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，我们知之甚少。通过预防损伤来治疗创伤性脑损伤的药物已经被开发出来，但到目前为止，这些药物还没有通过临床试验。因此，每年有170万美国人遭受创伤性脑损伤，却没有治疗方法。然而，最近fda批准的药物二甲胺四环素加n -乙酰半胱氨酸已被证明可以改善实验性脑外伤后的认知和记忆。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创伤性脑损伤来改善大脑功能的长期目标提供了依据。该建议将验证一个中心假设：二甲胺四环素（MINO）和n -乙酰半胱氨酸（NAC）促进脑外伤后的髓鞘再生和改善认知和记忆。三个具体目标将验证这一假设：1)在TBI的控制性皮质冲击（CCI）模型中，MINO加NAC在何时何地诱导髓鞘再生？初步数据显示，CCI可引起中线白质结构的广泛脱髓鞘，而MINO + NAC对这种脱髓鞘的影响很小。在2周内，MINO加NAC治疗增加了先前脱髓鞘白质束的髓磷脂含量。2) MINO + NAC可调节哪些细胞类型？初步数据表明，MINO + NAC通过增加抗炎、组织重塑M2小胶质细胞数量，减少促炎M1小胶质细胞数量来调节损伤白质中的小胶质细胞极性。MINO加NAC还能诱导少突胶质细胞增加脱髓鞘白质中的髓磷脂含量。3)髓鞘再生是否能改善认知和记忆？初步数据表明，CCI可阻止主动地点回避任务的习得和长期保留。MINO + NAC处理可提高获取和留存率。初步数据还显示，单侧立体定向注射溶血磷脂酰胆碱（LPC）进入毛膜会产生类似CCI的局部脱髓鞘和认知缺陷。与CCI不同，lpc脱髓鞘纤维会自发地重新形成髓鞘。纤维的再髓鞘形成伴随着由脱髓鞘产生的认知缺陷的逆转。这项研究具有创新性和重要意义，因为它探索了一个新的发现，即脑外伤后髓鞘再生能力不会丧失，而且可以通过药物恢复。如果实验成功，将大大增加我们对脑损伤病理生理的认识，并为MINO和NAC的药物作用提供重要信息。MINO和NAC的安全性和有效性是公认的，因为这两种药物都被fda批准用于TBI以外的用途，并且作为单一药物用于多种脑部疾病的临床试验。重新使用fda批准的药物

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.