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Contrasting effects of adenosine A1 and A2 receptor ligands in different chemoconvulsive rodent models
H Klitgaard1, L J Knutsen, C Thomsen
1Pharmaceuticals Research, Novo Nordisk A/S, Måløv, Denmark.
Abstract:
The pro- and anticonvulsive properties of selective adenosine A1 and A2 receptor agonists and antagonists were investigated in mice using seizure models involving a specific blockade of adenosine A1 and A2 receptors, modulation of the gamma-aminobutyric acid/benzodiazepine receptor complex or activation with the excitatory amino acid glutamate. The selective adenosine A1 receptor agonists N-cyclopentyladenosine (CPA) and R-N-(phenylisopropyl) adenosine (R-PIA) in doses of 1 and 10 mg/kg i.p. potentiated seizures induced by the selective adenosine A1 receptor antagonist 8-[4-[[[[(2-aminoethyl)amino]carbonyl]methyl]oxy]-phenyl]- 1,3-dipropylxanthine (XAC). Likewise, the selective adenosine A2 receptor agonists N-[(2-methylphenyl)methyl]adenosine (metrifudil) and N-[2-(3,5-dimethoxyphenyl)-2-(2-methylphenyl)ethyl]adenosine (DPMA), in doses of 30 and 100 mg/kg i.p., respectively, potentiated seizures induced by the selective adenosine A2 receptor antagonist 3,7-dimethyl-1-propargylxanthine (DMPX). In contrast, the adenosine A1 and A2 receptor agonists both antagonized seizures induced by methyl-6,7-dimethoxy-4-ethyl-beta-carboline-3-carboxylate (DMCM--an inverse agonist at benzodiazepine receptors) and the adenosine A1 receptor agonists also protected against seizures induced by glutamate. Paradoxically, the selective adenosine A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT) antagonized DMCM- and pentylenetetrazole-induced seizures. Thus, it appears that adenosine A1 and A2 receptor agonists can be both pro- and anticonvulsive depending on the mechanism of action of the chemoconvulsant used in the seizure model. The findings with CPT suggest that other types of adenosine analogues than agonists may possess anticonvulsive properties.
Insights
Adenosine receptor agonists and antagonists exhibit both pro- and anticonvulsive effects in mice, depending on the seizure induction method. This suggests complex roles for adenosine signaling in epilepsy.
Area of Science:
- Neuroscience
- Pharmacology
- Epilepsy Research
Background:
- Adenosine receptors play a crucial role in regulating neuronal excitability.
- The involvement of specific adenosine receptor subtypes (A1 and A2) in seizure activity is not fully understood.
- Investigating adenosine receptor modulation offers potential therapeutic avenues for epilepsy.
Purpose of the Study:
- To determine the pro- and anticonvulsive properties of selective adenosine A1 and A2 receptor agonists and antagonists.
- To elucidate the influence of different seizure induction mechanisms on adenosine receptor function.
- To explore the potential of adenosine receptor modulators as anticonvulsant agents.
Main Methods:
- Utilized various mouse seizure models, including those involving specific receptor blockade, GABA/benzodiazepine receptor modulation, and glutamate activation.
- Administered selective adenosine A1 and A2 receptor agonists and antagonists.
- Observed and quantified seizure potentiation or antagonism in response to drug administration.
Main Results:
- Adenosine A1 and A2 receptor agonists potentiated seizures induced by specific receptor antagonists.
- Both agonist types antagonized seizures induced by a benzodiazepine receptor inverse agonist and glutamate.
- A selective adenosine A1 receptor antagonist demonstrated anticonvulsive effects against certain seizure types.
Conclusions:
- Adenosine A1 and A2 receptor agonists can exert both pro- and anticonvulsive effects, contingent on the underlying seizure mechanism.
- The findings highlight the complex and context-dependent role of adenosine signaling in epilepsy.
- Non-agonist adenosine analogues, such as antagonists, may possess significant anticonvulsant properties.