Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade.
Neuroprotection by adenosine in the brain: From A(1) receptor activation to A (2A) receptor blockade.
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DOI：
10.1007/s11302-005-0649-1
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发表时间：
2005-06
影响因子：
3.5
通讯作者：
Cunha, Rodrigo A
中科院分区：
文献类型：
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作者：
Cunha, Rodrigo A
腺苷是一种神经调质，通过最丰富的抑制性腺苷A1受体（A1R）和不太丰富但广泛分布的易化性A2AR起作用。通常认为A1R在神经保护中起关键作用，因为它们减少谷氨酸释放和高兴奋神经元。事实上，A1R在神经元损伤开始时的激活减轻了脑损伤，而其阻断加重了成年动物的损伤。然而，有一个下调的中央A1受体在慢性有害的情况下。相比之下，A2AR在有害的大脑条件下上调，并且它们的阻断在成年动物中赋予强大的脑神经保护作用。A2AR拮抗剂的脑神经保护作用在慢性有害脑状况中得以维持，而没有可观察到的外周效应，因此证明了A2AR拮抗剂作为神经变性疾病如帕金森病和阿尔茨海默病、缺血性脑损伤和癫痫的新型保护剂的兴趣。与A1R激活相比，A2AR阻断的更大意义并不意味着A1R激活与神经保护策略无关。事实上，有人提出，A2AR拮抗剂与旨在爆发细胞外腺苷水平（通过抑制腺苷激酶）以激活A1R的策略相结合，可能构成基于腺苷神经调节系统的更强大的脑神经保护策略。这种策略在成年动物中应该是有用的，特别是在老年人中（脑病变普遍存在），但对于腺苷受体对脑损伤的影响不同的胎儿或新生儿无效。
Adenosine is a neuromodulator that operates via the most abundant inhibitory adenosine A1 receptors (A1Rs) and the less abundant, but widespread, facilitatory A2ARs. It is commonly assumed that A1Rs play a key role in neuroprotection since they decrease glutamate release and hyperpolarize neurons. In fact, A1R activation at the onset of neuronal injury attenuates brain damage, whereas its blockade exacerbates damage in adult animals. However, there is a down-regulation of central A1Rs in chronic noxious situations. In contrast, A2ARs are up-regulated in noxious brain conditions and their blockade confers robust brain neuroprotection in adult animals. The brain neuroprotective effect of A2AR antagonists is maintained in chronic noxious brain conditions without observable peripheral effects, thus justifying the interest of A2AR antagonists as novel protective agents in neurodegenerative diseases such as Parkinson’s and Alzheimer’s disease, ischemic brain damage and epilepsy. The greater interest of A2AR blockade compared to A1R activation does not mean that A1R activation is irrelevant for a neuroprotective strategy. In fact, it is proposed that coupling A2AR antagonists with strategies aimed at bursting the levels of extracellular adenosine (by inhibiting adenosine kinase) to activate A1Rs might constitute the more robust brain neuroprotective strategy based on the adenosine neuromodulatory system. This strategy should be useful in adult animals and especially in the elderly (where brain pathologies are prevalent) but is not valid for fetus or newborns where the impact of adenosine receptors on brain damage is different.