Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine.
Better together? Treating traumatic brain injury with minocycline plus N-acetylcysteine.
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DOI：
10.4103/1673-5374.336136
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发表时间：
2022-12
影响因子：
6.1
通讯作者：
Bergold, Peter J.
中科院分区：
文献类型：
--
作者：
Lawless, Siobhan;Bergold, Peter J.
关键词：
创伤性脑损伤具有复杂的病理生理学，会产生快速和延迟的脑损伤。受伤后立即开始快速损伤。创伤性脑损伤的治疗通常延迟数小时，因此只有延迟的损伤才能用药物靶向。迟发性创伤性脑损伤包括神经炎症、氧化损伤、细胞凋亡和谷氨酸毒性。创伤性脑损伤病理生理学的速度和复杂性都给药物开发带来了很大的障碍。重新利用食品和药物管理局批准的药物可能是一种高效的方法，使治疗进入临床。本文综述了米诺环素和N-乙酰半胱氨酸作为单独药物的临床前结果，并将其与米诺环素加N-乙酰半胱氨酸组合进行了比较。米诺环素和N-乙酰半胱氨酸都是食品和药物管理局批准的具有多效性治疗效果的药物。作为单独的药物，米诺环素和N-乙酰半胱氨酸耐受性良好，具有已知的药代动力学，并通过完整的血脑屏障进入大脑。在大于抗微生物作用所需的浓度下，米诺环素是一种有效的抗炎米诺环素，也可作为抗氧化剂并抑制多种促进脑损伤的酶，包括金属蛋白酶、半胱天冬酶和聚ADP-核糖聚合酶-1。单独的N-乙酰半胱氨酸也是一种抗氧化剂。它增加大脑谷胱甘肽，防止脂质氧化，保护线粒体。N-乙酰半胱氨酸还可作为抗炎剂，并通过激活Xc胱氨酸-谷氨酸抗转运蛋白增加细胞外谷氨酸。米诺环素和N-乙酰半胱氨酸的这些多重作用使它们成为治疗创伤性脑损伤的有吸引力的候选者。当在损伤后一小时内首次给药时，米诺环素或N-乙酰半胱氨酸改善了多创伤性脑损伤动物模型中的一组不同的治疗结果测量。少数创伤性脑损伤的临床试验已经确定了米诺环素或N-乙酰半胱氨酸的安全性，并表明这两种药物都有一定的疗效。临床前研究表明，米诺环素加N-乙酰半胱氨酸具有积极的协同作用，导致治疗效果和更长的治疗时间窗，这是单个药物所未见的。这篇综述比较了米诺环素和N-乙酰半胱氨酸，单独和组合的行动。有证据表明，联合用药比单独用药对治疗创伤性脑损伤有更大的效用。
Traumatic brain injury has a complex pathophysiology that produces both rapid and delayed brain damage. Rapid damage initiates immediately after injury. Treatment of traumatic brain injury is typically delayed many hours, thus only delayed damage can be targeted with drugs. Delayed traumatic brain injury includes neuroinflammation, oxidative damage, apoptosis, and glutamate toxicity. Both the speed and complexity of traumatic brain injury pathophysiology present large obstacles to drug development. Repurposing of Food and Drug Administration-approved drugs may be a highly efficient approach to get therapeutics to the clinic. This review examines the preclinical outcomes of minocycline and N-acetylcysteine as individual drugs and compares them to the minocycline plus N-acetylcysteine combination. Both minocycline and N-acetylcysteine are Food and Drug Administration-approved drugs with pleiotropic therapeutic effects. As individual drugs, minocycline and N-acetylcysteine are well tolerated, with known pharmacokinetics, and enter the brain through an intact blood-brain barrier. At concentrations greater than needed for anti-microbial action, minocycline is a potent anti-inflammatory minocycline, also acts as an antioxidant and inhibits multiple enzymes that promote brain injury including metalloproteases, caspases, and polyADP-ribose-polymerase-1. N-acetylcysteine alone is also an antioxidant. It increases brain glutathione, prevents lipid oxidation, and protects mitochondria. N-acetylcysteine also acts as an anti-inflammatory as well as increases extracellular glutamate by activating the Xc cystine-glutamate anti-transporter. These multiple actions of minocycline and N-acetylcysteine have made them attractive candidates to treat traumatic brain injury. When first dosed within the one hour after injury, either minocycline or N-acetylcysteine improves a diverse set of therapeutic outcome measures in multiple traumatic brain injury animal models. A small number of clinical trials for traumatic brain injury have established the safety of minocycline or N-acetylcysteine and suggested that either drug has some efficacy. Preclinical studies have shown that minocycline plus N-acetylcysteine have positive synergy resulting in therapeutic effects and a more prolonged therapeutic time window not seen with the individual drugs. This review compares the actions of minocycline and N-acetylcysteine, individually and in combination. Evidence supports that the combination has greater utility to treat traumatic brain injury than the individual drugs.
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