We have identified several growth factors and cytokines that can protect neurons against dysfunction and death in experimental models of Alzheimer's disease, Parkinson's disease and stroke. These trophic factors activate signaling pathways that stimulate the expression of genes whose encoded proteins increase resistance of neurons to oxidative and metabolic stress. Neuroprotective Actions of BDNF. We have found that brain-derived neurotrophic factor (BDNF) is a key mediator of the neuroprotective effects of dietary restriction in animal models of Parkinson's and Huntington's diseases. BDNF protects neurons against excitotoxic and oxidative insults. In addition, we found that BDNF promotes neurogenesis in the hippocampus, and mediates the enhancement of neurogenesis by dietary restriction. BDNF activates a positive feedback loop for the regulation of neurogenesis by inducing the production of nitric oxide by newly generated neurons. The nitric oxide then acts on neural progenitor cells to induce their differentiation into neurons. In other studies we have found that caloric restriction reduces damage to dopaminergic neurons and improves functional outcome in a non-human primate model of Parkinson's disease. The beneficial effect of CR is associated with increased amounts of BDNF and glial cell line-derived neurotrophic factor (GDNF), a growth factor which is now in early clinical trials in patients with Parkinson's disease. In related studies we have found that the antidepressant paroxetine can suppress neuronal degeneration and improve motor function and survival in a mouse model of Hungtington's disease by a mechanism involving increased production of BDNF. In addition, we have identified GLP-1 (glucagon-like peptide 1) as a neuroprotective neuropeptide with the potential to ameliorate neuronal dysfunction and degeneration in some neurodegenerative conditions.
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