Microglial activation has been suggested to play important roles in various neurodegenerative diseases by phagocytosis and producing various factors such as nitric oxide (NO), proinflammatory cytokines. Excessive production of NO, as a consequence of increased inducible nitric oxide synthase (iNOS) in microglia, contributes to the neurodegeneration. During a search for compounds that regulate endoplasmic reticulum (ER) stress, a dibenzoylmethane derivative, 2,2’-dimethoxydibenzoylmethane (DBM 14–26) was identified as a novel neuroprotective agent (Takano et al., Am. J. Physiol. Cell Physiol. 293, C1884-1894, 2007). We previously reported in cultured astrocytes that DBM 14–26 protected hydrogen peroxide-induced cell death and inhibited lipopolysaccharide (LPS)-induced NO production (Takano et al., J. Neurosci. Res. 89, 955–965, 2011). In the present study, we assessed the effects of DBM 14–26 on microglia using the mouse cell line BV-2 and found that DBM 14–26 inhibited LPS-induced iNOS expression and NO production also in microglia. DBM 14–26 also suppressed LPS-induced IL-1β expression. Conditioned medium of BV-2 cells stimulated by LPS significantly decreased cell viability of neuron (human neuroblastoma SH-SY5Y cells) compared with the absence of LPS. Conditioned medium of BV-2 cells stimulated by LPS in the presence of DBM 14–26 did not significantly decreased cell viability of neuron. These results indicate that microglial activation by LPS causes neuronal cell death and DBM 14–26 protect neuron through the inhibition of microglial activation. Functional regulation of microglia by DBM 14–26 could be a therapeutic candidate for the treatment of neurodegenerative diseases.

已经表明，小胶质细胞活化通过吞噬作用和产生各种因素如一氧化氮（NO），促炎细胞因子在各种神经退行性疾病中起重要作用。由于小胶质细胞中诱导型一氧化氮合酶（iNOS）含量增加，导致NO产生过多，导致神经变性。在寻找调节内质网（ER）应激的化合物时，发现二苯甲酰甲烷衍生物2,2'-二甲氧基二苯甲酰甲烷（DBM 14–26）是一种新型的神经保护剂（Takano等人，Am。J. Physiol。Cell）。生理学293，C1884-1894，2007）。我们先前曾在培养的星形胶质细胞中报道过，DBM 14–26保护过氧化氢诱导的细胞死亡并抑制脂多糖（LPS）诱导的NO产生（Takano等人，J.神经科学。水库。89，955–965，2011）。在本研究中，我们使用小鼠细胞系BV-2评估了DBM 14–26对小胶质细胞的作用，并发现DBM 14–26在小胶质细胞中也抑制LPS诱导的iNOS表达和NO的产生。DBM 14–26还抑制LPS诱导的IL-1β表达。与不存在LPS的情况相比，LPS刺激的BV-2细胞的条件培养基显着降低了神经元（人神经母细胞瘤SH-SY5Y细胞）的细胞活力。在存在DBM 14–26的情况下，LPS刺激的BV-2细胞的条件培养基不会显着降低神经元的细胞活力。这些结果表明，LPS激活的小胶质细胞会导致神经元细胞死亡，DBM 14–26通过抑制小胶质细胞的激活来保护神经元。