Substantia Nigra / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D000078308:Tiagabine
C495041:Gdnf protein, rat; D051100:Glial Cell Line-Derived Neurotrophic Factor; D009414:Nerve Growth Factors; D009419:Nerve Tissue Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D009557:Nipecotic Acids; D009574:Nitro Compounds; D011422:Propionates; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D018079:Receptors, GABA; D002795:Choline O-Acetyltransferase; C015392:3-nitropropionic acid; D000078308:Tiagabine