Targeting HDAC6 for the treatment of neuropathic pain

HDAC6，慢性疼痛的新治疗靶点 慢性神经性疼痛是一种严重的医疗状况，也是一种重要的未得到满足的医疗需求。 目前的一线药物成功地缓解了一部分患者的症状，但他们的活动 通常需要几周到几个月的给药时间，在临床前模型中也观察到了这种延迟。 相比之下，最近的临床前研究表明，广效组蛋白去酯化酶(HDAC) 抑制剂，如曲古抑素A(TSA)和琥珀酰苯胺异羟肟酸(SAHA)，迅速 缓解各种神经病理性疼痛模型的痛觉过敏。这表明HDAC抑制是一种 为开发新的治疗方法开辟了很有前途的途径。然而，确切的机制是 这种快速的止痛活性背后仍然难以捉摸。描述特定的HDAC 亚型，HDAC底物，以及调节这些止痛作用的大脑网络，将 为设计副作用改善的新药提供重要的见解。 我们的初步数据表明，HDAC6的选择性药理阻断是一种主要的 胞浆IIB亚型，足以充分概括广谱的镇痛活性 作用HDAC抑制剂，即使这种异构体在体内不能使染色质去乙酰化。在……下面 目的：我们将结合最先进的异构体选择性药理探针和条件性 用一对HDAC6等位基因研究HDAC6在痛觉障碍中的作用 与周围神经损伤有关的类似行为。具体地说，我们将使用多余的神经 神经病理性疼痛模型以验证HDAC6在某些脊髓上活动的假设 5-羟色胺能中缝核(RN)等部位是 感觉过敏和/或类似抑郁的行为的发展。在AIM II下，我们将 追踪HDAC6在接下来的时间点的表达和活性的变化 诱导神经损伤。我们还将监测HDAC6磷酸化的变化和 神经病理性疼痛下HDAC6的两个有效靶点Hsp90和α-微管蛋白的乙酰化 各州。最后，我们将评估HDAC6对RN细胞因子表达的影响。

HDAC6, a new therapeutic target for chronic pain Chronic neuropathic pain is a severe medical condition and an important unmet medical need. Current first-line medications successfully provide relief in a subset of patients but their activity usually require weeks to months of administration a delay also observed in preclinical models. In contrast, recent preclinical studies show that broad-acting histone deceatylase (HDAC) inhibitors, such as trichostatin A (TSA) and Suberoylanilide hydroxamic acid (SAHA), rapidly relieve hyperalgesia in various models of neuropathic pain. This points to HDAC inhibition as a promising avenue for the development of new treatments. However, the exact mechanisms underlying this rapid analgesic activity remain elusive. Characterizing the specific HDAC isoforms, the HDAC substrates, and brain networks that mediate these analgesic effects, will provide important insights for the design of newer medications with improved side-effect profile. Our preliminary data indicate that the selective pharmacological blockade of HDAC6, a mainly cytoplasmic class IIB isoform, is sufficient to fully recapitulate the analgesic activity of broad acting HDAC inhibitors, even though this isoform does not deacetylate chromatin in vivo. Under Aim I we will combine state of the art isoform-selective pharmacological probes and conditional loss of function of HDAC6 using a floxed HDAC6 allele to investigate the role of HDAC6 in pain- like behaviors associated with peripheral nerve injury. Specifically, we will use the spare nerve model of neuropathic pain to test the hypothesis that HDAC6 activity at certain supraspinal sites, such as the serotonergic Raphe Nuclei (RN), is necessary and sufficient for the development of sensory hypersensitivity and/or depression-like behaviors. Under Aim II, we will track changes in the expression and activity of HDAC6 at successive time-points after the induction of nerve injury. We will also monitor changes in the phosphorylation of HDAC6 and the acetylation of Hsp90 and alpha-tubulin, two validated targets of HDAC6, under neuropathic pain states. Finally, we will assess the impact of HDAC6 in cytokine expression in the RN.