br Functional consequences of ADK regulation

Functional consequences of ADK regulation on astrocyte function As outlined above (see introduction), ADK critically regulates the extracellular adenosine levels in Solamargine (Boison, 2006, Etherington et al., 2009). Changes in the levels of adenosine, as a result of the regulation of ADK expression/function in epileptic tissue, may influence astroglial function through activation of different ARs, which have been detected in astrocytes [for reviews see (Boison et al., 2010, Aronica et al., 2012b)]. Activation of A1R on astrocytes has been shown to reduce their proliferation in vitro (Rathbone et al., 1991, Ciccarelli et al., 1994), as well as to mediate cytoprotective effects (Ciccarelli et al., 2007, D’Alimonte et al., 2007, Bjorklund et al., 2008). In addition, astrocyte function and proliferation may secondarily influence the activation of A1Rs expressed on microglial cells, which has been shown to attenuate neuroinflammation (Tsutsui et al., 2004, Synowitz et al., 2006). Adenosine mediates its actions on astrocytes also through the A2ARs, which are also expressed in microglia and induced following different types of brain injury or inflammation (Cunha, 2005, Rebola et al., 2011). Activation of glial A2ARs has been suggested to control neuroinflammation (Nishizaki et al., 2002, Rebola et al., 2011). Acting via the astroglial A2ARs, adenosine may also regulate the extracellular concentration of glutamate (Li et al., 2001, Nishizaki et al., 2002) and inhibit the production of nitric oxide [NO; (Brodie et al., 1998)]. In contrast to the A1Rs, activation of A2ARs increases astrocyte proliferation (Hindley et al., 1994, Brambilla et al., 2003). Thus, activation of A2ARs may play a critical role in promoting astrogliosis in epileptic brain, particularly when occurring in concert with changes in A1Rs expression (Fig. 1). Interestingly, a downregulation of A1Rs (which negatively modulates astrocyte proliferation) has been observed during epileptogenesis (Ekonomou et al., 2000, Rebola et al., 2003). As discussed above, induction of astrogliosis is associated with an upregulation of ADK (Fig. 2), leading to a reduction in extracellular levels of adenosine [(Boison, 2006); Fig. 1]. Inflammatory molecules, such as IL-1β, up-regulated in epileptogenic tissue from TLE patients [for review see (Aronica and Crino, 2011, Vezzani et al., 2011)] may also play a role in the regulation of adenosine cycle in astrocytes. Accordingly, IL-1β has been shown to increase the expression of ADK in human astrocytes in culture, suggesting a potential modulatory crosstalk between the astrocyte-based adenosine cycle and inflammation (Aronica et al., 2011). Increasing evidence points towards a critical role of ARs in neuron–glia communication and neuroinflammation (Boison, 2010, Gomes et al., 2011). Activation of A2BRs has been shown to induce the release of IL-6 from astrocytes and the activation of the A3Rs to promote the synthesis of the chemokine MCP-1 [monocyte chemotactic protein-1; for reviews see (Hasko et al., 2005, Abbracchio and Ceruti, 2007, Gomes et al., 2011)]. Thus, it is tempting to hypothesize that a dysfunction in adenosine’s homeostasis may critically influence balance of pro- and anti-inflammatory processes, leading to uncontrolled inflammation that may contribute to the development of the epileptic process and/or cognitive dysfunction [for reviews see (Vezzani et al., 2011, Boison et al., 2012)]. ADK expression levels may also play a role in the regulation of tumor growth and apoptotic cell death in astrocytomas (Abbracchio et al., 1997, Synowitz et al., 2006, Dehnhardt et al., 2007, Gessi et al., 2010, Gessi et al., 2011). Accordingly, increased ADK mRNA expression has been detected in human cancer samples outside the brain, such as in colorectal cancer (Giglioni et al., 2008). Moreover, it has been demonstrated that extracellular adenosine reduced the viability of cultured astrocytoma cells (Sai et al., 2006), suggesting that induction of ADK might represent a strategy to improve survival of tumor cells.