重新洗牌豆瓣:停止大脑的自我损害

    三分之一的中风幸存者永远无法恢复全部的脑功能并生活自理。现在，科学家们认为他们找到了原因。当中风杀死一个带状区域的脑细胞后，一种叫伽马氨基丁酸（GABA）的神经传递素将破坏残存的，看起来还健康的脑组织。研究者建议，如果能抑制伽马氨基丁酸，则可能使遭受中风痛苦的大脑更好地克服因此产生的损害。

When a stroke hits, physicians have few options. If they catch it early enough, they can administer the clot-busting drug tPA to keep even more brain cells from dying—but tPA is not appropriate for all types of stroke. Physicians can also prescribe physical therapy, which can occasionally help recover impaired motor function. Yet there are no approved drugs that help the brain heal. 

    发生中风时，医生通常无计可施。如果他们能够在早期发现中风征兆，那么可以通过给病人服用抗栓塞药物（TPA）以避免更多的脑细胞死亡，但这种药物不是对所有种类的中风都有效。医生也可以让病人进行物理治疗，这样有时可以帮助病人恢复受损的运动机能。但目前仍旧没有被人们认可的药物来治愈大脑。

For its part, the brain appears to try a sort of natural drug therapy to limit the spread of damage. It releases extra amounts of GABA, which reduces the firing of neurons. GABA initially prevents stroke-damaged brain tissue from becoming overexcited and dying. But University of California, Los Angeles (UCLA), investigators led by Thomas Carmichael, a specialist in stroke, and Istvan Mody, an expert in inhibition, wondered whether GABA might also interfere with the brain's plasticity, the ability of healthy regions to take over for injured ones. 

    大脑本身会试图对受损部分进行一种自然药物治疗，从而限制破坏程度的扩大。它会释放过量的伽马氨基丁酸（GABA），以降低中风对受损位置神经元的刺激。伽马氨基丁酸最初会抑制中风破坏的大脑组织过分兴奋和死亡。但加州大学洛杉矶分校以中风专家托马斯卡迈克尔，以及抑制作用专家伊什特万穆为首的研究员们考虑，伽马氨基丁酸是否有可能同时抑制大脑的重塑性，也就是健康区域逐渐接管受损区域功能的能力。

Previous studies had tried to address this question, but they produced confusing results. The UCLA team hypothesized that others had failed to distinguish between two types of inhibition—phasic, in which GABA acts upon specific receptors at nerve cell sites called synapses, and tonic, in which the neurotransmitter acts on other receptors elsewhere on the nerve cell. "We looked at all the properties of neural transmission after stroke, and we found the most prominent change was an increase in the tonic form of inhibition in the cortical region next to the stroke damage," says graduate student and study co-author Ben Huang. So the group gave stroke-afflicted rodents a drug that could specifically block GABA-mediated tonic inhibition but left phasic inhibition intact. The mice had suffered damage in areas that control movement, yet they recovered about 50% more function in their limbs than similar rodents treated with a control therapy, the team reports online today in Nature.

    过去的研究曾试图解决这个问题，但他们得出了令人困惑的结果。加州大学的研究组设想其他人可能没有区分开两种抑制力 — 一种是短暂性抑制，伽马氨基丁酸对神经细胞突触上的个别受体产生作用。另一种是持续性抑制，这时伽马氨基丁酸作用于神经元细胞其他位置的其他受体。“我们观察了中风后神经传输得所有特性发现，最显著地变化是中风破坏处相近的皮层区的持续性抑制增加了。”著作共同撰稿人，研究生黄贲说。于是，研究小组给中风后的啮齿类动物服用可以单纯阻止伽马氨基丁酸持续性抑制，而不影响其短暂性抑制的药物。根据研究小组今天发布在《自然》杂志网上的报告，运动系统控制区域受损的老鼠四肢恢复了大约50%以上的功能，比其他只接受物理治疗的啮齿类动物要高得多。

The findings suggest a new, potentially therapeutic window for treating stroke, says Carmichael. Physicians might be able to give a GABA-blocking drug after stroke, for example. The key would be proper timing: after tonic inhibition had initially protected as many brain cells as possible but before it begins interfering with the brain's recovery attempts. The class of drugs used by the UCLA team to block GABA receptors is currently in clinical development for other conditions, such as memory loss, and has been well-tolerated in small studies. However, the drugs have not yet been tested on stroke patients. Clinical trials are a long way off, cautions Carmichael, because more animal studies by other labs must be performed first. 

    卡迈克尔说，这项发现为中风治疗提供了一种新的，有潜力的方案。比如，医生们可以给中风患者服用伽马氨基丁酸的抑制药物。问题的关键在于合适的时间：要在持续性抑制拯救了足够多得脑细胞之后，和它开始干涉脑恢复之前。这类伽马氨基丁酸受体的抑制药物现正被加州大学的研究小组用于其他方面的临床研究，如失忆，并在一些小的研究上得到了广泛的认同。但这种药物还没有在中风病人中实验。临床试验还有很长的路要走，卡迈克尔很谨慎，因为必须先在其他实验室做更多的动物研究才行。

Nonetheless, other neuroscientists say the work offers a new direction for developing stroke drugs. "The result is very gratifying because for many, many years people have focused on excitatory synapses and excitatory connections in terms of brain plasticity," says Takao Hensch, a developmental plasticity researcher in the Molecular and Cellular Biology Department at Harvard University. "It's only in the recent past that we've started to appreciate that the balance of excitation to inhibition is what's important."

    然而，其他神经科学家认为这项研究为研制中风药物提供了新的思路。“研究结果是很可喜的，因为很多很多年以来，人们的研究集中在大脑可塑性的兴奋性突触和兴奋性连接上，” 高尾贵雄说，他是哈佛大学分子与细胞生物学系的一名发育可塑性研究员。“就在前段时间，我们才开始意识到激发抑制平衡是多么的重要。”