The brain is one of the most vulnerable organs to ischemia. Therefore, scientists have been pursuing research to save the brain against ischemia, and have also spent a great deal of time and money developing drugs to treat stroke. There have been more than 1000 clinical trials on stroke targeting neurons, but most of them have failed [1]. Dr. Barres believes that a neuron-related strategy is insufficient to save the brain and will not result in effective therapeutic drugs for stroke. He has stated “Glial cells know how to save the brain, but researchers have not known yet” [2]. Despite the difficulties encountered in developing drugs and therapies for stroke, major progress has been made in research on ischemic tolerance. In this phenomenon, organs that experience prior mild non-invasive ischemic preconditioning (PC) acquire tolerance to subsequent invasive ischemic stress. This ischemic tolerance is commonly observed clinically and experimentally. The endogenous neuroprotective effects by PC were originally reported in the heart ^[3][4][3,4], but were also observed in the kidneys [5], liver [6], skeletal muscle [7], and the brain ^[8][9][8,9]. Since the discovery of ischemic tolerance [3], it has received tremendous attention because it shows robust neuroprotective effects. With regard to cerebral ischemic tolerance, there have been a large number of studies about mechanisms of ischemic tolerance ^[10][11][10,11], but almost all studies were performed from the point of view of neurons.

2. Localization and Functions of P2X7Rs

Purinergic signaling was proposed as extracellular signaling molecules in 1972, and recently focus has been put on the therapeutic potential of both P1 (adenosine) and P2 receptors ^[12][17]. For example, P2Y12 is a G protein-coupled receptor, and its antagonists inhibit aggregation in platelets and thus are widely used for the treatment of thrombosis and stroke ^[13][18]. Among seven subtypes of P2X ion channel receptors, P2X7Rs are a non-selective cation channel gated eATP, and it has been revealed that they play a crucial role in the CNS ^[14][19]. Although P2X7Rs are ion channels, they differ from other subtypes of P2X receptors in that P2X7Rs are much less sensitive to eATP, require ~mM eATP to be activated, have a long intracellular C terminus, and form a large pore when activated ^[15][20]. Therefore, the activation of P2X7Rs not only increases cation permeability, but also increases the permeability of larger molecules and various C-terminus-mediated intracellular signal cascades. These cascades include phosphatidylinositol 3-kinase/Akt, extracellular signal-regulated kinase, and mitogen-activated protein kinases ^[16][17][21,22]. Therefore, the roles of P2X7Rs are diverse and control various physiological and pathological events. These events include the release of proinflammatory cytokines, such as tumor necrosis factor ^[18][23] and interleukin-1β ^[19][24], proliferation ^[20][25], induction of cell death ^[21][26], phagocytosis ^[22][27], and inflammatory responses ^[23][28]. In the adult brain, P2X7Rs are mainly expressed in microglia. In physiological conditions, P2X7Rs are not active simply because eATP in the healthy brain is insufficient to activate these weakly sensitive P2 receptors ^[24][25][29,30]. Additionally, the findings that P2X7R knockout mice are healthy and have no major phenotype in physiological conditions ^[26][31] support the idea that P2X7Rs do not function well in the healthy brain. However, unlike physiological conditions, P2X7Rs are upregulated and activated in various pathological conditions or diseases (Table 1). P2X7Rs are associated with the pathological process of neuropathic pain via inflammatory responses, such as the release of tumor necrosis factor-α and interleukin-1β. In spared nerve injury, which is a neuropathic pain model, P2X7Rs are increased in microglia, and a P2X7R antagonist can suppress the development of mechanical hypersensitivity ^[27][32].