Neuroinflammation contributes to delayed secondary cell death following traumatic brain injury (TBI), has the potential to chronically exacerbate the initial insult, and represents a therapeutic target that has largely failed to translate into human efficacy. Thalidomide-like drugs have effectively mitigated neuroinflammation across cellular and animal models of TBI and neurodegeneration but are complicated by adverse actions in humans. We hence developed N-adamantyl phthalimidine (NAP) as a new thalidomide-like drug to mitigate inflammation without binding to cereblon, a key target associated with the antiproliferative, antiangiogenic, and teratogenic actions seen in this drug class. We utilized a phenotypic drug discovery approach that employed multiple cellular and animal models and ultimately examined immunohistochemical, biochemical, and behavioral measures following controlled cortical impact (CCI) TBI in mice. NAP mitigated LPS-induced inflammation across cellular and rodent models and reduced oligomeric α-synuclein and amyloid-β mediated inflammation. Following CCI TBI, NAP mitigated neuronal and synaptic loss, neuroinflammation, and behavioral deficits, and is unencumbered by cereblon binding, a key protein underpinning the teratogenic and adverse actions of thalidomide-like drugs in humans. In summary, NAP represents a new class of thalidomide-like drugs with anti-inflammatory actions for promising efficacy in the treatment of TBI and potentially longer-term neurodegenerative disorders.

中文翻译：

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N-Adamantyl Phthalimidine：一种新的沙利度胺样药物，缺乏大脑结合并减轻创伤性脑损伤和 LPS 挑战中的神经元和突触丧失、神经炎症和行为缺陷

神经炎症会导致创伤性脑损伤 (TBI) 后的继发性细胞死亡延迟，有可能长期加剧最初的损伤，并且代表了一种治疗目标，但很大程度上未能转化为人类疗效。沙利度胺类药物在 TBI 和神经退行性变的细胞和动物模型中有效减轻了神经炎症，但在人类中因不良反应而变得复杂。因此，我们开发了N-金刚烷基邻苯二甲脒 (NAP) 作为一种新的沙利度胺类药物，可在不与 cereblon 结合的情况下减轻炎症，cereblon 是与此类药物中的抗增殖、抗血管生成和致畸作用相关的关键靶点。我们使用了一种表型药物发现方法，该方法采用了多种细胞和动物模型，并最终检查了小鼠受控皮质冲击 (CCI) TBI 后的免疫组织化学、生化和行为测量。NAP 减轻了 LPS 诱导的跨细胞和啮齿动物模型的炎症，并减少了寡聚 α-突触核蛋白和淀粉样蛋白-β 介导的炎症。在 CCI TBI 之后，NAP 减轻了神经元和突触损失、神经炎症和行为缺陷，并且不受 cereblon 结合的阻碍，这是一种支持沙利度胺类药物在人类中的致畸和不良作用的关键蛋白质。