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    • The results also showed that the A receptor http www

    2023-09-18

    The results also showed that the A3 receptor agonist increased the phosphorylated levels of Akt, leading to activation of the PI3K/Akt pathway. A3 K02288 stimulation has protective effects against RGC death following ischemia-reperfusion, glutamate toxicity, and optic nerve transection models (Galvao et al., 2015). Galvao et al. reported that the A3 receptor contributes to neuronal survival; however, the authors did not clearly describe its mechanism, but hypothesized that the neuroprotective effects might be associated with Ca2+ influx into neurons, because A3 receptor stimulation caused P2X7 receptor inhibition, resulting in suppression of Ca2+ influx (Zhang et al., 2006b, 2010). Notably, P2X7 receptors also activated the PI3K/Akt/glycogen synthase kinase-3β (GSK3-β) pathway (Diaz-Hernandez et al., 2008), and activation of PI3K/Akt has been reported to cause neural regeneration. For example, activation of the PI3K/Akt pathway inactivated GSK3-β (Grimes and Jope, 2001), and its inhibitor promoted neurite outgrowth in cultured hippocampal neuron (Yoshimura et al., 2005). A phosphatase and tensin homolog (PTEN) suppressed the PI3K/Akt/mammalian target of the rapamycin (mTOR) pathway and PTEN ablation promoted neural regeneration in the optic nerve (Park et al., 2008). These findings suggest that the neurite outgrowth-inducing effects of the A3 receptor agonist are related to the activation of the PI3K/Akt pathway, which is consistent with previous studies (Yoshimura et al., 2005; Park et al., 2008). Our subsequent studies using LY294002, a specific inhibitor of the PI3K/Akt pathway, showed that the neurite outgrowth-inducing effects of 2-Cl-IB-MECA were completely inhibited. Taken together, the results suggest that adenosine is able to promote neural regeneration in RGCs through the A3 receptor by activation of the PI3K/Akt pathway, but not by the cAMP pathway. IOP reduction is the most important clinical target in glaucoma treatment. The A3 receptor contributes to modulation of IOP. For example, Avila et al., showed that selective A3 receptor antagonists decreased IOP in mice in vivo (Avila et al., 2001, 2002). On the other hand, Avni et al. showed that a selective A3 receptor agonist significantly decreased IOP in humans (Avni et al., 2010). These previous reports suggest that both stimulation and inhibition of A3 AdoR signaling decrease IOP. Stimulation of the A3 receptor may therefore be a target for the development of novel glaucoma therapies because of its potent effects on IOP reduction and axon regeneration.
    Conclusions This study shows that the A3 receptor, in addition to its well-known neuroprotective and IOP-lowering effects, is the specific receptor involved in the neurite outgrowth-promoting effects of adenosine. Therefore, AdoR modulators may be useful for the development of novel anti-glaucoma medications.
    Grant information This work was supported by JSPS KAKENHI Grant 17H04351(to HT) and 16K11290 (to KI). The foundation and sponsor had no role in this work.
    Financial or proprietary interests Tanihara has received consulting fees from Kowa, and MSD, board membership fees from Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, and Pfizer Japan, and research grants from Kowa, Senju Pharmaceutical, Santen Pharmaceutical, Alcon Japan, Pfizer Japan, and Otsuka Pharmaceutical. Inoue has received a research grant from Novartis Pharma. Other authors have no financial interests. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
    Acknowledgements
    Introduction Neural progenitor cells (NPCs) are self-renewing, multipotent cells that are capable of differentiating into neurons, astrocytes, and oligodendrocytes in the central nervous system (CNS) (Lan et al., 2012). In addition, NPCs play a key role not only in the maintenance of the adult CNS but also in the ability to recover from injury and neurodegenerative disease (Johansson et al., 1999, Lois and Alvarez-Buylla, 1993, Morshead et al., 1998). It is well known that neurogenesis is dependent upon proper NPC proliferation, differentiation, directed migration, survival, maturation, and functional integration of progeny into neuronal circuits (Fallon et al., 2000, Ming and Song, 2005, Wu et al., 2009). Cell death is a characteristic of acute CNS disorders as well as neurodegenerative disease. The loss of cells is amplified by the lack of regenerative abilities for cell replacement and repair in the CNS. However, NPCs are activated in response to a variety of pathological states in brain injury and neurodegenerative disease. NPCs can respond brain injury by proliferation and differentiation, and this is conducive to ameliorating the pathogenesis of disease and repair injury (Dietrich and Kempermann, 2006, Mazurova et al., 2006). Therefore, it is essential to screen the factors and other compounds that are enhanced in NPC proliferation and to understand their signaling pathways.