ATP and adenosine-Two players in the control of seizures and epilepsy development

Abstract

Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.

Keywords: Adenosine; Adenosine triphosphate; Epilepsy; P1 receptors; P2 receptors; Purinergic signaling.

Fig. 1.. Sources of extracellular purines.

(A) Purines (ATP and adenosine) can be released into the extracellular space from both neurons and glia via exocytosis or non-exocytotic mechanisms including transporters (e.g., ATP-binding cassette (ABC) transporters for ATP and Nucleoside Transporters such as equilibrative nucleoside transporter (ENT) and concentrative nucleoside transporter (CNT) for adenosine) and membrane channels such as the P2X7R, and Pannexin-1 and Connexin-43 hemichannels. Purines are also released from dying cells escaping across a compromised lipid bilayer acting thereby as a danger signal. Once released, ATP is metabolized into different breakdown products including ADP, AMP and adenosine via the action of different ectonucleotidases as discussed in Chapter 5.

Fig. 2.. Targeting ATP and adenosine signaling as potential treatment for epilepsy.

Epileptogenesis, the development of epilepsy, can be triggered via a precipitating injury to the brain (e.g., traumatic brain injury (TBI), status epilepticus) causing numerous pathological changes (e.g., inflammation, cell death, epigenetic changes) which eventually lead to the occurrence of spontaneous, epileptic seizures. Increasing evidence has demonstrated that ATP and adenosine-dependent signaling plays a key role during seizure generation and the development and maintenance of epilepsy. Targeting specific components of the purinergic signaling cascade can attenuate the precipitating injury, modify the epileptogenic process as such, and finally suppress seizures in epilepsy.

Fig. 3.. Targeting of the purinergic system to treat epilepsy.

(A) Schematic illustrating possible intervention points targeting different components of the purinergic system to suppress seizures and to treat epilepsy. This includes: (1) Purine release mechanisms: Purines including ATP and adenosine are released in the brain from neurons and glial cells via active release mechanisms (e.g., via synaptic vesicles, pannexin-1 and connexin-43 hemichannels) or from dying cells. (2) ATP-metabolizing ectonucleotidases: Once release into the extracellular space, ATP is rapidly degraded into different breakdown products such as ADP, AMP and adenosine which often mediate opposing effects via their different receptors including P1 and P2 receptors. (3) Purinergic receptors: This includes P1 receptors (A₁, A_2A, A_2B, A₃) activated by extracellular adenosine and P2 receptors which are activated by extracellular adenine and uridine nucleotides (e.g., ATP) and are further subdivided into the ionotropic P2X receptor family and the metabotropic P2Y receptor family. (4) Adenosine kinase (ADK): ADK which is predominantly expressed in astrocytes catalyzes the phosphorylation of adenosine to AMP thereby removing extracellular adenosine. (B) Representative EEG traces depicting high amplitude high frequency spiking during intra-amygdala KA-induced status epilepticus. While treatment with the anti-seizure drug Carbamazepine had no effect on seizure severity during status epilepticus, the A₁R agonist CCPA and the ADK inhibitor 5-ITU suppressed seizure activity. The seizure-suppressive effects provided via 5-ITU were reversed by treatment with DPCPX (A₁R antagonists). (C) EEG traces during intra-amygdala KA-induced status epilepticus showing increased seizure severity when mice were treated with the P2Y₁ agonist MRS2500 and seizure suppression when treated with the P2Y₁ antagonists MRS2365. Each trace is from a different animal. Drugs/Vehicle was administered 15 min post-intra-amygdala KA injection.