The mechanism of heme oxygenase-1 action involved in the enhancement of neurotrophic factor expression.
Heme oxygenase-1 (HO-1) is up-regulated in response to oxidative stress and catalyzes the degradation of pro-oxidant heme to carbon monoxide (CO), iron and bilirubin. Bilirubin is a potent antioxidant and neuroprotectant. Neurotrophic factors of BDNF and GDNF also play important roles in survival and morphological differentiation of dopaminergic neurons. We have previously found that HO-1 induction by adenovirus containing human HO-1 gene (Ad-HO-1) in substantia nigra of rat increases BDNF and GDNF expression. We here further examined the possible mechanism of HO-1 action involved in the enhancement of neurotrophic factor expression. Treatment of anti-BDNF/GDNF antibody significantly enhanced dopaminergic neuronal death, whereas Ad-HO-1 co-treatment was able to antagonize the apoptosis-inducing effect of these antibodies. The confocal imaging shows that HO-1 induction appeared in dopaminergic neuron, astrocyte and microglia at 24 h after injecting Ad-HO-1. HO-1 induced-BDNF/GDNF mRNA expression in substantia nigra was 26/21 folds of that of the contralateral Ad-injected side. The downstream product bilirubin increased GDNF expression through ERK and PI3K-Akt pathways, and also enhanced NFkappaB (p65 and p50) nuclear translocation in glia-enriched cultures. In addition, bilirubin also enhanced BDNF expression through similar pathway in cortical neuron-enriched cultures. We also examined the effect of another HO-1 product, CO, by using CO donor. [Ru(CO)3Cl2]2 increased neurotrophic factor expression via sGC-PKG pathway in both neuron and glia. These results indicate that the downstream products of HO-1, i.e. bilirubin and CO, modulate BDNF and GDNF expression in neuron and astrocyte.
Hung
Shih-Ya
SY
Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Liou
Houng-Chi
HC
Fu
Wen-Mei
WM
D000818:Animals; D001253:Astrocytes / Q000201:enzymology / Q000378:metabolism*; D001921:Brain / Q000201:enzymology / Q000378:metabolism*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D016923:Cell Death / Q000502:physiology; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000201:enzymology / Q000378:metabolism; D018920:Coculture Techniques; D004298:Dopamine / Q000378:metabolism; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008636:Mesencephalon / Q000201:enzymology / Q000378:metabolism; D017628:Microglia / Q000201:enzymology / Q000378:metabolism; D009474:Neurons / Q000201:enzymology / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D055647:Rats, Transgenic; D017208:Rats, Wistar; D013378:Substantia Nigra / Q000201:enzymology / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D012333:RNA, Messenger; D051547:Heme Oxygenase-1; D004298:Dopamine