BRAIN-DERIVED NEUROTROPHIC FACTOR PREVENTS THE LOSS OF NIGRAL NEURONSINDUCED BY EXCITOTOXIC STRIATAL-PALLIDAL LESIONS

GABAergic neurons in the rat substantia nigra die after inhibitory inp uts to the nigra have been killed, and glutamatergic inputs disinhibit ed, by striatal-pallidal injections of ibotenic acid. This delayed tra nsneuronal injury model imitates the neuron loss observed in Huntingto n's disease, and may also imitate neuron loss distant from the primary injury in stroke and Parkinson's disease. Because the neurotrophins b rain-derived neurotrophic factor and neurotrophin-3 can prevent excito toxic killing of cultured GABA neurons, we tested whether either facto r could protect nigral neurons from transneuronal degeneration. A cont inuous, three week supranigral infusion of brain-derived neurotrophic Factor completely prevented the loss of nigral neurons caused by the i botenic acid-induced destruction of the caudate-putamen and globus pal lidus, and brain-derived neurotrophic factor increased nigral neuron s ize by 25%. These effects were specific to the TrkB tyrosine kinase re ceptor 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 st riatal or pallidal neurons. These results demonstrate that exogenously supplied brain-derived neurotrophic factor can prevent delayed, trans neuronal loss, and implicate decreased excitatory amino acid transmiss ion or diminished nigral neuron susceptibility to glutamate inputs in the protective effect of brain-derived neurotrophic factor. (C) 1998 I BRO. Published by Elsevier Science Ltd.