Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation

Neurotrophic factors, particularly the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and related molecules are proposed for the experimental treatment of neurodegenerative disease. Earlier observations had suggested down-regulation of the neurotrophin receptor response with chronic stimulation. We therefore tested for effects of acute and chronic NGF treatment in vivo on the tyrosine phosphorylation response of Trk-type neurotrophin receptors in adult and aged rats, Rats were treated for 1 week with daily injections of NGF directly into the striatum. Surprisingly, this chronic neurotrophin treatment induced long-lasting tyrosine phosphorylation of Trk type receptors beyond the last injection, A similar result was obtained with 1 week of daily injections of BDNF into the hippocampus. Persistent Trk tyrosine phosphorylation was also observed after single neurotrophin injections. With 1 mu g of NGF injected, Trk-type receptors were maximally stimulated from immediately after the injection until 3 days after the treatment, Maintaining Trk tyrosine phosphorylation required maintained energy levels in the tissue. Incubation of microslices of brain tissue from NGF-injected animals in glucose-free buffer completely 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-day survival times suggest that Trk protein remains tyrosine phosphorylated due to trophic protein which is only slowly being cleared out of the tissue during several days after the injection, Experiments with aged rats indicated similar extent and duration of Trk receptor activation after NGF administration in young adult and in aged brain. (C) 1996 Academic Press, Inc.