Injured neurons become dependent on trophic factors for survival. However, application of trophic factors to the site of injury is technically extremely challenging. Novel approaches are needed to circumvent this problem. Here, we unravel the mechanism of the emergence of dependency of injured neurons on brain-derived neurotrophic factor (BDNF) for survival. Based on this mechanism, we propose the use of the diuretic bumetanide to prevent the requirement for BDNF and consequent neuronal death in the injured areas. Responses to the neurotransmitter GABA change fromhyperpolarizing in intact neurons to depolarizing in injured neurons.We show in vivo in rats and ex vivo in mouse organotypic slice cultures that posttraumatic GABAA-mediated depolarization is a cause for the well known phenomenon of pathological upregulation of pan-neurotrophin receptor p75NTR. The increase in intracellular Ca2 triggered by GABA-mediated depolarization activates ROCK (Rho kinase), which in turn leads to the upregulation of p75NTR. We further show that high levels of p75NTR and its interaction with sortilin and proNGF set the dependency on BDNF for survival. Thus, application of bumetanide prevents p75NTR upregulation and neuronal death in the injured areas with reduced levels of endogenous BDNF
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