Neuroprotective Signaling Mechanisms of Telomerase Are Regulated by Brain-Derived Neurotrophic Factor in Rat Spinal Cord Motor Neurons

Telomerase can promote neuron survival and can be regulated by growth factors such as brain-derived neurotrophic factor (BDNF). Increases of BDNF expression and telomerase activity after brain injury suggest that telomerase may be involved in BDNF-mediated neuroprotection. We investigated BDNF regulation of telomerase in rat spinal cord motor neurons (SMNs). Our results indicate that BDNF increases telomerase expression and activity levels in SMNs and activates mitogen-activated protein kinase/extracellular signal-regulated kinases 1 and 2 and phosphatidylinositol-3-OH kinase/protein kinase B signals, and their downstream transcription factors nuclear factor-κB, c-Myc, and Sp1. Administration of the tyrosine kinase receptor B inhibitor K-252a, the mitogen-activated protein kinase 1 inhibitor PD98059, and the phosphatidylinositol-3-OH kinase inhibitor LY294002 abolished BDNF-induced upregulation of these transcription factors and telomerase expression. The nuclear factor-κB inhibitor Bay11-7082 also attenuated c-Myc and Sp1 expression and increased telomerase promoter activity. Spinal cord motor neurons with higher telomerase levels induced by BDNF became more resistant to apoptosis; survival of SMNs that overexpressed the catalytic protein component of telomerase with reverse transcriptase activity was also enhanced against apoptosis. The neuronal survival-promoting effect of telomerase was mediated through the regulation of Bcl-2, Bax, p53, and maintenance of mitochondrial membrane potential. Taken together, these data suggest that the neuroprotective effect of BDNF via telomerase is mediated by inhibition of apoptotic pathways.