Adenosine Kinase Isoforms in the Developing Rat Hippocampus after LiCl/Pilocarpine Status Epilepticus.

Petr Fábera,Pavel Mareš,Libor Uttl,Grygoriy Tsenov,Hana Kubová

doi:10.3390/ijms23052510

Abstract

LiCl/pilocarpine status epilepticus (SE) induced in immature rats leads, after a latent period, to hippocampal hyperexcitability. The excitability may be influenced by adenosine, which exhibits anticonvulsant activity. The concentration of adenosine is regulated by adenosine kinase (ADK) present in two isoforms—ADK-L and ADK-S. The main goal of the study is to elucidate the changes in ADK isoform expression after LiCl/pilocarpine SE and whether potential changes, as well as inhibition of ADK by 5-iodotubercidin (5-ITU), may contribute to changes in hippocampal excitability during brain development. LiCl/pilocarpine SE was elicited in 12-day-old rats. Hippocampal excitability in immature rats was studied by the model of hippocampal afterdischarges (ADs), in which we demonstrated the potential inhibitory effect of 5-ITU. ADs demonstrated significantly decreased hippocampal excitability 3 days after SE induction, whereas significant hyperexcitability after 20 days compared to controls was shown. 5-ITU administration showed its inhibitory effect on the ADs in 32-day-old SE rats compared to SE rats without 5-ITU. Moreover, both ADK isoforms were examined in the immature rat hippocampus. The ADK-L isoform demonstrated significantly decreased expression in 12-day-old SE rats compared to the appropriate naïve rats, whereas increased ADK-S isoform expression was revealed. A decreasing ADK-L/-S ratio showed the declining dominance of ADK-L isoform during early brain development. LiCl/pilocarpine SE increased the excitability of the hippocampus 20 days after SE induction. The ADK inhibitor 5-ITU exhibited anticonvulsant activity at the same age. Age-related differences in hippocampal excitability after SE might correspond to the development of ADK isoform levels in the hippocampus.

Highlights

Adenosine is considered an endogenous homeostatic and metabolic neuromodulator that fulfills its functions through the activation of G-protein-coupled receptors, including A1, A2A, A2B, and A3 [1–3]
We investigated the changes in adenosine kinase (ADK) isoform expression during hippocampal development and whether potential changes may contribute to changes in hippocampal excitability after an insult during early brain development
We studied the activity of a nonselective inhibitor of ADK, 5-iodotubercidin (5-ITU), on hippocampal ADs and its possible changes with age. 5-ITU has been demonstrated to increase extracellular adenosine levels in the rat brain [41] and may attenuate epilepsy development after status epilepticus (SE) in immature rodent brains [42]

Summary

Introduction

Adenosine is considered an endogenous homeostatic and metabolic neuromodulator that fulfills its functions through the activation of G-protein-coupled receptors, including A1, A2A, A2B, and A3 [1–3]. Adenosine acts as a seizure suppressor and seizure terminator, with the inhibitory effects mediated by both A1 and A2A receptors [4–6]. Adenosine is a crucial component of purinergic signaling and is tightly regulated by multiple enzymes and transporters [7]. Brain levels of adenosine are regulated primarily by the activity of adenosine kinase (ADK) [8], a key regulatory enzyme that catalyzes the phosphorylation of adenosine into 5 -adenosine-monophosphate (AMP) [9]. Slight changes in ADK expression may result in major changes in adenosine concentrations. The downregulation or pharmacological inhibition of ADK leads to increased concentrations of adenosine, resulting in diminished excitability in the brain [13]. Changes in ADK expression become crucial for regulating adenosine tone and may contribute to the process of epileptogenesis [16,17]

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