碳酸酐酶抑制在脑缺血及模型中的保护作用。

Protective effects of carbonic anhydrase inhibition in brain ischaemia and models.

机构信息

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Division of Pharmacology and Toxicology, University of Florence, Florence, Italy.

Department of Neuroscience, Psychology, Drug Research and Child Health (NEUROFARBA), Section of Pharmaceutical Sciences, University of Florence, Florence, Italy.

出版信息

J Enzyme Inhib Med Chem. 2021 Dec;36(1):964-976. doi: 10.1080/14756366.2021.1907575.

Ischaemic stroke is a leading cause of death and disability. One of the major pathogenic mechanisms after ischaemia includes the switch to the glycolytic pathway, leading to tissue acidification. Carbonic anhydrase (CA) contributes to pH regulation. A new generation of CA inhibitors, AN11-740 and AN6-277 and the reference compound acetazolamide (ACTZ) were investigated in two models of brain ischaemia: in rat hippocampal acute slices exposed to severe oxygen, glucose deprivation (OGD) and in an model of focal cerebral ischaemia induced by permanent occlusion of the middle cerebral artery (pMCAo) in the rat. , the application of selective CAIs significantly delayed the appearance of anoxic depolarisation induced by OGD. , sub-chronic systemic treatment with AN11-740 and ACTZ significantly reduced the neurological deficit and decreased the infarct volume after pMCAo. CAIs counteracted neuronal loss, reduced microglia activation and partially counteracted astrocytes degeneration inducing protection from functional and tissue damage.

缺血性中风是死亡和残疾的主要原因之一。缺血后的主要发病机制之一包括向糖酵解途径的转变，导致组织酸化。碳酸酐酶（CA）有助于 pH 值调节。新一代 CA 抑制剂 AN11-740 和 AN6-277 以及参考化合物乙酰唑胺（ACTZ）在两种脑缺血模型中进行了研究：在大鼠海马急性切片中暴露于严重的氧葡萄糖剥夺（OGD）和在大鼠中通过永久性阻断大脑中动脉（pMCAo）诱导的局灶性脑缺血模型中。结果表明，选择性 CAIs 的应用显著延迟了 OGD 诱导的缺氧去极化的出现。结果表明，亚慢性系统给予 AN11-740 和 ACTZ 可显著减轻 pMCAo 后的神经功能缺损和梗死体积。CAIs 对抗神经元丢失，减少小胶质细胞激活，并部分对抗星形胶质细胞变性，从而提供对功能和组织损伤的保护。