title: Role of the purinergic signaling in epilepsy.
abstract: Adenine nucleotides and adenosine are signaling molecules that activate purinergic receptors P1 and P2. Activation of A1 adenosine receptors has an anticonvulsant action, whereas activation of A2A receptors might initiate seizures. Therefore, a significant limitation to the use of A1 receptor agonists as drugs in the CNS might be their peripheral side effects. The anti-epileptic activity of adenosine is related to its increased concentration outside the cell. This increase might result from the inhibition of the equilibrative nucleoside transporters (ENTs). Moreover, the implantation of implants or stem cells into the brain might cause slow and persistent increases in adenosine concentrations in the extracellular spaces of the brain. The role of adenosine in seizure inhibition has been confirmed by results demonstrating that in patients with epilepsy, the adenosine kinase (ADK) present in astrocytes is the only purine-metabolizing enzyme that exhibits increased expression. Increased ADK activity causes intensified phosphorylation of adenosine to 5'-AMP, which therefore lowers the adenosine level in the extracellular spaces. These changes might initiate astrogliosis and epileptogenesis, which are the manifestations of epilepsy. Seizures might induce inflammatory processes and vice versa. Activation of P2X7 receptors causes intensified release of pro-inflammatory cytokines (IL-1β and TNF-α) and activates metabolic pathways that induce inflammatory processes in the CNS. Therefore, antagonists of P2X7 and the interleukin 1β receptor might be efficient drugs for recurring seizures and prolonged status epilepticus. Inhibitors of ADK would simultaneously inhibit the seizures, prevent the astrogliosis and epileptogenesis processes and prevent the formation of new epileptogenic foci. Therefore, these drugs might become beneficial seizure-suppressing drugs.
authors.affiliation: Neurology Clinic, Marek Cieślak, Toruń, Poland.
authors.forename: Marek
authors.initials: M
authors.lastname: Cieślak
authors.affiliation: Department of Crystallochemistry and Biocrystallography, Faculty of Chemistry, Nicolaus Copernicus University in Toruń, Toruń, Poland. Electronic address: awojt@chem.uni.torun.pl.
authors.forename: Andrzej
authors.initials: A
authors.lastname: Wojtczak
authors.affiliation: Department of Biochemistry, Faculty of Biology and Environment Protection, Nicolaus Copernicus University in Toruń, Toruń, Poland.
authors.forename: Michał
authors.initials: M
authors.lastname: Komoszyński
mesh_terms: D000241:Adenosine / Q000378:metabolism / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism; D000818:Animals; D004827:Epilepsy / Q000188:drug therapy / Q000378:metabolism*; D006801:Humans; D058920:Purinergic P2X Receptor Antagonists / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D043705:Receptor, Adenosine A2A / Q000378:metabolism*; D011983:Receptors, Purinergic / Q000378:metabolism; D058486:Receptors, Purinergic P2X7 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*
chemical_list: D058920:Purinergic P2X Receptor Antagonists; D043705:Receptor, Adenosine A2A; D011983:Receptors, Purinergic; D058486:Receptors, Purinergic P2X7; D000248:Adenosine Kinase; D000241:Adenosine
keywords: Adenosine kinase; Astrogliosis; Epilepsy; Epileptogenesis; Purinergic signaling