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

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TL;DR

This review synthesizes evidence that ATP and adenosine are key mediators of seizures and epileptogenesis, with adenosine acting as an endogenous anticonvulsant and ATP promoting hyperexcitability via purinergic receptors. Targeting the purinergic system, particularly P2X7R and adenosine kinase, shows disease-modifying potential in preclinical models, including sustained seizure reduction and reversal of DNA hypermethylation. These findings highlight novel therapeutic strategies for drug-resistant epilepsy and disease modification beyond symptomatic seizure control.

Full summary

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**Background:** Epilepsy affects ~1% of the global population (up to 70 million persons) and is characterized by spontaneous, unprovoked seizures. Over 30% of patients are resistant to current anti-seizure drugs, which are symptomatic and do not alter disease progression. The purines ATP and adenosine have emerged as key mediators of neuronal excitability and epileptogenesis. Adenosine functions as an endogenous anticonvulsant and seizure terminator, while ATP promotes hyperexcitability via P2 receptors. This review integrates recent findings on purinergic signaling in seizures and epilepsy, including release mechanisms, receptor subtypes, metabolism, and therapeutic strategies.

**Methods:** The authors conducted a narrative review of the literature, focusing on studies using rodent models of status epilepticus (e.g., pilocarpine, kainic acid), genetic models (e.g., WAG/Rij rats), and electrostimulation models. They also included clinical data from patients with temporal lobe epilepsy (TLE) and traumatic brain injury. Key areas covered include purine release during CNS insults, P1 (adenosine) and P2 (ATP) receptor expression and function, extracellular metabolism by ectoenzymes (e.g., CD39, CD73), intracellular adenosine metabolism via adenosine kinase (ADK), and therapeutic approaches such as ADK inhibitors, gene therapy, and the ketogenic diet.

**Key Results:** - Extracellular adenosine increases 6–31-fold during seizures in humans (During and Spencer, 1992) and 3-fold in rodent models of status epilepticus (Dona et al., 2016). ATP release is more variable: a 30-fold spike was reported after electrical stimulation (Wu and Phillis, 1978), but no increase was seen in some chemoconvulsant models unless ectoATPase was inhibited (Lietsche et al., 2016). During chronic epilepsy, ATP increased 4-fold during spontaneous seizures (Dona et al., 2016). - A1 receptor activation suppresses seizures, and A1R-knockout mice display spontaneous electrographic seizures and increased seizure spread (Fedele et al., 2006; Masino et al., 2011). A2A receptors are proconvulsant, with a 3-fold increase in hippocampal astrocytes of TLE patients (Barros-Barbosa et al., 2016a). - P2X7R is consistently upregulated after status epilepticus and in epilepsy. P2X7R antagonists (e.g., A-438079, JNJ-47965567) reduce seizure severity and neurodegeneration in status epilepticus models (Engel et al., 2012; Jimenez-Pacheco et al., 2013). In chronic epilepsy, JNJ-47965567 reduced total seizure number by >95% in some mice, with effects persisting after drug washout (Jimenez-Pacheco et al., 2016). - P2Y1R antagonism had context-dependent effects: pre-treatment exacerbated seizures, while post-treatment suppressed seizures and delayed epilepsy onset (Alves et al., 2019a). - ADK is overexpressed in epileptogenic brain areas. Transient treatment with the ADK inhibitor 5-ITU (1.6 mg/kg i.p. bid for 5 days) resulted in >95% seizure reduction in 59% of mice 6 weeks post-status epilepticus, with 3 mice seizure-free (Sandau et al., 2019). - Adenosine-releasing silk implants (250 ng/ventricle/day for 10 days) reduced seizure incidence by ≥70% at 12 weeks post-implantation in a rat TLE model, associated with reversal of DNA hypermethylation (Williams-Karnesky et al., 2013). - The ketogenic diet increases adenosine via multiple mechanisms, including downregulation of ADK, and shows antiepileptogenic effects in rodent models (Lusardi et al., 2015).

**Clinical Implications:** The purinergic system offers multiple therapeutic targets for epilepsy, including P2X7R antagonists, ADK inhibitors, and adenosine augmentation therapies. These approaches have shown disease-modifying potential in preclinical models, with sustained seizure reduction and reversal of epigenetic changes. However, most data come from rodent TLE models, and questions remain about cell-type-specific effects, sex differences, and safety of long-term treatment. The development of brain-penetrant P2X7R antagonists (e.g., JNJ-47965567) that are safe in clinical trials (Timmers et al., 2018) is promising. Additionally, blood purine levels may serve as biomarkers for seizure severity and epilepsy progression (Beamer et al., 2021). Future research should focus on multi-target strategies, validation in diverse epilepsy models, and translation to clinical settings.