Remyelination after traumatic brain injury

描述（由申请人提供）：关于大脑修复创伤性脑损伤（TBI）的能力知之甚少。已经开发了通过预防损伤来治疗TBI的药物，但迄今为止，这些药物的临床试验都失败了。因此，每年有170万美国人患有TBI，他们无法获得治疗。然而，最近，FDA批准的药物米诺环素加N-乙酰半胱氨酸已被证明可以改善实验性TBI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TBI来改善大脑功能的长期目标提供了理由。该提案将测试一个中心假设：米诺环素（MINO）和N-乙酰半胱氨酸（NAC）促进髓鞘再生，改善TBI后的认知和记忆。三个具体的目标将测试这一假设：1）在TBI的受控皮质撞击（CCI）模型中，MINO加NAC何时何地诱导髓鞘再生？初步数据显示CCI引起广泛的中线白色物质结构脱髓鞘，MINO加NAC对这种脱髓鞘作用不大。在2周内，MINO加NAC治疗增加了先前脱髓鞘的白色物质束中的髓鞘含量。2)MINO加NAC可调节哪些细胞类型？初步数据表明，MINO加NAC通过增加抗炎、组织重塑M2小胶质细胞的数量，同时减少促炎M1小胶质细胞，来调节受损白色物质中的小胶质细胞极性。MINO加NAC还诱导少突胶质细胞增加脱髓鞘白色物质中的髓鞘含量。3)髓鞘再生能改善认知和记忆吗？初步数据表明，CCI防止收购和长期保留的积极的地方回避任务。MINO加NAC治疗改善了获得和保留。初步数据还表明，单侧立体定位注射溶血磷脂酰胆碱（LPC）到伞产生局部脱髓鞘和认知功能障碍，类似CCI。与CCI不同，LPC脱髓鞘的菌毛自发地重新髓鞘化。菌毛的再髓鞘化伴随着由脱髓鞘产生的认知缺陷的逆转。这项拟议的研究既具有创新性又具有重要意义，因为它探索了新的发现，即TBI后髓鞘再生的能力不会丧失，并且可以通过药物恢复。如果成功的话，拟议的实验将大大增加我们对TBI的病理生理学的了解，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批准用于TBI以外的用途，并且作为单一药物正在临床试验中，用于各种脑部疾病。重复使用FDA批准的药物 也许是让治疗创伤性脑损伤的新药进入临床试验的最快途径。最终，从这项建议中获得的知识有可能大大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.