Erythropoietin and sonic hedgehog mediate the neuroprotective effects of brain-derived neurotrophic factor against mitochondrial inhibition.
Brain-derived neurotrophic factor (BDNF) deficiency and mitochondrial dysfunction have been implicated in the pathogenesis of Huntington's disease (HD). 3-Nitropropionic acid (3-NP) is a mitochondrial inhibitor commonly used as a pharmacological model mimicking HD. We have recently reported that preconditioning of primary rat cortical cultures with BDNF induces sonic hedgehog (SHH), which contributes to the protective effects of BDNF against 3-NP neurotoxicity. Because carbamylated erythropoietin (EPO) may induce SHH, we investigated whether BDNF-dependent SHH expression and 3-NP resistance require prior induction of EPO. We found that BDNF induced EPO expression at both mRNA and protein levels. BDNF-mediated SHH induction and 3-NP resistance were abolished by the soluble EPO receptor (sEPO-R), an EPO inhibitor. Recombinant rat EPO (rEPO) induced SHH and attenuated 3-NP neurotoxicity. The rEPO-dependent neuroprotection was suppressed by the SHH inhibitor cyclopamine (CPM); however, sEPO-R failed to affect SHH neuroprotection. Furthermore, the rEPO-dependent neuroprotection was not suppressed by the BDNF neutralizing antibody, which completely abolished BDNF-mediated 3-NP resistance at the same dosage. Overall, our results demonstrate that BDNF-dependent SHH expression and 3-NP resistance require prior induction of EPO, thus establishing a signaling cascade of "BDNF-->EPO-->SHH-->3-NP resistance" in rat cortical neurons.
Wu
Chia-Lin
CL
Institute of Brain Science and Brain Research Center, National Yang-Ming University, Taipei, Taiwan.
Chen
Shang-Der
SD
Yin
Jiu-Haw
JH
Hwang
Chi-Shin
CS
Yang
Ding-I
DI
D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000378:metabolism / Q000473:pathology; D004351:Drug Resistance; D004921:Erythropoietin / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D053823:Hedgehog Proteins / Q000502:physiology*; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000378:metabolism / Q000494:pharmacology*; D009574:Nitro Compounds / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011422:Propionates / Q000037:antagonists & inhibitors / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D017467:Receptors, Erythropoietin / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology
D019208:Brain-Derived Neurotrophic Factor; D053823:Hedgehog Proteins; D018696:Neuroprotective Agents; D009574:Nitro Compounds; D011422:Propionates; D017467:Receptors, Erythropoietin; C546888:Shh protein, rat; D004921:Erythropoietin; C015392:3-nitropropionic acid