The ATP-gated P2X7 receptor contributes to the development of
drug-resistant status epilepticus in mice
Abstract
Background and Purpose Refractory status epilepticus is a clinical
emergency associated with high mortality and morbidity. Increasing
evidence suggests neuroinflammatory pathways contribute to the
development of drug-refractoriness during status epilepticus. The
ATP-gated P2X7 receptor (P2X7R) has been described as potential link
between inflammation and increased hyperexcitability. The aim of the
present study was to determine the contribution of the P2X7R to
drug-refractory status epilepticus and its therapeutic potential.
Experimental Approach Status epilepticus was induced via a unilateral
microinjection of kainic acid into the amygdala in adult mice. Severity
of status epilepticus was compared in animals overexpressing or
knock-out in the P2X7R, after inflammatory priming by the pre-injection
of bacterial lipopolysaccharide (LPS) and in mice treated with
P2X7R-targeting and anti-inflammatory drugs. Key Results P2X7R
overexpressing mice were unresponsive to several anticonvulsants
(lorazepam, midazolam, phenytoin and carbamazepine) during status
epilepticus. P2X7R expression was increased in microglia during
drug-refractory status epilepticus, P2X7R overexpression led to a
pro-inflammatory phenotype in microglia during status epilepticus and
the anti-inflammatory drug minocycline restored normal responsiveness to
anticonvulsants in P2X7R overexpressing mice. Pre-treatment of wildtype
mice with LPS increased P2X7R levels in the brain and promoted the
development of pharmaco-resistant status epilepticus, which was overcome
by either a genetic deletion of the P2X7R or the administration of the
P2X7R antagonists AFC-5128 or ITH15004. Conclusion and Implications Our
results demonstrate that P2X7R-induced pro-inflammatory effects
contribute to resistance to pharmacotherapy during status epilepticus
and suggest therapies targeting the P2X7R as novel adjunctive treatments
for drug-refractory status epilepticus.