Effects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat

doi:10.1016/0014-2999(95)00557-9

European Journal of Pharmacology

Volume 294, Issues 2–3, 29 December 1995, Pages 383-389

https://doi.org/10.1016/0014-2999(95)00557-9 Get rights and content

Abstract

The protective effects of the selective adenosine A₁ receptor agonist, 2-chloro-N⁶-cyclopentyladenosine (CCPA), the selective adenosine A_2A receptor agonist, 2-hexynyl-5′-N-ethylcarboxamidoadenosine (2HE-NECA), and the non-selective agonist, 5′-N-ethylcarboxamidoadenosine (NECA) were studied against lethal seizures induced by intraperitoneal (i.p.) injection of pentylenetetrazole (80 mg/kg). In acute studies there was a dose-dependent reduction of lethal seizures, as shown by the low dose's protecting 50% of animals (PD₅₀): 0.11, 0.05 and 0.05 mg/kg i.p. for CCPA, 2HE-NECA and NECA, respectively. In the repeated administration studies the animals received either vehicle or drug i.p. twice daily for 12 days. The drug doses were twice the PD₅₀ value: 0.3 mg/kg for CCPA or 0.1 mg/kg for both 2HE-NECA and NECA. 2HE-NECA and NECA maintained their protective activity against pentylenetetrazole-induced seizures (63% or 60% vs. 60% or 58% in acute studies, respectively). Conversely, repeated treatment with CCPA resulted in a marked decrease of its effects (67% vs. 30% in acute studies; P < 0.05). The data indicate that in addition to adenosine A₁ the A_2A receptors also appear to be involved in the protection from seizures. The anticonvulsant effects induced by repeated stimulation of adenosine A₁ receptors are subject to tolerance, whereas effects depending on adenosine A_2A receptor activation are maintained.

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Despite continuous advances in understanding the underlying pathogenesis of hyperexcitable networks and lowered seizure thresholds, the treatment of epilepsy remains a clinical challenge. Over one third of patients remain resistant to current pharmacological interventions. Moreover, even when effective in suppressing seizures, current medications are merely symptomatic without significantly altering the course of the disease. Much effort is therefore invested in identifying new treatments with novel mechanisms of action, effective in drug-refractory epilepsy patients, and with the potential to modify disease progression. Compelling evidence has demonstrated that the purines, ATP and adenosine, are key mediators of the epileptogenic process. Extracellular ATP concentrations increase dramatically under pathological conditions, where it functions as a ligand at a host of purinergic receptors. ATP, however, also forms a substrate pool for the production of adenosine, via the action of an array of extracellular ATP degrading enzymes. ATP and adenosine have assumed largely opposite roles in coupling neuronal excitability to energy homeostasis in the brain. This review integrates and critically discusses novel findings regarding how ATP and adenosine control seizures and the development of epilepsy. This includes purine receptor P1 and P2-dependent mechanisms, release and reuptake mechanisms, extracellular and intracellular purine metabolism, and emerging receptor-independent effects of purines. Finally, possible purine-based therapeutic strategies for seizure suppression and disease modification are discussed.
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Thus, the effects observed with the combination of NECA plus CBZ (delay and control of convulsions spreading) could be due in part to this modulation of efflux transporters protein levels, which allows the restoration of the anticonvulsant effect in CBZ resistant rats, probably by facilitating its delivery to the brain. On the other hand, the administration of just NECA in CBZ resistant rats increased only the latencies to convulsions, suggesting that this delay in the evolution of convulsions is probably due to brain activation of adenosine receptors (Adami et al., 1995; Zhang et al., 1990). We observed that the administration of DPCPX (a selective A1R antagonist), prevented the anticonvulsant behavioral effects generated by systemic NECA administration.
Up-regulation of efflux transporters in brain capillaries may lead to the decreased therapeutic efficacy of antiepileptic drugs in patients with Drug Resistant Epilepsy. Adenosine receptor activation in brain capillaries can modulate blood-brain barrier permeability by decreasing the protein levels and function of efflux transporters. Therefore, we aimed to investigate whether the activation of adenosine receptors improves convulsions outcome in carbamazepine (CBZ) resistant animals and modulates the protein levels of efflux transporters (P-GP, MRP1, MRP2) in brain capillaries. We employed the window-pentylenetetrazol (PTZ) kindling model to develop CBZ resistant rats by CBZ administration during the post-kindling phase, and tested if these animals displayed subsequent resistance to other antiepileptic drugs. Crucially, we investigated if the administration of a broad-spectrum adenosine agonist (NECA) improves convulsions control in CBZ resistant rats. Of potential therapeutic relevance, in CBZ resistant rats NECA restored the anticonvulsant effect of CBZ. We also evaluated how the resistance to CBZ and the activation of adenosine receptors with NECA affect protein levels of efflux transporters in brain capillaries, as quantified by western blot. While CBZ resistance was associated with the up-regulation of both P-GP/MRP2 in brain capillaries, with the administration of NECA in CBZ resistant rats, we observed a decrease of P-GP and an increase of MRP2 levels, in brain capillaries. Since the activation of adenosine receptors improves the outcome of convulsions probably through the modulation of the efflux transporters protein levels in brain capillaries, adenosine agonists could be useful as an adjunct therapy for the control of Drug Resistant Epilepsy.
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Adami et al. [59] showed that in the pentylenetetrazole-induced seizures the anticonvulsant effects caused by repeated stimulation of adenosine A1 receptors are subject to tolerance. In acute studies, the selective adenosine A1 receptor agonist, 2-chloro-N(6)-cyclopentyladenosine (CCPA), provided a dose-dependent reduction in seizures induced by intraperitoneal injection of pentylenetetrazole [60], whereas repeated treatment with CCPA resulted in a marked decrease of its effects [59]. In another study, intrathalamic micro-injections of 2-CLA caused significant decreases in both seizure duration and seizure severity in pentylenetetrazole-induced seizures in rats.
Adenosine is present in all cells and is implicated in the control of the function of every tissue and organ. The elevated adenosine levels seem to play a significant role in a protection against cellular damage in the regions with increased metabolic demand and prevent the subsequent dysfunction of the affected organs. Furthermore, adenosine has been shown to play an important role not only in the regulation of pathophysiological processes, but also in the modulation of normal physiological processes, for example, the regulation of sleep and arousal as well as by impact on pre- or postsynaptic receptors involved in releasing neurotransmitters (e.g. glutamate, acetylcholine, norepinephrine, 5-hydroxytryptamine, dopamine, GABA and others).
Experimental studies provide evidence supporting the role of adenosine as an endogenous anticonvulsant agent. Numerous adenosine agonists acting through A₁, A₂ and A₃ receptors were proven as potent anticonvulsant compounds in a wide variety of animal models of epilepsy. However, despite their efficacy in such models, adenosine receptor agonists do not appear to be good candidates for successful clinical applications. The therapeutic range of systemically administered adenosine receptor agonists is very narrow and they often produce profound adverse events. It seems, therefore, that adenosine receptor agonists could only be used clinically when co-administered with other antiepileptic drugs or when used in local therapies, where their side effect profile is much more tolerable. An alternative strategy would be to enhance the natural adenosinergic feedback mechanism triggered by seizures by using adenosine uptake inhibitors. This approach seems very attractive as it would allow limiting the action only in the active areas such as seizure foci and thus, preventing the systemic side effects.
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Chronic glutamate NMDA receptor stimulation, from glutamate released by astrocytes, reduced seizures, probably by increasing the density of A1 receptors in the cortex and hippocampus (Tian et al., 2005; Von Lubitz et al., 1995a). The anti-convulsant effects induced by repeated stimulation of A1 receptors are subject to tolerance, whereas the effects of A2A receptor activation are maintained in pentylenetetrazol-induced convulsions (Adami et al., 1995). Loss of A1 receptors may contribute to human temporal lobe epilepsy (Glass et al., 1996).
Purinergic neurotransmission, involving release of ATP as an efferent neurotransmitter was first proposed in 1972. Later, ATP was recognised as a cotransmitter in peripheral nerves and more recently as a cotransmitter with glutamate, noradrenaline, GABA, acetylcholine and dopamine in the CNS. Both ATP, together with some of its enzymatic breakdown products (ADP and adenosine) and uracil nucleotides are now recognised to act via P2X ion channels and P1 and P2Y G protein-coupled receptors, which are widely expressed in the brain. They mediate both fast signalling in neurotransmission and neuromodulation and long-term (trophic) signalling in cell proliferation, differentiation and death. Purinergic signalling is prominent in neurone–glial cell interactions. In this review we discuss first the evidence implicating purinergic signalling in normal behaviour, including learning and memory, sleep and arousal, locomotor activity and exploration, feeding behaviour and mood and motivation. Then we turn to the involvement of P1 and P2 receptors in pathological brain function; firstly in trauma, ischemia and stroke, then in neurodegenerative diseases, including Alzheimer's, Parkinson's and Huntington's, as well as multiple sclerosis and amyotrophic lateral sclerosis. Finally, the role of purinergic signalling in neuropsychiatric diseases (including schizophrenia), epilepsy, migraine, cognitive impairment and neuropathic pain will be considered.
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Low frequency stimulation (LFS) has an inhibitory effect on rapid perforant path kindling acquisition. In the present study the role of adenosine A₁ and A_2A receptors in mediating this inhibitory effect was investigated. Rats were kindled by perforant path stimulation using rapid kindling procedures (12 stimulations per day). LFS (0.1 ms pulse duration at 1 Hz, 200 pulses, and 50–150 μA) was applied to the perforant path immediately after termination of each rapid kindling stimulation. 1,3-Dimethyl-8-cyclopenthylxanthine (CPT; 50 μM), a selective A₁ antagonist and ZM241385 (ZM, 200 μM), a selective A_2A antagonist were daily microinjected into the lateral ventricle 5 min before kindling stimulations. LFS had an inhibitory effect on kindling development. Pretreatment of animals with CPT reduced the inhibitory effect of LFS on kindling rate and suppressed the effects of LFS on potentiation of population EPSP during kindling acquisition. In addition, CPT was able to antagonize the effects of LFS on kindling-induced increase in early (10–50 ms intervals) and late (300–1000 ms intervals) paired pulse depression. ZM pretreatment had no effect on antiepileptogenic effects of LFS in kindling acquisition. In addition, LFS prevented the kindling-induced elevation of cyclic AMP (cAMP) levels in kindled animals. Based on these results, we suggest that the antiepileptogenic effects of LFS on perforant path kindling might be mediated through activation of adenosine A₁, but not A_2A receptors. Moreover, modulation of cAMP levels by LFS may potentially be an important mechanism which explains the anticonvulsant effects of LFS in kindled seizures.

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¹: Present address: ‘Mario Negri’ Institute for Pharmacological Research, Milan, Italy.

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Regular paperEffects of repeated administration of selective adenosine A1 and A2A receptor agonists on pentylenetetrazole-induced convulsions in the rat

Abstract

Brain Res.

Eur. J. Pharmacol.

Int. Rev. Neurobiol.

Pharmacol. Biochem. Behav.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

J. Biol. Chem.

Neuropharmacology

Trends Biochem. Sci.

Exp. Neurol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Prolonged agonist exposure induces imbalance of A1 and A2 receptor-mediated functions in rat brain slices

Drug Dev. Res.

Adenosine involved in kindled seizures

Adenosine receptors in brain membranes: binding of N6 cyclohexyl [3H]adenosine and 1,3-diethyl-8[3H]phenylxanthine

Characterization of the A2 adenosine receptor labeled by [3H]NECA in rat striatal membranes

Mol. Pharmacol.

Repeated administration of selective adenosine A1 and A2 receptor agonists in the spontaneously hypertensive rat: tolerance develops to A1-mediated hemodynamic effect

J. Pharmacol. Exp. Ther.

Anticonvulsant doses of 2-chloro-N6-cyclopentyladenosine, an adenosine A1 receptor agonist, reduce GABAergic transmission in different areas of the mouse brain

J. Pharmacol. Exp. Ther.

2-Alkynyl derivatives of adenosine and adenosine-5′-N-ethyluronamide as a selective agonist at A2 adenosine receptors

J. Med. Chem.

Adenosine and epileptic seizures

Is adenosine an endogenous anticonvulsant?

Epilepsia

Regular paper
Effects of repeated administration of selective adenosine A₁ and A_2A receptor agonists on pentylenetetrazole-induced convulsions in the rat

Prolonged agonist exposure induces imbalance of A₁ and A₂ receptor-mediated functions in rat brain slices

Adenosine receptors in brain membranes: binding of N⁶ cyclohexyl [³H]adenosine and 1,3-diethyl-8[³H]phenylxanthine

Characterization of the A₂ adenosine receptor labeled by [³H]NECA in rat striatal membranes

Repeated administration of selective adenosine A₁ and A₂ receptor agonists in the spontaneously hypertensive rat: tolerance develops to A₁-mediated hemodynamic effect

Anticonvulsant doses of 2-chloro-N⁶-cyclopentyladenosine, an adenosine A₁ receptor agonist, reduce GABAergic transmission in different areas of the mouse brain

2-Alkynyl derivatives of adenosine and adenosine-5′-N-ethyluronamide as a selective agonist at A₂ adenosine receptors