Differential neuroprotection by A1 receptor activation and A2A receptor inhibition following pilocarpine-induced status epilepticus

Abstract

Aiming at a better understanding of the role of A(2A) in temporal lobe epilepsy (TLE), we characterized the effects of the A(2A) antagonist SCH58261 (7-(2-phenylethyl)-5-amino-2(2-furyl)-pyrazolo-[4,3-e]-1,2,4-triazolo[1,5-c]pyrimidine) on seizures and neuroprotection in the pilocarpine model. The effects of SCH58261 were further analyzed in combination with the A(1) agonist R-Pia (R(-)-N(6)-(2)-phenylisopropyl adenosine). Eight groups were studied: pilocarpine (Pilo), SCH+Pilo, R-Pia+Pilo, R-Pia+SCH+Pilo, Saline, SCH+Saline, R-Pia+Saline, and R-Pia+SCH+Saline. The administration of SCH58261, R-Pia, and R-Pia+SCH58261 prior to pilocarpine increased the latency to SE, and decreased either the incidence of or rate of mortality from SE compared with controls. Administration of R-Pia and R-Pia+SCH58261 prior to pilocarpine reduced the number of Fluoro-Jade B-stained cells in the hippocampus and piriform cortex when compared with control. This study showed that pretreatment with R-Pia and SCH58261 reduces seizure occurrence, although only R-Pia has neuroprotective properties. Further studies are needed to clarify the neuroprotective role of A(2A) in TLE.

Adenosine A2A receptor and ecto-5′-nucleotidase/CD73 are upregulated in hippocampal astrocytes of human patients with mesial temporal lobe epilepsy (MTLE)

“…This feature is in agreement with previous studies using animal models showing that the A 2A receptor exists at relative low levels in the hippocampus [42,43], but its amount dramatically increases in epileptic animals [19,20,44]. As a matter of fact, increasing evidences show that activation of the adenosine A 2A receptor favors seizure activity in different epileptic syndromes [17,18,20,[22][23][24]. Neuronal excitation in epilepsy likely leads to enhanced synaptic A 2A activation, which may aggravate synaptotoxicity and thereby the degeneration of normal circuitry contributing to the progressive course of epilepsy.…”

“…Thus, involvement of the A 2A receptor in diverse pathologies of the central nervous system, including epilepsy [17][18][19][20][21][22][23][24][25], may be due to counteraction of the neuroprotective role of adenosine via the A 1 receptor [24]. Most studies demonstrating the proconvulsive effect of the A 2A receptor have been performed in rodents, both in mice [17][18][19]26] and rats [20][21][22][23][24]. Results from these investigations suggest that selective A 2A receptor antagonists might offer protection against diverse epileptic syndromes, such as temporal lobe epilepsy, highlighting the idea that the A 2A receptor may be an attractive pharmacological target for the treatment of epilepsy.…”

The Antiepileptic Potential of Nucleosides

“…Increased seizure latency [118] Pilocarpine-induced (intraperitoneal injection) seizures in rats Reduced seizure occurrence [268] Pilocarpine-induced (intraperitoneal injection) seizures in rats Anticonvulsant effect [180] R-PIA (A1 receptor agonist)…”

“…Pilocarpine-induced (intraperitoneal injection) seizures in rats Proconvulsant effect [180] Pilocarpine-induced (intraperitoneal injection) seizures in rats Reduced seizure occurrence [268] Audiogenic seizures (audiogenic-seizure-sensitive DBA/2 mice) Proconvulsant effect [95] SCH 58261 (A2A receptor antagonist)…”

“…3A) [118,168,216,237] and D-, L-, R-and S-N 6 -(2-phenylisopropyl) adenosine (D-, L-, R-and S-PIA; A 1 agonists) ( Table 3; Fig. 3A) [118,168,180] were effective against bicuculline-and/or kainicacid-, pilocarpin-, 3-nitropropionic-acid-, 3-mercaptopropionicacid-and PTZ-induced seizures/epileptiform activity as well as 4-aminopyridine-induced epileptiform bursting activity [235,[265][266][267][268][269][270][271] and in the rat kindling model [119,[272][273][274][275][276][277]. It has also been demonstrated that R-PIA prolonged the latency to convulsions in a hypoxia-induced model [278] and CPA delayed the time onset of clonic convulsions in aminophylline-induced seizures [279].…”