After a severe, high-level spinal cord injury (SCI), plasticity to intraspinal circuits below injury results in heightened spinal sympathetic reflex activity and detrimentally impacts peripheral organ systems. Such sympathetic hyperreflexia is immediately apparent as an episode of autonomic dysreflexia (AD), a life-threatening condition characterized by sudden hypertension and reflexive bradycardia following below-level sensory inputs; for example, pressure sores or impacted fecal matter. Over time, plasticity within the spinal sympathetic reflex (SSR) circuit contributes to the progressive intensification of AD events, as the frequency and severity of AD events increase greatly beginning ∼2 weeks post-injury (wpi). The neuroimmune system has been implicated in driving sympathetic hyperreflexia, as inhibition of the cytokine soluble tumor necrosis factor-alpha (sTNFα) using the biological mimetic XPro1595 beginning within days post-SCI has been shown to attenuate the development of AD. Here, we sought to further understand the effective therapeutic time window of XPro1595 to diminish sympathetic hyperreflexia, as indicated by AD. We delayed the commencement of continuous intrathecal administration of XPro1595 until 2 weeks after a complete, thoracic level 3 injury in adult rats. We examined the severity of colorectal distension-induced AD biweekly. We found that initiation of sTNFα inhibition at 2 wpi does not attenuate the severity or intensification of sympathetic hyperreflexia compared with saline-treated controls. Coupled with previous data from our group, these findings suggest that central sTNFα signaling must be targeted prior to 2 weeks post-SCI in order to decrease sympathetic hyperreflexia.

中文翻译：

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高位胸脊髓损伤后两周可溶性肿瘤坏死因子-α的药理抑制不影响交感神经反射亢进


严重的高位脊髓损伤 (SCI) 后，损伤下方椎管内回路的可塑性会导致脊髓交感神经反射活动增强，并对周围器官系统产生不利影响。这种交感神经反射亢进表现为自主神经反射异常（AD）的发作，这是一种危及生命的疾病，其特征是在低于水平的感觉输入后突然出现高血压和反射性心动过缓；例如，压疮或受影响的粪便。随着时间的推移，脊髓交感反射 (SSR) 回路内的可塑性会导致 AD 事件的逐渐加剧，因为 AD 事件的频率和严重程度从损伤后约 2 周 (wpi) 开始大幅增加。神经免疫系统与驱动交感神经反射亢进有关，因为在 SCI 后几天内开始使用生物模拟物 XPro1595 抑制细胞因子可溶性肿瘤坏死因子-α (sTNFα) 已被证明可以减弱 AD 的发展。在这里，我们试图进一步了解 XPro1595 减少 AD 所示的交感神经反射亢进的有效治疗时间窗。我们将 XPro1595 连续鞘内给药的开始时间推迟到成年大鼠胸部 3 级完全损伤后 2 周。我们每两周检查一次结直肠扩张引起的 AD 的严重程度。我们发现，与盐水处理的对照组相比，在感染后 2 周开始 sTNFα 抑制并不会减轻交感神经反射亢进的严重程度或加剧。结合我们小组之前的数据，这些发现表明，必须在 SCI 后 2 周之前针对中枢 sTNFα 信号传导，以减少交感神经反射亢进。