Purinergic Mechanisms in Epilepsy

Abstract

Adenosine is a powerful neuromodulator that has a range of functions in various cells and tissues throughout the body. In the brain adenosine controls many varied processes through a range of receptors. Research over the past 25 years has implicated adenosine, acting predominantly through the A1 receptor, in seizure control and epilepsy. Most of this work has utilized animal models and there are still only a handful of studies in humans. In this article, I will focus on specific aspects of the role of adenosine in epilepsy, in particular its role in terminating seizures and preventing status epilepticus, a prolonged and neurologically dangerous seizure state. I will also discuss the few reports that have studied adenosine in human epilepsy in an attempt to bridge the gap between pre-clinical studies and the clinic. The great challenge for researchers is to translate knowledge about adenosine and epilepsy from the lab to the clinic to develop new medications to treat people suffering from epilepsy and status epilepticus.Keywords: Adenosine, Seizure arrest, status epilepticus, human epilepsy.Adenosine is a powerful neuromodulator that has a range of functions in various cells and tissues throughout the body. In the brain adenosine controls many varied processes through a number of receptors (A1, A2a, A2b, A3). In particular, research over the past 25 years has implicated adenosine in seizure control and epilepsy. Most of this work has utilized animal models and there are still only a handful of studies in humans. Twenty-one years ago I wrote a review article entitled "Purinergic Mechanisms in Epilepsy" which was published in Progress in Neurobiology [1]. At that time there was a growing body of research which suggested very strongly that adenosine played a major role in controlling epileptic seizures although there was controversy regarding the role of basal versus seizure-induced adenosine levels. Many hundreds of studies have been published since that review appeared (a PubMed search using "adenosine and epilepsy" found 607 papers published between 1988 and 2009). In this article I wish to address 3 questions. First, has our understanding of the role of adenosine in epilepsy progressed during this time period and, in particular, are there any human studies that shed further light on the role of adenosine in epilepsy? Second, are we any closer to designing drugs (and/or other therapies) based upon our knowledge of adenosine in epilepsy for people with epilepsy and/or status epilepticus? Finally, how can we facilitate the translation of basic research in this area to the clinic? ADENOSINE AND EPILEPSY -HUMAN STUDIESAlthough there is a vast literature on the role of adenosine in epilepsy using in vivo and in vitro animal models there is a scarcity of data in humans. It is not the intent of this article to review the literature studying adenosine in seizures in animal models. This work has been *Address correspondence to this author at the Department of Pharmacology and the Centre for Brain Research, Facul...

Hyperthermia‐induced seizures produce long‐term effects on the functionality of adenosine A1 receptor in rat cerebral cortex

“…Thus, activation of A 1 R inhibits the release of several neurotransmitters including L‐Glutamate, the main excitatory neurotransmitter in the Central Nervous System. In this line, previous studies have shown that (a) the density of A 1 R increases in different animal models of epilepsy (Angelatou, Pagonopoulou, & Kostopoulos, ; Pagonopoulou, Angelatou, & Kostopoulos, ; Tchekalarova, Sotiriou, Georgiev, Kostopoulos, & Angelatou, ; Vanore, Giraldez, Lores, Arnaiz, & Girardi, ) although the opposite has also been reported in different rodent models of epilepsy (Ochiishi, Takita, Ikemoto, Nakata, & Suzuki, ; Rebola et al, ; Young & Dragunow, ), and (b) A 1 R agonist acutely administered reduces seizures in animal models, whereas selective A 1 R antagonist increases the duration and severity of seizures (Dragunow, ; Tomé, Silva, & Cunha, ). Although upon activation A 1 R can evoke multiple responses such as activation of inwardly rectifying K + channels and inhibition of Ca 2+ channels, a previous study demonstrated that inhibition of the AC‐cAMP‐PKA pathway inhibits L‐Glutamate release and epileptiform activity in the entorhinal cortex, an essential structure involved in temporal lobe epilepsy (Wang et al, ).…”

Hyperthermia‐induced seizures alter adenosine A1 and A2A receptors and 5′‐nucleotidase activity in rat cerebral cortex

“…In this regard, the short‐term up‐regulation of A 1 R observed in the present work could potentiate the neuroprotective role of A 1 R against subsequent seizures. Previous works have shown that A 1 R agonist administered acutely reduce seizures in animal models, whereas selective A 1 R antagonist increases the duration and severity of seizures (see review Dragunow ; Tomé et al . ).…”