Upregulation of adenosine kinase in astrocytes in experimental and human temporal lobe epilepsy

Abstract

Purpose Adenosine kinase (ADK) represents the key metabolic enzyme for the regulation of extracellular adenosine levels in the brain. In adult brain, ADK is primarily present in astrocytes. Several lines of experimental evidence support a critical role of ADK in different types of brain injury associated with astrogliosis, which is also a prominent morphological feature of temporal lobe epilepsy (TLE). We hypothesized that dysregulation of ADK is an ubiquitous pathological hallmark of TLE. Methods Using immunocytochemistry and western blot analysis, we investigated ADK protein expression in a rat model of TLE during epileptogenesis and the chronic epileptic phase and compared those findings with tissue resected from TLE patients with mesial temporal sclerosis (MTS). Key findings In rat control hippocampus and cortex, a low baseline expression of ADK was found with mainly nuclear localization. One week after the electrical induction of status epilepticus (SE), prominent up-regulation of ADK became evident in astrocytes with a characteristic cytoplasmic localization. This increase in ADK persisted at least for 3-4 months after SE in rats developing a progressive form of epilepsy. In line with the findings from the rat model, expression of astrocytic ADK was also found to be increased in the hippocampus and temporal cortex of TLE patients. In addition, in vitro experiments in human astrocyte cultures showed that ADK expression was increased by several pro-inflammatory molecules (interleukin-1β and LPS). Significance These results suggest that dysregulation of ADK in astrocytes is a common pathological hallmark of TLE. Moreover, in vitro data suggest the existence of an additional layer of modulatory crosstalk between the astrocyte-based adenosine cycle and inflammation. Whether this interaction also can play role in vivo needs to be further investigated.

The Antiepileptic Potential of Nucleosides

“…However, a subsequent high, acute Ado concentration promotes glial activation and astrogliosis, one of the relevant features of the epileptic brain [153], via stimulation of A 2A receptors [154,155]. The expression of ADK by glial fibrillary acidic protein (GFAP)-positive astrocytes and the overexpression of ADK in parallel with the formation of astrogliosis has been observed [27,65,93,156]. Additionally, although A 1 receptors may reduce astrogliosis [157], expression of astrocytic A 1 receptors may be reduced by epileptogenesis [158][159][160][161].…”

“…Additionally, although A 1 receptors may reduce astrogliosis [157], expression of astrocytic A 1 receptors may be reduced by epileptogenesis [158][159][160][161]. A 2A receptors are upregulated by high Ado levels [27]; thus, the crucial role of Ado receptor expression in astrogliosis, the astrogliosisinduced increase in ADK activity and the disruption of Ado homeostasis have been suggested in epilepsy [151,156,162,163]. It was concluded that (i) upregulation of ADK in chronic epilepsy mainly occurs in astrocytes via Adoreceptor-induced astrogliosis in the adult brain, (ii) high ADK activity in astrocytes results in a decrease of Ado concentration, which may induce chronic recurrent seizures, (iii) consequently, ADK may be the link between astrogliosis and neuronal dysfunction in epilepsy and (iv) astrogliosis and concomitant epileptic seizures may be prevented by Ado receptor modulation [65,93,164,165].…”

“…A lipopolysaccharide (LPS)-induced increase in IL-1 may also result in cortical epileptiform discharges [190], and the induction of IL-1 expression in astrocytes may have a role in the occurrence of absence seizures [191]. Because IL-1 and LPS increased ADK expression in astrocyte cultures [156], the link between the LPS-induced increase in IL-1 and absence epileptic activity [192,193] may be the decreased level of endogenous anticonvulsant Ado by ADK. In addition, LPS and IL-1 induced the release of ATP from hippocampal slices [194], which may be metabolized extracellularly to Ado by ectonucleotidases [72,75,76] resulting in stimulation of A 2A receptors, which may downregulate the expression of A 1 receptors [195] and enhance Ado uptake by ENT transporters [196].…”

Overexpression of Adenosine Kinase in Patients with Epilepsy Associated With Sturge-Weber Syndrome

“…Experimental researches demonstrate that overexpression of ADK per se might be sufficient to trigger electrographic seizures [8,15,18,19,22]. Clinical evidence also demonstrates that ADK as a common pathologic hallmark and a target for treatment in intractable epilepsy such as temporal epilepsy [8,9], tumor-Overexpression of Adenosine Kinase in Patients with Epilepsy Associated With Sturge-Weber Syndrome related epilepsy [11], Rasmussen encephalitis [10,24], and focal cortical dysplasia [12].…”

“…Chronic ischemia in the cortical areas affected by leptomeningeal angiomatosis has been usually considered to be the epileptogenic mechanism [7]. Increasing clinical evidence from specimen surgically resected from patients with drug-resistant epilepsy, including temporal lobe epilepsy [8,9], Rasmussen encephalitis [10], astroglial tumorrelated epilepsy [11], and focal cortical dysplasia [12], demonstrated that overexpression of astroglial adenosine kinase (ADK) contributing to seizures generation in human chronic epilepsy. However, in our study, it is first time to literarily report a link between adenosine and SWS.…”