Table 2.
Pharmacological approaches to modulate adenosine metabolism and signaling in epilepsy (selected examples).
| Receptor subtype / adenosine metabolism | Process | Epilepsy model | Strategy | Outcome | References |
|---|---|---|---|---|---|
| A 1 R | Status epilepticus | Intrahippocampal KA (50 nl of 20 mM solution) in mice (males and females) | A1R-KO | Lethal SE in A1R-KO mice. | (Fedele et al. 2006) |
| Status epilepticus | Theophylline-associated seizures (5, 10, and 25 mg/kg i.p) in rats | DPCPX (0.5 or 5 mg/kg i.p) | A1R antagonism led to increased seizure activity and duration. | (Fukuda et al. 2010) | |
| Epilepsy | i.p. pilocarpine (320 mg/kg) in rats (males) | A1R agonist RPia (25 μg/kg/day i.p); A1R antagonist DPCPX (50 μg/kg/day i.p) administered for 10 consecutive days, starting from 4 months post-SE | A1R agonist reduced seizure rate and hippocampal excitability; while the opposite effect was observed using A1R antagonists. | (Amorim et al. 2016) | |
| Brain injury | Controlled cortical impact (CCI) in mice (males) | A1R-KO | Lethal SE in A1R-KO mice. | (Kochanek et al. 2006) | |
| Pharmacoresistant epilepsy | Intrahippocampal injection of KA (200 ng in 50 nl) in mice (males) | A1R agonist CCPA (1.5 or 3 mg/ kg i.p) | A1R agonism led to suppression of drug resistant seizures in mice. | (Gouder et al. 2003) | |
| Pharmacoresistant seizures | Human temporal neocortical slices; SLEs e induced by perfusing slices with ACSF containing 8 mM K+ and 50 μM bicuculline methiodide | A1R agonist SDZ WAG 994 (1 μM); A1R antagonist DPCPX (1 μM) | A1R agonist completely suppressed SLEs in 73% of slices including slices derived from pharmacoresistant patients; A1R antagonism prevented suppression of SLEs. | (Klaft et al. 2016) | |
| A 2A R | Epileptogenesis | i.p KA injections (10 mg/kg); Amygdala kindling (1-s train at 50 Hz with pulses of 1 ms and 500 μA) in rats (males) | A2AR antagonist, SCH58261 (0.05 mg/kg i.p) administered 30 min before KA injections | A2AR antagonism led to suppression of epileptogenesis in amygdala kindled rats; in i.p KA rats, A2AR antagonism prevented seizure-induced neurodegeneration in the hippocampus. | (Canas et al. 2018) |
| Epileptogenesis | PTZ kindling (40 – 90 mg/kg, i. p.) and pilocarpine i.p. (350 mg/ kg, i.p.) in mice (sex not specified) | A2AR –KO | A2AR-KO mice are partially resistant to limbic seizures; A2ARs are involved in excitatory neurotransmission and seizure aggravation. | (El Yacoubi et al. 2009) | |
| A2B and A3R | Epilepsy | Human hippocampal slices | A2BR antagonist (MRS1706, 10 nM) or A3R antagonist (MRS1334, 30 nM) | Both A2B and A3R antagonists altered the stability of GABA. Reduced GABA-induced rundown currents in membranes. | (Roseti et al. 2008) |
| Adenosine production (CD73) | Epilepsy | Human TLE and MTLE hippocampus | NT5E measurement through Western blot analysis | Increase in NT5E in tissue from patients with epilepsy | (Barros-Barbosa et al. 2016) |
| Adenosine metabolism (ADK) | Epileptogenesis | Intrahippocampal injection of KA (400 ng in 200 nl) in mice (males) | ADK inhibitor 5-ITU, (1.6 mg/ kg, b.i.d) i.p for 5 days from day 3 to day 8 after SE | 5-ITU used transiently after status epilepticus suppress epileptogenesis. | (Sandau et al. 2019) |
| Epilepsy | MES-induced seizures in rats (60-Hz current of 150 mA for 0.2 s via corneal electrodes) (males) | 5-iodotubercidin, 5-deoxy-5-iodotubercidin and 5-amino-5-deoxyadenosine | ADK inhibitors showed suppression of seizure activity induced by electroshock. | (Ugarkar et al. 2000) | |
| Epilepsy | Intrahippocampal KA (1 nmol) in transgenic mice (males) | ADK inhibitor, 5ITU (3.1 mg/kg) i.p; Adktm1– /– -Tg(UbiAdk) (ADK overexpressing mice) | ADK overexpressed mice showed spontaneous seizure activity and exacerbation of seizures induced by KA, which was successfully treated by ADK inhibitor 5-ITU. | (Fedele et al. 2005) | |
| Pharmacoresistant epilepsy | Intrahippocampal injection of KA (200 ng in 50 nl) in mice (males) | ADK inhibitor 5-ITU, (3.1 mg/ kg), i.p | ADK inhibitors suppressed seizure activity including pharmacoresistant seizures. | (Gouder et al. 2004) |
Abbreviations: ADK, Adenosine kinase; ACSF, Artificial cerebrospinal fluid; CCPA, 2-chlorN6cyclopentyladenosine; DPCPX, 8-Cyclopentyl-1,3-dipropylxanthine; GABA, Gama amino butyric acid; i.p., intraperitoneal; KA, Kainic acid; KO, knock out; MES, Maximal electric shock; MRS1334, 1,4-Dihydro-2-methyl-6-phenyl-4-(phe-nylethynyl)-3,5-pyridinedicarboxylic acid 3-ethyl-5-[(3-nitrophenyl)methyl] ester; MRS1706, N-(4-Acetylphenyl)-2-[4-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)phenoxy]acetamide; MTLE, Mesial temporal lobe epilepsy; NT5E, Ecto-5’-nucleotidase; PTZ, Pentylenetetrazol; 5ITU, 5-indotubercidin; SE, Status epilepticus; SLE, Seizure-like events; TLE, Temporal lobe epilepsy.