Glial adenosine kinase – A neuropathological marker of the epileptic brain

Abstract

Experimental research over the past decade has supported the critical role of astrocytes activated by different types of injury and the pathophysiological processes that underlie the development of epilepsy. In both experimental and human epileptic tissues astrocytes undergo complex changes in their physiological properties, which can alter glio-neuronal communication, contributing to seizure precipitation and recurrence. In this context, understanding which of the molecular mechanisms are crucially involved in the regulation of glio-neuronal interactions under pathological conditions associated with seizure development is important to get more insight into the role of astrocytes in epilepsy. This article reviews current knowledge regarding the role of glial adenosine kinase as a neuropathological marker of the epileptic brain. Both experimental findings in clinically relevant models, as well as observations in drug-resistant human epilepsies will be discussed, highlighting the link between astrogliosis, dysfunction of adenosine homeostasis and seizure generation and therefore suggesting new strategies for targeting astrocyte-mediated epileptogenesis.

Adenosine Kinase, a Common Pathologic Biomarker for Human Pharmacoresistant Epilepsy

“…Interestingly, strong neuronal expression of ADK has been detected in human fetal brains (gestational week 13; temporal cortex) [26]. Dynamic changes in ADK gene transcription during early postnatal brain development was also documented, and binding of transcription factor specificity protein 1 to the ADK promoter influences the regulation of ADK expression [27].…”

“…The neuronal expression of ADK in the lesion of RE cortex maybe inflammation associated, indicating a potential additional layer of modulatory cross talk between the astrocyte-based adenosine cycle and inflammation [17]. Another hypothesis on neuronal expression of ADK in RE is that the early stage of developmental microenvironment alteration might destroy the transition of neuronal ADK from fetal to postnatal brains [25,26]. Potential gene regulatory mechanisms including DNA promoter methylation, histone modifications and transcription factor binding may influence the dynamic regulation of the ADK gene during early postnatal brain development and maturation.…”

Combined electrophysiological and biosensor approaches to study purinergic regulation of epileptiform activity in cortical tissue

“…Indeed, ADK over-expressing mice exhibited spontaneous seizures and fatal kainic acid-induced status epilepticus (KASE), whereas ADKdeficient mice showed reduced KASE-induced seizures and brain damage and were protected against subsequent KASE-induced epileptogenesis (Li et al, 2008). Accordingly, ADK and the adenosine-dependent changes that contribute to astrogliosis are promising targets in both injuryinduced epileptogenesis and indeed established but refractory epilepsy (Aronica et al, 2013).…”

Epilepsy Related to Developmental Tumors and Malformations of Cortical Development

“…Enzymatic changes may also occur in peritumoral tissue, impairing neurotransmitter synthesis and storage, and contributing to tumor-associated epilepsy [79]. Attention as been particularly focused on the changes in adenosine kinase (key metabolic enzyme for the regulation of extracellular adenosine levels) occurring in peritumoral tissue of glioma patients ( [91]; for a review see [92]) Finally, association with cortical dysplasia (as discussed below; [6]) also has to be considered in the evaluation of the epileptogenicity of GG.…”