Effect of adenosine receptor modulation on pentylenetetrazole‐induced seizures in rats

Abstract

1 The e ects of adenosine, the adenosine analogue, 2-chloroadenosine (2-CADO), the speci®c adenosine A 1 receptor agonist, N 6 -cyclopentyladenosine (CPA) and A 2 receptor agonist 5'-(Ncyclopropyl) carboxamidoadenosine (CPCA), were examined against seizures induced by acute administration of pentylenetetrazole (PTZ), 60 mg kg 71 , and PTZ kindled seizures, in rats. 2 Adenosine 1000 mg kg 71 , i.p., 5 min pretreatment and CPA 10 mg kg 71 i.p., 60 min pretreatment, showed signi®cant protection against acute PTZ-induced seizures while, CPCA up to 10 mg kg 71 was ine ective. The adenosine analogue 2-CADO in a dose of 5 mg kg 71 was only partially protective and on increasing the dose to 10 mg kg 71 , this protection was lost. 3 Theophylline, a non speci®c adenosine receptor antagonist at 50 mg kg 71 and the speci®c adenosine A 1 receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine (DPCPX), at 1 mg kg 71 , if administered before the maximally protective doses of adenosine and CPA, completely reversed the protection a orded by them against PTZ seizures. While, pretreatment with the adenosine A 2 receptor antagonist, 3,7-dimethyl-1-propargylxanthine (DMPX), failed to reverse the protection. 4 Adenosine and the adenosine A 1 receptor agonist in doses that protected against seizures after acute PTZ administration, o ered only incomplete protection when tested against PTZ kindled seizures.5 The e ects of adenosine and adenosine receptor agonists on mean arterial pressure, heart rate and rectal temperature were studied, to rule out the possibility of their systemic e ects mediating the protection of PTZ seizures. All these agents produced a fall in mean arterial pressure, heart rate and hypothermia in the doses exhibiting an anticonvulsant response. While the e ect on blood pressure and heart rate was immediate i.e. seen within 5 min and, maintained throughout the observation period, the development of hypothermia lagged behind the onset of hypotension and bradycardia. However, there was no correlation between haemodynamic and hypothermic response and the anticonvulsant e ect. 6 The results indicate that the adenosine mediated anticonvulsant e ect is via stimulation of A 1 receptors. Hypotension and hypothermia do not appear to contribute to the protection observed with adenosine and the adenosine A 1 receptor agonists.

The adenosine kinase hypothesis of epileptogenesis

“…The latter finding implies that augmentation of the adenosine system might be a general strategy for the treatment of otherwise refractory epilepsy. The potential of A 2A receptor activation for seizure suppression has been investigated in only few studies and the results are partly controversial and seem to depend on the animal models and drugs used (De Sarro et al, 1999;Huber et al, 2002;Malhotra and Gupta, 1997;Zhang et al, 1994).…”

“…The low blood brain barrier permeability and pronounced peripheral side effects of adenosine receptor agents (Malhotra and Gupta, 1997) constitute a significant limitation to their therapeutic use. Even the combination of the non-brain permeable non-selective adenosine receptor antagonist 8-sulfophenytheophylline with brain permeable selective adenosine receptor agonists failed to abolish centrally mediated sedative side effects in a rat model of audiogenic brain stem epilepsy (Huber et al, 2002).…”

The Antiepileptic Potential of Nucleosides

“…Pentylenetetrazole-induced (intraperitoneal injection) seizures in rats Seizure protection [204] Pentylenetetrazole-induced (intravenous application) seizures in rats Increased seizure threshold…”

“…Kindling (rat amygdala, and hippocampus) model Seizure suppression, seizure prevention [115,116,213,[258][259][260] Pilocarpine-induced (intraperitoneal injection) seizures in rats Blocked seizure appearance [258,261] Pilocarpine-induced (hippocampus) seizures in rats Seizure protection [262] Lithium-pilocarpine-induced status epilepticus in rats Protective effect [216] Pentylenetetrazole-induced (intravenous application) seizures in rats Increased seizure threshold [265] Pentylenetetrazole-induced (intraperitoneal injection) seizures in rats Partial seizure protection [204] Pentylenetetrazole-induced (intraperitoneal injection) seizures in mice Increased seizure latency [118] Pentylenetetrazole-induced seizures in rats Suppressed/abolished tonic phase of generalized tonicclonic seizures [255] Kainic acid-induced (intraperitoneal injection) seizures in mice Increased seizure latency [118] Electroshock-induced seizures in rats Protective effect [263] Bicuculline-induced (rat prepiriform cortex) seizures Seizure protection [267] Bicuculline-induced (rat hippocampal slices) epileptiform activity Decreased epileptiform activity [168] 3-mercaptopropionic acid-induced (intraperitoneal injection) seizures in mice…”

“…Bicuculline-induced (rat hippocampus) seizures (focally injected Ado by infusion pump into hippocampus) Seizure prevention [117] Kainic acid-induced (intraperitoneal injection) seizures in rats (delivery of Ado by osmotic micropump into hippocampus) Seizure reduction [138] Lithium-pilocarpine-induced status epilepticus in rats (intraperitoneal application of Ado) Protective effect [216] Penicillin-induced (rat cortex) epileptiform activity (intracortical and intracerebroventricular application of Ado) Decreased epileptiform activity [120] Pentylenetetrazole-induced (intraperitoneal injection) seizures in rats Seizure protection [204] Pentylenetetrazole-induced (intraperitoneal injection) seizures in mice Increased seizure latency [118] Wistar Albino Glaxo/Rijswijk (WAG/Rij) rats (animal model of human absence epilepsy) Increased absence epileptic activity [309] 4-aminopyridine-induced (rat hippocampal slices; Mg…”