P2X7 receptor in epilepsy; role in pathophysiology and potential targeting for seizure control

Abstract

The P2X7 receptor is an ATP-gated non-selective cation-permeable ionotropic receptor selectively expressed in neurons and glia in the brain. Activation of the P2X7 receptor has been found to modulate neuronal excitability in the hippocampus and it has also been linked to microglia activation and neuroinflammatory responses. Accordingly, interest developed on the P2X7 receptor in disorders of the nervous system, including epilepsy. Studies show that expression of the P2X7 receptor is elevated in damaged regions of the brain after prolonged seizures (status epilepticus) in both neurons and glia. P2X7 receptor expression is also increased in the hippocampus in experimental epilepsy. Recent data show that mice lacking the P2X7 receptor display altered susceptibility to status epilepticus and that drugs targeting the P2X7 receptor have potent anticonvulsant effects. Together, this suggests that P2X7 receptor ligands may be useful adjunctive treatments for refractory status epilepticus or perhaps pharmacoresistant epilepsy. This review summarizes the evidence of P2X7 receptor involvement in the pathophysiology of epilepsy and the potential of drugs targeting this receptor for seizure control.

Keywords: Adenosine 5’-triphosphate; anticonvulsant; epilepsy; hippocampal sclerosis; interleukin 1 beta; status epilepticus.

Figure 1

P2X7 receptor expression in hippocampal neurons and microglia. A. Representative photomicrograph showing a field view of the adult mouse hippocampus from a P2X7 receptor reporter mouse which expresses enhanced green fluorescent protein (EGFP) immediately downstream of the P2rx7 promoter. Sections were stained with primary antibodies against GFP. Note, GFP-positive cells are mainly localized within the dentate gyrus (DG). B. Higher magnification view of GFP-positive granule neurons of the dentate gyrus. C. Higher magnification view of GFP-positive cells with morphological features of microglia. Scale bar; 250 μm in A, and 50 μm in B and C.

Figure 2

P2X7 receptor antagonists reduce release of interleukin-1β and seizure-damage after status epilepticus in mice. A. Graph showing interleukin-1β (IL-1β) levels measured by ELISA in hippocampal extracts 24 h after status epilepticus (SE). The induction of IL-1β was strongly reduced in seizure mice injected with P2X7 receptor antagonist BBG (1 pmol) 15 min after triggering SE. B. Photomicrographs from the CA3 subfield of the hippocampus 24 h after SE in mice, stained for damaged neurons using Fluoro-Jade B (black dots are damaged neurons). Injection 15 min after SE of the P2X7 receptor antagonist A-438079 (A43) strongly reduced damage. Bar, 150 μM. Data in A, B are adapted and reproduced with permission from Engel et al. FASEB J. [62].

Figure 3

P2X7 receptor and status epilepticus. A. Representative EEG spectrograms showing frequency and amplitude data during kainate-induced status epilepticus for a wild-type (WT) mouse and a mouse lacking the P2X7 receptor (P2rx7-/-). B. Representative EEG spectrograms during recordings after triggering status epilepticus for vehicle (veh) and P2X7 receptor antagonist (A-438079 (A-43), 1.75 nmol) injected mice. Note, reduced seizure severity in P2rx7-/- and A43-treated mice. C. Representative EEG trace recordings from mice after triggering status epilepticus. Time markings on left of each panel refer to point when either Veh, lorazepam or A43 were injected 60 min post-status epilepticus (when seizures are normally continuous). Lorazepam partly reduces seizures but does not abolish them whereas the combination of lorazepam and A43 results in full seizure termination. Data are adapted and reproduced with permission from Engel et al. FASEB J. [62].