Department of Psychology, University of Alberta, Edmonton, Alberta, Canada.
Neuroscience and Mental Health Institute, University of Alberta, Edmonton, Alberta, Canada.
PLoS One. 2019 Jan 10;14(1):e0210660. doi: 10.1371/journal.pone.0210660. eCollection 2019.
After intracerebral hemorrhage (ICH), brain edema commonly occurs and can cause death. Along with edema, there are significant alterations in the concentrations of key ions such as sodium, potassium, and chloride, which are essential to brain function. NKCC1, a cation-chloride cotransporter, is upregulated after brain damage, such as traumatic injury and ischemic stroke. NKCC1 brings sodium and chloride into the cell, possibly worsening ion dyshomeostasis. Bumetanide, a specific NKCC1 antagonist, blocks the transport of chloride into cells, and thus should attenuate the increases in chloride, which should lessen brain edema and improve neuronal functioning post-ICH, as with other injuries. We used the collagenase model of ICH to test whether bumetanide treatment for three days (vs. vehicle) would improve outcome. We gave bumetanide beginning at two hours or seven days post-ICH and measured behavioural outcome, edema, and brain ion content after treatment. There was some evidence for a minor reduction in edema after early dosing, but this did not improve behaviour or lessen injury. Contrary to our hypothesis, bumetanide did not normalize ion concentrations after late dosing. Bumetanide did not improve behavioural outcome or affect lesion volume. After ICH, bumetanide is safe to use in rats but does not improve functional outcome in the majority of animals.
脑出血 (ICH) 后，脑水肿通常会发生，并可能导致死亡。随着水肿的出现，钠离子、钾离子和氯离子等关键离子的浓度会发生显著变化，而这些离子对大脑功能至关重要。NKCC1 是一种阳离子-氯离子共转运体，在脑损伤（如创伤性损伤和缺血性中风）后会被上调。NKCC1 将钠离子和氯离子带入细胞内，可能会加重离子失衡。布美他尼是一种特异性 NKCC1 拮抗剂，可阻断氯离子进入细胞内，因此应该减轻氯离子的增加，从而减轻 ICH 后和其他损伤后的脑水肿和改善神经元功能。我们使用胶原酶 ICH 模型来测试 bumetanide 治疗三天（与载体相比）是否会改善预后。我们在 ICH 后两小时或七天开始给予 bumetanide，并在治疗后测量行为结果、脑水肿和脑内离子含量。早期给药后有一些轻微减少水肿的证据，但这并没有改善行为或减轻损伤。与我们的假设相反，bumetanide 并没有在晚期给药后使离子浓度正常化。bumetanide 并未改善行为结果或影响病变体积。在 ICH 后，bumetanide 在大鼠中使用是安全的，但不能改善大多数动物的功能预后。
