Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury.
Delayed dosing of minocycline plus N-acetylcysteine reduces neurodegeneration in distal brain regions and restores spatial memory after experimental traumatic brain injury.
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DOI：
10.1016/j.expneurol.2021.113816
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发表时间：
2021-11
影响因子：
5.3
通讯作者：
Bergold PJ
中科院分区：
文献类型：
--
作者：
Whitney K;Nikulina E;Rahman SN;Alexis A;Bergold PJ
治疗创伤性脑损伤(TBI)的多种药物均未通过临床试验。随着受伤和治疗之间时间间隔的增加，大多数药物都会失效。治疗时间窗不足是临床试验失败的主要原因。很少有药物开发出足够长的治疗时间窗口来治疗脑损伤，因为如果治疗被推迟几个小时到几天，人们对哪些大脑功能可以成为靶点知之甚少。在小鼠闭合性脑损伤(CHI)实验模型中，我们确定了多个损伤参数，这些参数通过在伤后72小时首次使用米诺(Mino)加N-乙酰半胱氨酸(NAC)的药物联合治疗而得到改善。CHI产生空间记忆缺陷，导致Barnes迷宫表现受损，海马神经元丢失，双侧海马神经元、树突、棘突和突触受损。NeuMN72治疗可以恢复Barnes迷宫的获得和保持，防止海马神经元的丢失，限制对树突、棘突和突触的损伤，并加速微管相关蛋白2(MAP2)表达的恢复，微管相关蛋白2是维持正确的树突结构和突触密度的关键蛋白。这些数据表明，除了树突的结构完整性外，损伤后几天首次给药，还可以成功地靶向脊椎和突触密度。即使在受伤后72小时首次给药，Mino Plus NAC仍具有显著的药效，这使Mino plus NAC成为治疗临床脑外伤的有前途的候选药物。
Multiple drugs to treat traumatic brain injury (TBI) have failed clinical trials. Most drugs lose efficacy as the time interval increases between injury and treatment onset. Insufficient therapeutic time window is a major reason underlying failure in clinical trials. Few drugs have been developed with therapeutic time windows sufficiently long enough to treat TBI because little is known about which brain functions can be targeted if therapy is delayed hours to days after injury. We identified multiple injury parameters that are improved by first initiating treatment with the drug combination minocycline (MINO) plus N-acetylcysteine (NAC) at 72 hours after injury (MN72) in a mouse closed head injury (CHI) experimental TBI model. CHI produces spatial memory deficits resulting in impaired performance on Barnes maze, hippocampal neuronal loss, and bilateral damage to hippocampal neurons, dendrites, spines and synapses. neuMN72 treatment restores Barnes maze acquisition and retention, protects against hippocampal neuronal loss, limits damage to dendrites, spines and synapses, and accelerates recovery of microtubule associated protein 2 (MAP2) expression, a key protein in maintaining proper dendritic architecture and synapse density. These data show that in addition to the structural integrity of the dendritic arbor, spine and synapse density can be successfully targeted with drugs first dosed days after injury. Retention of substantial drug efficacy even when first dosed 72 hours after injury makes MINO plus NAC a promising candidate to treat clinical TBI.
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影响因子：
3.7
作者：
Eakin K;Baratz-Goldstein R;Pick CG;Zindel O;Balaban CD;Hoffer ME;Lockwood M;Miller J;Hoffer BJ
通讯作者：
Hoffer BJ
大鼠创伤性脑损伤后对脑炎症反应的抑制作用：N-乙酰半胱氨酸的潜在神经保护机制。
影响因子：
4.6
作者：
Chen, Gang;Shi, Jixin;Hu, Zhigang;Hang, Chunhua
通讯作者：
Hang, Chunhua
树突状棘的超微结构：突触和脊柱形态之间的相关性。
影响因子：
4.3
作者：
Arellano JI;Benavides-Piccione R;Defelipe J;Yuste R
通讯作者：
Yuste R
影响因子：
2.9
作者：
Bigler ED
通讯作者：
Bigler ED
影响因子：
4.2
作者：
Campbell, John N.;Register, David;Churn, Severn B.
通讯作者：
Churn, Severn B.