Abstract

Proinflammatory cytokines such as tumor necrosis factor (TNF), with its now appreciated key roles in neurophysiology as well as neuropathophysiology, are sufficiently well-documented to be useful tools for enquiry into the natural history of neurodegenerative diseases. We review the broader literature on TNF to rationalize why abruptly-acquired neurodegenerative states do not exhibit the remorseless clinical progression seen in those states with gradual onsets. We propose that the three typically non-worsening neurodegenerative syndromes, post-stroke, post- traumatic brain injury (TBI), and post cardiac arrest, usually become and remain static because of excess cerebral TNF induced by the initial dramatic peak keeping microglia chronically activated through an autocrine loop of microglial activation through excess cerebral TNF. The existence of this autocrine loop rationalizes post-damage repair with perispinal etanercept and proposes a treatment for cerebral aspects of COVID-19 chronicity. Another insufficiently considered aspect of cerebral proinflammatory cytokines is the fitness of the endogenous cerebral anti-TNF system provided by norepinephrine (NE), generated and distributed throughout the brain from the locus coeruleus (LC). We propose that an intact LC, and therefore an intact NE-mediated endogenous anti-cerebral TNF system, plus the DAMP (damage or danger-associated molecular pattern) input having diminished, is what allows post-stroke, post-TBI, and post cardiac arrest patients a strong long-term survival advantage over Alzheimer’s disease and Parkinson’s disease sufferers. In contrast, Alzheimer’s disease and Parkinson’s disease patients remorselessly worsen, being handicapped by sustained, accumulating, DAMP and PAMP (pathogen-associated molecular patterns) input, as well as loss of the LC-origin, NE-mediated, endogenous anti-cerebral TNF system. Adrenergic receptor agonists may counter this.

中文翻译：

---

对肿瘤坏死因子和神经退行性疾病发病机制的更广泛了解催生了新的治疗方法

摘要

肿瘤坏死因子 (TNF) 等促炎细胞因子在神经生理学和神经病理生理学中发挥着关键作用，现已得到充分证实，可成为研究神经退行性疾病自然史的有用工具。我们回顾了有关 TNF 的更广泛的文献，以合理解释为什么突然获得的神经退行性状态不会表现出渐进性神经退行性状态中所见的无情临床进展。我们提出，三种典型的非恶化神经退行性综合征，即中风后、创伤性脑损伤（TBI）和心脏骤停后，通常会变得并保持静止状态，因为最初的戏剧性峰值导致小胶质细胞长期激活，从而引起过量的脑肿瘤坏死因子（TNF）。通过过量的脑 TNF 激活小胶质细胞的自分泌循环。这种自分泌环路的存在使脊髓周围依那西普的损伤后修复合理化，并提出了一种治疗 COVID-19 慢性脑部疾病的方法。脑促炎细胞因子的另一个未充分考虑的方面是由去甲肾上腺素（NE）提供的内源性脑抗TNF系统的适应性，NE由蓝斑（LC）产生并分布在整个大脑中。我们认为，完整的 LC，因此完整的 NE 介导的内源性抗脑 TNF 系统，加上 DAMP（损伤或危险相关分子模式）输入的减少，是中风后、TBI 后和术后恢复的原因。心脏骤停患者比阿尔茨海默病和帕金森病患者具有强大的长期生存优势。相比之下，阿尔茨海默病和帕金森病患者的病情会无情地恶化，因为持续积累的 DAMP 和 PAMP（病原体相关分子模式）输入以及 LC 来源、NE 介导的内源性抗脑 TNF 的丧失而受到阻碍。系统。肾上腺素能受体激动剂可能会对抗这种情况。