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    • br Conclusions and clinical relevance Astrogliosis and an in

    2024-03-27


    Conclusions and clinical relevance Astrogliosis and an increase in ADK is a pathologcial hallmark of epilepsy. The consequence of increased ADK in the epileptic Adenine sulfate receptor is a decrease in the ambient adenosine tone and A1R activity. As a result, systemic administration of A1R agonists or ADK inhibitors successfully attenuates seizure activity (Fredholm, 2003, Jacobson and Gao, 2006, Boison, 2011). However, the use of systemic A1R agonists, ADK inhibitors or adenosine as a therapeutic strategy for epilepsy treatment is limited due to negative side effects including bradycardia, vasoconstriction in the kidney and sedation (Albrecht-Kupper et al., 2012). Thus, it is imperative that novel therapeutic approaches, which focally restore normal adenosine levels, are developed for epilepsy treatment. The prospects for these new therapies are likely to be successful based on the efficacy of adenosine augmentation in rodents. Multiple studies have established that focal delivery of adenosine to the brain, via either transplantation of ADK deficient embryonic stem cells (Li et al., 2007b, Ren et al., 2007, Li et al., 2009, Ren and Boison, 2010) or biodegradable adenosine loaded silk based polymers (Wilz et al., 2008, Szybala et al., 2009), prevents seizures and epileptogenesis. Additionally, the ketogenic diet, which is effective in treating refractory epileptic patients, has been shown to mediate anticonvulsant actions through the A1R (Masino et al., 2011). By further developing adenosine augmentation therapies for clinical use it may be possible to revolutionize the neurocentric approach to treating epilepsy; thereby, finding a cure.
    Biology of the CD73-extracellular adenosine pathway The adenosinergic pathway is a complex system of enzymes, transporters and receptors regulating the conversion of pro-inflammatory and immuno-stimulatory extracellular ATP into immunosuppressive adenosine [1]. In this system, CD73 has a unique function in that it regulates production of immunosuppressive adenosine. CD73, also called ecto-5′-nucleotidase (encoded by the NT5E gene), is a 70-kD glycosylphosphatidylinositol (GPI) anchored cell-surface homodimer. CD73 can also be cleaved from the cell surface and an enzymatically active soluble CD73 can be found in extracellular fluids and blood [2]. CD73 is the principal enzyme responsible for the breakdown of extracellular AMP into adenosine [3]. Extracellular AMP is generally generated from phospho-hydrolysis of ATP by ecto-ATPDases such as CD39. Extracellular AMP can further be generated by an alternative, CD39-independent pathway, involving the degradation of extracellular NAD+ through the sequential enzymatic activity of CD38 and CD203a/PC-1 [4]. CD73-derived adenosine exerts its biological function by binding to one of the four G protein-coupled adenosine receptors (A1, A2a, A2b, and A3), via cellular uptake through equilibrative or concentrative nucleoside transporters (ENTs and CNTs, respectively) or via catabolism into inosine by adenosine deaminase. Because of its short half-life, extracellular adenosine essentially mediates its biologic functions in the proximal cellular environment. Activation of cyclic AMP (cAMP) elevating A2a (expressed on lymphocytes and myeloid cells) and A2b receptors (expressed on myeloid cells) is immunosuppressive, and as such serve to maintain immune homeostasis. Notably, A2a adenosine receptors are significantly upregulated following T cell activation [5]. Activation of A2a receptor potently suppresses T cell receptor signaling through activation of type I protein kinase A (PKA) and its phosphorylation of C-terminal Src kinase (Csk), inhibiting the Src family tyrosine kinases Lck and Fyn [6]. The cAMP-elevating and immunosuppressive effects of adenosine on T cells were first described by Wolberg et al. in 1975 [7]. During inflammatory and hypoxic conditions, activation of the CD73-adenosinergic pathways provides a negative feedback in order to limit excessive tissue damage caused by sustained immune cell activation. In 1997, Jonathan Blay and colleagues reported that solid tumors contained higher levels of extracellular adenosine than surrounding normal tissue (10–20-fold higher), suggesting a role for adenosine in tumor progression [8]. In 1998, Linda F. Thompson and colleagues reported that targeting CD73 with a neutralizing mAb promoted human lymphocyte proliferation [9]. In 2006, Sitkovsky and colleagues demonstrated that the local accumulation of adenosine suppressed anti-tumor immunity via the A2a receptor on effector T cells [10]. Building on this work, we demonstrated in 2009 that CD73-deficient mice have increased anti-tumor immunity and that targeting CD73 could delay tumor growth in mice [11], observations that were subsequently validated by independent groups [12].