Neurotrophic factors and ethanol neurotoxicity

Abstract

Neurotrophins are essential for the growth, differentiation, and survival of neurons during development and in the adult. Considerable data have accumulated over the last few decades implicating classical neurotrophins, Nerve Growth Factor (NGF), Brain-Derived Neurotrophic Factor (BDNF), and Neurotrophins 3 and 4 (NT-3/4), in many aspects of ethanol addiction, neurotoxicity, and repair after ethanol withdrawal. Genetic screens in Drosophila have identified novel neurotrophic factors and signaling intermediates involved in acute tolerance and pharmacodynamic adaptation to prolonged exposure in rodent. Ethanol modulates neurotrophic factor expression in vivo in a time- and region-specific fashion. Ethanol inhibits neurotrophin signaling acutely in vivo and in vitro in many brain regions. Conversely, acute and chronic ethanol exposure can upregulate neurotrophin-associated signaling pathways, particularly in brain nuclei associated with anxiety and addiction. Cell death induced by high concentrations of ethanol can be mitigated by exogenous neurotrophins indicating that neurotrophin induction in vivo may also be neuroprotective but ultimately fails over time. Neurotrophin levels in serum and plasma of patients with alcohol use disorders are dynamic and may serve as a surrogate for central nervous system levels. The kinetics suggest that increased levels during withdrawal may be involved in repair, but these analysis are complicated by genetic polymorphisms and the blood component analyzed, particularly with BDNF which is polymorphic in human populations and also produced by platelets. Neurotrophins are intricately involved in pharmacodynamic compensation with prolonged ethanol exposure, addiction-related plasticity, and neurotoxicity, but considerable work remains to be performed and replicated. Recent pharmacological advances targeting neurotrophins and neurotrophin signaling may ultimately be useful for treating ethanol-induced neurodegeneration and aberrant plasticity associated with addiction.