Remyelination after traumatic brain injury

描述(申请人提供)：对大脑修复创伤性脑损伤(TBI)的能力知之甚少。已经开发出通过预防损伤来治疗脑损伤的药物，但到目前为止，这些药物都未能通过临床试验。因此，每年患有脑外伤的170万美国人没有治疗方法。然而，最近FDA批准的药物，米诺环素加N-乙酰半胱氨酸，被证明可以改善实验性脑损伤后的认知和记忆。这些药物的作用机制尚不清楚。这些观察结果为通过修复而不是预防脑损伤来改善大脑功能的长期目标提供了理由。这项提议将检验一个中心假设：米诺(Mino)和N-乙酰半胱氨酸(NAC)促进脑外伤后再髓鞘形成并改善认知和记忆。三个特定的目标将验证这一假说：1)Mino加NAC在受控皮质冲击(CCI)脑损伤模型中何时何地诱导再髓鞘形成？初步数据显示，CCI会导致中线白质结构的广泛脱髓鞘，而Mino加NAC对这种脱髓鞘几乎没有影响。在2周内，Mino加NAC治疗增加了先前脱髓鞘的白质束中的髓鞘含量。2)Mino Plus NAC调制哪些细胞类型？初步数据表明，Mino+NAC通过增加抗炎、组织重塑的M2小胶质细胞的数量，而减少促炎的M1小胶质细胞，来调节损伤白质中的小胶质细胞极性。Mino加NAC还可诱导少突胶质细胞增加脱髓鞘白质中的髓鞘含量。3)髓鞘再生能改善认知和记忆吗？初步数据显示，CCI阻止了主动位置回避任务的习得和长期保持。Mino加NAC处理可提高获得率和保持率。初步数据还显示，单侧立体定向注射溶血磷脂酰胆碱(LPC)到海马伞可产生类似于CCI的局限性脱髓鞘和认知障碍。与CCI不同的是，LPC脱髓鞘的菌毛会自发地重新髓鞘。海马伞的再髓鞘形成伴随着脱髓鞘所产生的认知缺陷的逆转。这项拟议的研究具有创新性和重要意义，因为它探索了新的发现，即脑外伤后重新髓鞘形成的能力不会丧失，并且可以通过药物恢复。如果成功，这些拟议的实验将大大增加我们对脑损伤病理生理学的了解，并提供有关Mino和NAC药物作用的重要信息。Mino和NAC的安全性和有效性是公认的，因为这两种药物都是FDA批准的用于脑损伤以外的用途，并且作为单一药物正在进行临床试验，用于各种脑部疾病。FDA批准的药物的重复使用 可能是将治疗脑损伤的新药投入临床试验的最快途径。归根结底，从这项建议中获得的知识有可能极大地提高创伤性脑损伤后的生活质量。

DESCRIPTION (provided by applicant): Little is known about the ability of the brain to repair traumatic brain injury (TBI). Drugs have been developed that treat TBI by preventing injury, but to date these drugs have failed clinical trials. As a result, there are no treatments available to the 1.7 million Americans who annually sustain TBI. Recently, however, the FDA-approved drugs, minocycline plus N-acetyl cysteine, have been shown to improve cognition and memory after experimental TBI. The mechanism of how these drugs work is unknown. These observations provide the justification for the long-term goal to improve brain function by repairing, rather than preventing, TBI. This proposal will test a central hypothesis that: Minocycline (MINO) and N-acetyl cysteine (NAC) promote remyelination and improve cognition and memory following TBI. Three specific aims will test this hypothesis: 1) When and where does MINO plus NAC induce remyelination in the controlled cortical impact (CCI) model of TBI? Preliminary data show that CCI produces widespread demyelination of midline white matter structures, and MINO plus NAC has little effect on this demyelination. Within 2 weeks, MINO plus NAC treatment increased myelin content in previously demyelinated white matter tracts. 2) Which cell types are modulated by MINO plus NAC? Preliminary data indicate that MINO plus NAC modulate microglial polarity in injured white matter by increasing the numbers of anti-inflammatory, tissue-remodeling M2 microglia while decreasing pro-inflammatory M1 microglia. MINO plus NAC also induce oligodendrocytes to increase myelin content in demyelinated white matter. 3) Does remyelination improve cognition and memory? Preliminary data show that CCI prevents acquisition and long-term retention of an active place avoidance task. Both acquisition and retention are improved by MINO plus NAC treatment. Preliminary data also show that an unilateral stereotaxic injection of lysophosphotidylcholine (LPC) into the fimbria produces a localized demyelination and cognitive deficits similar to CCI. Unlike CCI, the LPC-demyelinated fimbria spontaneously remyelinates. Remyelination of the fimbria is accompanied by reversal of the cognition deficits produced by demyelination. This proposed research is both innovative and significant because it explores the novel finding that the ability to remyelinate is not lost following TBI and can be restored with drugs. If successful, the proposed experiments will substantively increase our knowledge of the pathophysiology of TBI as well as provide important information on the drug action of MINO and NAC. The safety and efficacy of MINO and NAC are well-established because both drugs are FDA-approved for uses other than TBI and are in clinical trials, as single drugs, for a variety of brain diseases. The re-use of FDA-approved drugs is perhaps the fastest route to get new drugs to treat TBI into clinical trials. Ultimately, the knowledge gained from this proposal has the potential to greatly improve quality of life after traumatic brain injury.