Brain-derived neurotrophic factor prevents the loss of nigral neurons induced by excitotoxic striatal-pallidal lesions.
GABAergic neurons in the rat substantia nigra die after inhibitory inputs to the nigra have been killed, and glutamatergic inputs disinhibited, by striatal-pallidal injections of ibotenic acid. This delayed transneuronal injury model imitates the neuron loss observed in Huntington's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins brain-derived neurotrophic factor and neurotrophin-3 can prevent excitotoxic killing of cultured GABA neurons, we tested whether either factor could protect nigral neurons from transneuronal degeneration. A continuous, three week supranigral infusion of brain-derived neurotrophic factor completely prevented the loss of nigral neurons caused by the ibotenic acid-induced destruction of the caudate-putamen and globus pallidus, and brain-derived neurotrophic factor increased nigral neuron size by 25%. These effects were specific to the TrkB tyrosine kinase receptor that mediates brain-derived neurotrophic factor actions, since supranigral infusions of saline or the TrkC preferring neurotrophin-3, did not prevent nigral neuron loss or induce a hypertrophic response. Neither trophic factor influenced the ibotenic acid destruction of striatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, transneuronal loss, and implicate decreased excitatory amino acid transmission or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor.
Volpe
B T
BT
Department of Neurology and Neuroscience, Cornell University Medical College, White Plains, NY, USA.
Wildmann
J
J
Altar
C A
CA
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002452:Cell Count / Q000187:drug effects; D016923:Cell Death / Q000187:drug effects; D003342:Corpus Striatum / Q000187:drug effects* / Q000473:pathology; D005917:Globus Pallidus / Q000187:drug effects* / Q000473:pathology; D008297:Male; D009498:Neurotoxins / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000187:drug effects* / Q000473:pathology* / Q000503:physiopathology
D019208:Brain-Derived Neurotrophic Factor; D009498:Neurotoxins