CANNABINOIDS AND INFLAMMATION: RELEVANCE TO MULTIPLE SCLEROSIS

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 全球约有250万人被诊断出患有神经退行性疾病多发性硬化症(MS)。尽管专利药物的数量继续快速增加，但由于涉及复杂的生理途径，许多神经疾病的有效治疗仍然难以实现。大麻类化合物是来自大麻属植物的生物活性化合物，已成为治疗MS等疾病中神经炎性疾病的有希望的治疗剂。我们工作的长期目标是确定这些天然化合物是治疗MS的潜在选择，并阐明它们介导其作用的途径。在本项目的具体目标1中，我们使用培养的神经胶质细胞作为模型，测试大麻素化合物、柳柳酸和大麻二醇抑制神经炎症标记物，如一氧化氮和促炎细胞因子和趋化因子的能力。具有这种能力的药物是治疗以慢性神经炎症为特征的疾病(如MS)的良好候选药物。由于神经退行性变通常是由这些炎症条件引起的，因此理想的治疗方法将抑制炎症反应，保护周围神经元免受炎症介质诱导的损伤。在具体目标2中，我们测试我们的化合物是否提供这种保护。我们通过两种毒性炎症细胞因子(干扰素-γ和肿瘤坏死因子-α)治疗来诱导皮质神经元的凋亡，并评估我们化合物的预治疗在防止随后的神经元死亡方面的有效性。在具体目标3中，我们使用大麻素受体拮抗剂来确定观察到的抗炎和神经保护作用是否通过经典的CB1和CB2受体介导。 通过这些拟议的目标，我们希望为改善治疗方案提供理论基础，以解决以MS等神经退行性疾病为特征的慢性神经炎，表征大麻类化合物介导疾病调节作用的机制应有助于开发比其他类别药物风险更低、副作用更少的靶向药物。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Approximately 2.5 million people worldwide have been diagnosed with the neurodegenerative disease multiple sclerosis (MS). Though the number of patented drugs continues to rapidly increase, effective treatments for many neural diseases remain elusive because of the complex physiologic pathways involved. Cannabinoids, bioactive compounds from the Cannabis sativa plant, have emerged as promising therapeutic agents for neuroinflammatory conditions found in diseases such as MS. The long-term goal of our work is to characterize these natural compounds as potential therapeutic options for MS and elucidate pathways through which they mediate their effects. In this project's Specific Aim 1 we use cultured glial cells as a model for testing the abilities of cannabinoid compoundsajulemic acid and cannabidiolto suppress markers of neuroinflammation such as nitric oxide and pro-inflammatory cytokines and chemokines. Drugs with such abilities are good candidates for treating diseases characterized by chronic neuroinflammation, such as MS. Since neurodegeneration often results from these inflammatory conditions, an ideal treatment would suppress the inflammatory response and protect surrounding neurons from damage induced by mediators of inflammation. In Specific Aim 2, we test whether our compounds provide such protection. We induce apoptosis in cortical neurons by treatment with 2 toxic inflammatory cytokines, interferon-gamma and tumor necrosis factor-alpha), and assess effectiveness of pre-treatment with our compounds in preventing subsequent neuronal death. In Specific Aim 3, we use cannabinoid receptor antagonists to determine whether observed anti-inflammatory and neuroprotective effects are mediated through classic CB1 and CB2 receptors. Through these proposed aims, we expect to provide the rationale for improved therapeutic options to address chronic neuroinflammation characterizing neurodegenerative diseases like MS. Characterization of the mechanisms by which the cannabinoid compounds mediate disease-modulating effects should aid the development of targeted drugs with less risk and fewer side effects than other classes of pharmaceuticals.