Ledeboer Annemarie, Liu Tongyao, Shumilla Jennifer A, Mahoney John H, Vijay Sharmila, Gross Matthew I, Vargas Joseph A, Sultzbaugh Lance, Claypool Mark D, Sanftner Laura M, Watkins Linda R, Johnson Kirk W
Department of Preclinical Development, Avigen Inc., Alameda, CA 94502, USA.
Neuron Glia Biol. 2006 Nov;2(4):279-91. doi: 10.1017/S1740925X0700035X.
Controlling neuropathic pain is an unmet medical need and we set out to identify new therapeutic candidates. AV411 (ibudilast) is a relatively nonselective phosphodiesterase inhibitor that also suppresses glial-cell activation and can partition into the CNS. Recent data strongly implicate activated glial cells in the spinal cord in the development and maintenance of neuropathic pain. We hypothesized that AV411 might be effective in the treatment of neuropathic pain and, hence, tested whether it attenuates the mechanical allodynia induced in rats by chronic constriction injury (CCI) of the sciatic nerve, spinal nerve ligation (SNL) and the chemotherapeutic paclitaxel (Taxol). Twice-daily systemic administration of AV411 for multiple days resulted in a sustained attenuation of CCI-induced allodynia. Reversal of allodynia was of similar magnitude to that observed with gabapentin and enhanced efficacy was observed in combination. We further show that multi-day AV411 reduces SNL-induced allodynia, and reverses and prevents paclitaxel-induced allodynia. Also, AV411 cotreatment attenuates tolerance to morphine in nerve-injured rats. Safety pharmacology, pharmacokinetic and initial mechanistic analyses were also performed. Overall, the results indicate that AV411 is effective in diverse models of neuropathic pain and support further exploration of its potential as a therapeutic agent for the treatment of neuropathic pain.
控制神经性疼痛是一项尚未满足的医疗需求，我们着手寻找新的治疗候选药物。AV411（异丁司特）是一种相对非选择性的磷酸二酯酶抑制剂，它还能抑制神经胶质细胞的激活，并可进入中枢神经系统。最近的数据有力地表明，脊髓中激活的神经胶质细胞在神经性疼痛的发生和维持中起作用。我们假设AV411可能对治疗神经性疼痛有效，因此测试了它是否能减轻坐骨神经慢性压迫损伤（CCI）、脊神经结扎（SNL）和化疗药物紫杉醇（Taxol）在大鼠中诱导的机械性异常性疼痛。连续多日每天两次全身给予AV411导致CCI诱导的异常性疼痛持续减轻。异常性疼痛的逆转程度与加巴喷丁观察到的相似，联合用药时疗效增强。我们进一步表明，多日给予AV411可减轻SNL诱导的异常性疼痛，并逆转和预防紫杉醇诱导的异常性疼痛。此外，AV411联合治疗可减轻神经损伤大鼠对吗啡的耐受性。还进行了安全药理学、药代动力学和初步机制分析。总体而言，结果表明AV411在多种神经性疼痛模型中有效，并支持进一步探索其作为治疗神经性疼痛药物的潜力。
