Pharmacological Institute, College of Medicine, National Taiwan University, Taipei 100, Taiwan.
Neuropharmacology. 2010 Feb;58(2):321-9. doi: 10.1016/j.neuropharm.2009.11.003. Epub 2009 Nov 20.
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.
血红素加氧酶-1（HO-1）在氧化应激下上调，催化前氧化剂血红素降解为一氧化碳（CO）、铁和胆红素。胆红素是一种有效的抗氧化剂和神经营养因子。BDNF 和 GDNF 等神经营养因子也在多巴胺能神经元的存活和形态分化中发挥重要作用。我们之前发现，腺病毒载体中人类 HO-1 基因（Ad-HO-1）诱导的黑质 HO-1 表达增加了 BDNF 和 GDNF 的表达。我们在这里进一步研究了 HO-1 作用增强神经营养因子表达的可能机制。抗 BDNF/GDNF 抗体的处理显著增强了多巴胺能神经元的死亡，而 Ad-HO-1 共同处理能够拮抗这些抗体的促凋亡作用。共聚焦成像显示，HO-1 诱导在注射 Ad-HO-1 后 24 小时出现在多巴胺能神经元、星形胶质细胞和小胶质细胞中。HO-1 诱导的黑质 BDNF/GDNF mRNA 表达是对侧 Ad 注射侧的 26/21 倍。下游产物胆红素通过 ERK 和 PI3K-Akt 通路增加 GDNF 表达，并增强富含胶质的培养物中 NFkappaB（p65 和 p50）核易位。此外，胆红素还通过富含皮质神经元的培养物中的类似途径增强了 BDNF 的表达。我们还通过使用 CO 供体研究了另一种 HO-1 产物 CO 的作用。[Ru(CO)3Cl2]2 通过 sGC-PKG 通路在神经元和胶质细胞中增加了神经营养因子的表达。这些结果表明，HO-1 的下游产物，即胆红素和 CO，调节神经元和星形胶质细胞中 BDNF 和 GDNF 的表达。
