INTRAPARENCHYMAL NGF INJECTIONS IN ADULT AND AGED RATS INDUCE LONG-LASTING TRK TYROSINE PHOSPHORYLATION

Neurotrophic factors, particularly the neurotrophins nerve growth fact or (NGF) and brain-derived neurotrophic factor (BDNF) and related mole cules are proposed for the experimental treatment of neurodegenerative disease. Earlier observations had suggested down-regulation of the ne urotrophin receptor response with chronic stimulation. We therefore te sted for effects of acute and chronic NGF treatment in vivo on the tyr osine phosphorylation response of Trk-type neurotrophin receptors in a dult and aged rats, Rats were treated for 1 week with daily injections of NGF directly into the striatum. Surprisingly, this chronic neurotr ophin treatment induced long-lasting tyrosine phosphorylation of Trk t ype receptors beyond the last injection, A similar result was obtained with 1 week of daily injections of BDNF into the hippocampus. Persist ent Trk tyrosine phosphorylation was also observed after single neurot rophin injections. With 1 mu g of NGF injected, Trk-type receptors wer e maximally stimulated from immediately after the injection until 3 da ys after the treatment, Maintaining Trk tyrosine phosphorylation requi red maintained energy levels in the tissue. Incubation of microslices of brain tissue from NGF-injected animals in glucose-free buffer compl etely abolished all Trk tyrosine phosphorylation signals. Recovery of the tissue in presence of glucose restored the signals in microslices derived from NGF-injected animals, in absence of acute NGF treatment. This result, together with dose-response comparisons after 2-h and 2-d ay survival times suggest that Trk protein remains tyrosine phosphoryl ated due to trophic protein which is only slowly being cleared out of the tissue during several days after the injection, Experiments with a ged rats indicated similar extent and duration of Trk receptor activat ion after NGF administration in young adult and in aged brain. (C) 199 6 Academic Press, Inc.