Coppi Elisabetta, Cherchi Federica, Gibb Alasdair J
Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy.
Department of Neuroscience, Physiology and Pharmacology, University College London, London, UK.
Neural Regen Res. 2024 Feb;19(2):255-257. doi: 10.4103/1673-5374.375309.
During brain ischemia, excitotoxicity and peri-infarct depolarization injuries occur and cause cerebral tissue damage. Indeed, anoxic depolarization, consisting of massive neuronal depolarization due to the loss of membrane ion gradients, occurs in vivo or in vitro during an energy failure. The neuromodulator adenosine is released in huge amounts during cerebral ischemia and exerts its effects by activating specific metabotropic receptors, namely: A, A, A, and A. The A receptor subtype is highly expressed in striatal medium spiny neurons, which are particularly susceptible to ischemic damage. Evidence indicates that the A receptors are upregulated in the rat striatum after stroke and the selective antagonist SCH58261 protects from exaggerated glutamate release within the first 4 hours from the insult and alleviates neurological impairment and histological injury in the following 24 hours. We recently added new knowledge to the mechanisms by which the adenosine A receptor subtype participates in ischemia-induced neuronal death by performing patch-clamp recordings from medium spiny neurons in rat striatal brain slices exposed to oxygen and glucose deprivation. We demonstrated that the selective block of A receptors by SCH58261 significantly reduced ionic imbalance and delayed the anoxic depolarization in medium spiny neurons during oxygen and glucose deprivation and that the mechanism involves voltage-gated K channel modulation and a presynaptic inhibition of glutamate release by the A receptor antagonist. The present review summarizes the latest findings in the literature about the possibility of developing selective ligands of A receptors as advantageous therapeutic tools that may contribute to counteracting neurodegeneration after brain ischemia.
在脑缺血期间，会发生兴奋性毒性和梗死周围去极化损伤，进而导致脑组织损伤。事实上，缺氧去极化是由于膜离子梯度丧失导致大量神经元去极化，在能量衰竭期间可在体内或体外发生。神经调质腺苷在脑缺血期间大量释放，并通过激活特定的代谢型受体发挥作用，即：A1、A2A、A2B和A3。A2A受体亚型在纹状体中等棘状神经元中高度表达，这些神经元对缺血损伤特别敏感。有证据表明，中风后大鼠纹状体中的A2A受体上调，选择性拮抗剂SCH58261可在损伤后的前4小时内防止谷氨酸过度释放，并在接下来的24小时内减轻神经功能障碍和组织学损伤。我们最近通过对暴露于氧和葡萄糖剥夺的大鼠纹状体脑片中的中等棘状神经元进行膜片钳记录，为腺苷A2A受体亚型参与缺血诱导的神经元死亡的机制增添了新的知识。我们证明，在氧和葡萄糖剥夺期间，SCH58261对A2A受体的选择性阻断显著减少了离子失衡，并延迟了中等棘状神经元的缺氧去极化，其机制涉及电压门控钾通道调节以及A2A受体拮抗剂对谷氨酸释放的突触前抑制。本综述总结了文献中关于开发A2A受体选择性配体作为可能有助于对抗脑缺血后神经退行性变的有利治疗工具的最新发现。
