The Potential of Didox as an Oral Therapy for Multiple Sclerosis

描述（由申请人提供）： 项目总结/摘要 目前多发性硬化症（MS）的治疗方法减缓了疾病的进展，但不能促进康复。因此，需要额外的治疗来提供有利于神经元稳定和神经修复的CNS环境。Didox是一系列独特的多酚化合物中的一员，这些化合物具有多方面的生物化学特性，有可能为MS提供治疗益处。 为了验证这一 为了验证这一假设，我们使用注射给药的Didox和脱髓鞘疾病的慢性实验性变态反应性脑脊髓炎（EAE）模型进行实验。我们发现以这种方式给予Didox可以预防脱髓鞘疾病的发作和严重程度。该药物还能够完全逆转已建立疾病的临床症状。与EAE研究相关的进一步数据表明，炎性细胞因子的产生减少，导致水肿减轻和免疫细胞向CNS中的免疫浸润减少;这种浸润通常在该模型中观察到。 该提案的目的是通过评估Didox的效力进一步阐明其治疗潜力 在许多相关EAE模型中作为口服药物给药时。将通过经口管饲法向患有慢性EAE或复发缓解型EAE的小鼠施用经口Didox。将在疾病发作前、疾病高峰时和疾病平台期后（慢性EAE）以及在疾病发作前、第一次缓解期间和第二次缓解期间（持续缓解型EAE）给予药物。在将相同的研究扩展到MS的另外两种模型之前，将详细研究这两种EAE模型：慢性进行性EAE模型和继发性进行性EAE模型。将采用灵敏度和特异性HPLC/质谱法跟踪血液和CNS中didox的动力学。 将评价药物在所有EAE模型中维持恢复的能力。 将评价导致药物诱导恢复的分子、细胞和免疫学机制。 如所指出的，目前用于多发性硬化症的疗法主要预防疾病的进展，但不逆转MS的症状。相反，Didox治疗可以通过抑制炎症、预防CNS的免疫浸润和减少水肿来促进适于恢复的CNS环境，从而允许临床恢复和可能的髓鞘再生发生。更重要的是，这种化合物已经在人体中进行了测试，能够穿过CNS的血脑屏障，并且在其他疾病模型中口服耐受性良好。此外，迫切需要新的口服药物疗法来阻止慢性进展性MS以及继发性MS，并计划进行初步研究以评估Didox在这方面的作用。根据我们的初步观察，我们认为，didox有很好的潜力，是一个有效的口服治疗多发性硬化症。是 预期本提案的结果将为启动该新药的临床试验提供依据。

DESCRIPTION (provided by applicant): PROJECT SUMMARY/ABSTRACT Current therapies for multiple sclerosis (MS) slow the progression of the disease but do not promote recovery. Therefore additional therapies are required to provide a CNS environment conducive for neuronal stabilization and neurorepair. Didox is a member of a unique series of polyphenol compounds that are multifaceted and have biochemical properties that have the potential to provide therapeutic benefit in MS. To test this hypothesis we conducted experiments using didox administered by injection and the chronic experimental allergic encephalomyelitis (EAE) model of demyelinating disease. We found that Didox given in this manner can prevent the onset and severity of demyelinating disease. The drug also had the ability to completely reverse the clinical symptoms of established disease. Further data associated with the EAE studies demonstrated that the production of inflammatory cytokines are reduced, leading to reduction of edema and decreased immune infiltration of immune cells into the CNS; this infiltration is normally observed in this model. The objective o this proposal is to further elucidate the therapeutic potential of Didox by evaluating its potency when given as an oral drug in a number of relevant EAE models. Oral didox will be administered by oral gavage to mice affected with either chronic EAE or relapsing remitting EAE. The drug will be given prior to the onset of disease, at the peak of disease and after the disease plateaus (in the case of chronic EAE) and prior to the onset of disease during the first remission and during the second remission in the case of elapsing remitting EAE. These two EAE models will be studied in detail before extending the same studies to two other models of MS: the chronic progressive EAE model and the secondary progressive EAE model. The kinetics of didox in the blood and CNS will be followed with a sensitive and specific HPLC/Mass spectrometry method. The ability of the drug to sustain recovery in all EAE models will be evaluated. The molecular, cellular and immunological mechanisms responsible for the drug- induced recovery will be evaluated. As noted, current therapies for multiple sclerosis mostly prevent the progression of the disease but do not reverse the symptoms of MS. In contrast Didox treatment may promote a CNS environment amenable to recovery by suppressing inflammation, preventing immune infiltration of the CNS and reducing edema, allowing clinical recovery and possibly remyelination to occur. Of additional importance, this compound has already been tested in humans, is able to traverse the blood-brain barrier of the CNS, and is tolerated well orally in other disease models. Also there is an urgent need for new oral drug therapies to arrest chronic progressive MS as well as secondary MS and preliminary studies to evaluate didox in this regard are planned. Based on our preliminary observations, we believe that didox has excellent potential to be an effective oral treatment for multiple sclerosis. It is anticipated that the results of this proposal will provide the basis for initiating clinical trial of this novel drug.