br Expression of ADK in
Expression of ADK in the normal brain In adult brain, ADK is primarily expressed in astrocytes. Immunocytochemical analysis of adult rat and mouse Apatinib revealed predominant astrocytic expression throughout the hippocampus and cortex. Two isoforms of ADK have been identified in mammals, a long nuclear isoform and a short cytoplasmic isoform (Cui et al., 2009). Nuclear ADK immunoreactive material (IR) was observed in a subpopulation of resting astroglial cells, whereas cytoplasmic expression was weak or below detectable levels (Fedele et al., 2005, Li et al., 2008b, Aronica et al., 2011). A similar cellular expression pattern was detected in the temporal cortex of rats with predominantly nuclear ADK in resting glial cells (Aronica et al., 2011). Although the specific role of these isoforms in brain has still to be established, the nuclear ADK is likely involved in epigenetic mechanisms as regulator of methyltransferase reactions, whereas the cytoplasmic isoform is thought to regulate the extracellular levels of adenosine [(discussed above; for review see (Boison, 2008)]. Accordingly, reduced adenosine tone has been detected in mice constitutively overexpressing a transgene for the cytoplasmic isoform of ADK (Fedele et al., 2005, Pignataro et al., 2007, Li et al., 2008aa). Moreover a recent study indicates a role for the cytoplasmic isoform in sleep regulation (Palchykova et al., 2010). The function of ADK isoforms in developing human brain is still unclear. Developmental studies performed in mouse brain indicate a switch from neuronal expression during the perinatal period to a near exclusive astrocytic expression in adult brain (Studer et al., 2006). These observations point to a dual functionality of this enzyme and suggest a key role for ADK in the brain that may affect important cellular functions of neural progenitor cells, such as proliferation, survival and neural plasticity. Interestingly, strong expression of ADK has been detected in human fetal brain (gestational week, GW 13; temporal cortex); with these high levels observed by Western blot analysis in total cortical homogenates being a possible reflection of the enzyme’s expression in the deep compartments of the cortical wall (VZ/SVZ; ventricular/subventricular zone) at early stages of corticogenesis (unpublished observations). Whether a dysregulation of ADK expression/function early during development could contribute to cognitive dysfunction in children with epilepsy deserves further investigation.
Expression of ADK in the epileptic brain Astrogliosis is a pathological hallmark of various types of medically refractory focal epilepsy, including epilepsy that develops following traumatic, ischemic or infectious brain injury (Sofroniew and Vinters, 2010). Astrogliosis is also the prominent morphological feature of hippocampal sclerosis (HS), which represents the most common neuropathological finding in adult patients undergoing surgery for intractable temporal lobe epilepsy (TLE) (Thom, 2009). Activation of astrocytes is also observed in focal malformations of cortical development (such as focal cortical dysplasia [FCD] and cortical tubers in tuberous sclerosis complex [TSC]), which are recognized causes of chronic medically intractable epilepsy in children and young adults [for review see (Aronica et al., 2012a)]. In addition, astroglial tumors (particularly slow-growing, low-grade tumors) represents a common cause of epilepsy in both adults and pediatric patients (van Breemen et al., 2007). Over the past decade, an increasing number of observations have shown the existence of rapid regulatory cross-talks between neurons and glia during synaptic transmission, suggesting an astrocytic basis for epilepsy (Seifert and Steinhauser, 2011). Astrocytes can influence network excitability in epilepsy through different mechanisms, including a dysfunctional adenosine homeostasis, which may result from changes in ADK expression levels (Boison, 2008).