College of Pharmacy, Institute of Pharmaceutical Science and Technology, Hanyang University, Ansan 15588, Korea.
Department of Physiology, Faculty of Medicine, Istanbul Medipol University, 34810 Istanbul, Turkey.
Int J Mol Sci. 2021 Jul 13;22(14):7495. doi: 10.3390/ijms22147495.
Stroke is one of the leading causes of death and disability worldwide. However, treatment options for ischemic stroke remain limited. Matrix-metalloproteinases (MMPs) contribute to brain damage during ischemic strokes by disrupting the blood-brain barrier (BBB) and causing brain edemas. Carnosine, an endogenous dipeptide, was found by us and others to be protective against ischemic brain injury. In this study, we investigated whether carnosine influences MMP activity. Brain MMP levels and activity were measured by gelatin zymography after permanent occlusion of the middle cerebral artery (pMCAO) in rats and in vitro enzyme assays. Carnosine significantly reduced infarct volume and edema. Gelatin zymography and in vitro enzyme assays showed that carnosine inhibited brain MMPs. We showed that carnosine inhibited both MMP-2 and MMP-9 activity by chelating zinc. Carnosine also reduced the ischemia-mediated degradation of the tight junction proteins that comprise the BBB. In summary, our findings show that carnosine inhibits MMP activity by chelating zinc, an essential MMP co-factor, resulting in the reduction of edema and brain injury. We believe that our findings shed new light on the neuroprotective mechanism of carnosine against ischemic brain damage.
中风是全球范围内导致死亡和残疾的主要原因之一。然而，缺血性中风的治疗选择仍然有限。基质金属蛋白酶（MMPs）通过破坏血脑屏障（BBB）并导致脑水肿，导致缺血性中风时的脑损伤。我们和其他人发现，内源性二肽肌肽对缺血性脑损伤具有保护作用。在这项研究中，我们研究了肌肽是否会影响 MMP 活性。通过大鼠大脑中动脉永久性闭塞（pMCAO）后的明胶酶谱和体外酶测定，测量脑 MMP 水平和活性。肌肽可显著减少梗死体积和水肿。明胶酶谱和体外酶测定表明，肌肽通过螯合锌抑制脑 MMPs。我们表明，肌肽通过螯合锌抑制 MMP-2 和 MMP-9 的活性，锌是 MMP 的必需辅助因子。肌肽还减少了缺血介导的 BBB 紧密连接蛋白的降解。总之，我们的研究结果表明，肌肽通过螯合锌抑制 MMP 活性，锌是 MMP 的必需辅助因子，从而减少水肿和脑损伤。我们相信，我们的发现为肌肽对缺血性脑损伤的神经保护机制提供了新的见解。
