Mizuno Tetsuya, Kurotani Tohru, Komatsu Yukio, Kawanokuchi Jun, Kato Hideki, Mitsuma Norimasa, Suzumura Akio
Department of Neuroimmunology, Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan.
Neuropharmacology. 2004 Mar;46(3):404-11. doi: 10.1016/j.neuropharm.2003.09.009.
The phosphodiesterase inhibitor, ibudilast, has many effects on lymphocytes, endothelial cells, and glial cells. We examined the neuroprotective role of ibudilast in neuron and microglia co-cultures. Ibudilast significantly suppressed neuronal cell death induced by the activation of microglia with lipopolysaccharide (LPS) and interferon (IFN)-gamma. To examine the mechanisms by which ibudilast exerts a neuroprotective role against the activation of microglia, we examined the production of inflammatory and anti-inflammatory mediators and trophic factors following ibudilast treatment. In a dose-dependent manner, ibudilast suppressed the production of nitric oxide (NO), reactive oxygen species, interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha and enhanced the production of the inhibitory cytokine, IL-10, and additional neurotrophic factors, including nerve growth factor (NGF), glia-derived neurotrophic factor (GDNF), and neurotrophin (NT)-4 in activated microglia. Thus, ibudilast-mediated neuroprotection was primarily due to the inhibition of inflammatory mediators and the upregulation of neurotrophic factor. In the CA1 region of hippocampal slices, long-term potentiation (LTP) induced by high frequency stimulation (HFS) could be inhibited with LPS and interferon-gamma stimulation. Ibudilast returned this LTP inhibition to the levels observed in controls. These results suggest that ibudilast may be a useful neuroprotective and anti-dementia agent counteracting neurotoxicity in activated microglia.
磷酸二酯酶抑制剂异丁司特对淋巴细胞、内皮细胞和神经胶质细胞有多种作用。我们研究了异丁司特在神经元与小胶质细胞共培养中的神经保护作用。异丁司特能显著抑制脂多糖（LPS）和干扰素（IFN）-γ激活小胶质细胞所诱导的神经元细胞死亡。为了探究异丁司特对小胶质细胞激活发挥神经保护作用的机制，我们检测了异丁司特处理后炎症和抗炎介质以及营养因子的产生。异丁司特以剂量依赖的方式抑制一氧化氮（NO）、活性氧、白细胞介素（IL）-1β、IL-6和肿瘤坏死因子（TNF）-α的产生，并增强抑制性细胞因子IL-10以及其他神经营养因子的产生，这些神经营养因子包括神经生长因子（NGF）、胶质细胞源性神经营养因子（GDNF）和神经营养素（NT）-4，在激活的小胶质细胞中均有增强。因此，异丁司特介导的神经保护主要归因于对炎症介质的抑制和神经营养因子的上调。在海马切片的CA1区，高频刺激（HFS）诱导的长时程增强（LTP）可被LPS和干扰素-γ刺激所抑制。异丁司特可使这种LTP抑制恢复到对照组所观察到的水平。这些结果表明，异丁司特可能是一种有用的神经保护和抗痴呆药物，可对抗激活的小胶质细胞中的神经毒性。
