Carbamazepine Attenuates Astroglial L-Glutamate Release Induced by Pro-Inflammatory Cytokines via Chronically Activation of Adenosine A2A Receptor

Abstract

Carbamazepine (CBZ) binds adenosine receptors, but detailed effects of CBZ on astroglial transmission associated with adenosine receptor still need to be clarified. To clarify adenosinergic action of CBZ on astroglial transmission, primary cultured astrocytes were acutely or chronically treated with CBZ, proinflammatory cytokines (interferon γ (IFNγ) and tumor necrosis factor α (TNFα)), and adenosine A2A receptor (A2AR) agonist (CGS21680). IFNγ and TNFα increased basal, adenophostin-A (AdA)-evoked, and 2-amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA)-evoked astroglial L-glutamate releases. In physiological condition, CGS21680 increased basal astroglial L-glutamate release but glutamate transporter inhibition prevented this CGS21680 action. CBZ did not affect basal release, whereas glutamate transporter inhibition generated CBZ-induced glutamate release. Furthermore, AdA-evoked and AMPA-evoked releases were inhibited by CBZ but were unaffected by CGS21680. Contrary to physiological condition, chronic administrations of IFNγ and TNFα enhanced basal, AdA-, and AMPA-evoked releases, whereas IFNγ and TNFα decreased and increased CGS21680-evoked releases via modulation A2AR expression. Both chronic administration of CGS21680 and CBZ suppressed astroglial L-glutamate release responses induced by chronic cytokine exposer. Especifically, chronic administration of CBZ and CGS21680 prevented the reduction and elevation of A2AR expression by respective IFNγ and TNFα. These findings suggest that A2AR agonistic effects of CBZ contribute to chronic prevention of pathomechanisms developments of several neuropsychiatric disorders associated with proinflammatory cytokines.

Upregulated Connexin 43 Induced by Loss-of-Functional S284L-Mutant α4 Subunit of Nicotinic ACh Receptor Contributes to Pathomechanisms of Autosomal Dominant Sleep-Related Hypermotor Epilepsy

“…Astrocytes were prepared using a protocol adapted from previously described methods [47][48][49]. Pregnant Sprague-Dawley rats (SLC, Sizuoka, Japan) were housed individually in cages, kept in air-conditioned rooms (temperature, 22 ± 2 • C) set at 12 h light/dark cycle, with free access to food and water.…”

“…The ACSF comprised NaCl 150.0 mM, KCl 3.0 mM, CaCl 2 1.4 mM, MgCl 2 0.8 mM, and glucose 5.5 mM, buffered to pH 7.3 with 20 mM HEPES buffer. The remaining adherent cells contained 95% GFAP-positive and A2B5-negative cells detected using immunohistochemical staining [47][48][49]. After the wash out, plasma membrane proteins of cultured astrocytes were extracted using Minute Plasma Membrane Protein Isolation Kit (Invent Biotechnologies, Plymouth, MN, USA).…”

“…These different responses of S286L-TG between 50 mM and 100 mM potassium-evoked stimulations suggest that S286L-TG does not acquire electrophysiological hypersensitivity in focus regions (M2C) [21], but acquires abnormality in extracellular potassium-sensitive L-glutamate release regulation systems. The neurotransmitter exocytosis is activated by 25 mM potassium-evoked stimulation [58], whereas the generation of astroglial gliotransmitter release requires higher than 50 mM potassium-evoked stimulation [47,49,59]. Additionally, astroglial L-glutamate release through astroglial connexin hemichannel is also activated by 100 mM potassium-evoked stimulation [33,34].…”

Special Issue: G Protein-Coupled Adenosine Receptors: Molecular Aspects and Beyond

“…Thus, restoring the unbalanced A 2A R/D 2 R heteromer function potentially associated with PD may help to better understand the disease etiology and to design selective combined pharmacotherapeutic strategies [20]. Then, Okada et al demonstrate that both acute and chronic administrations of therapeutic-relevant concentrations of carbamazepine (CBZ)-an anticonvulsive drug that also binds to adenosine receptors-suppress excitatory astroglial glutamatergic transmission associated with IP3-R and AMPA-R [21]. Importantly, the A 2A R agonistic action of CBZ contributes to chronic mechanisms of carbamazepine against several neuropsychiatric disorders via inhibition of astroglial pathomechanisms of proinflammatory responses of IFNγ and TNFα [21].…”

“…Then, Okada et al demonstrate that both acute and chronic administrations of therapeutic-relevant concentrations of carbamazepine (CBZ)-an anticonvulsive drug that also binds to adenosine receptors-suppress excitatory astroglial glutamatergic transmission associated with IP3-R and AMPA-R [21]. Importantly, the A 2A R agonistic action of CBZ contributes to chronic mechanisms of carbamazepine against several neuropsychiatric disorders via inhibition of astroglial pathomechanisms of proinflammatory responses of IFNγ and TNFα [21]. Irrera et al investigate the efficacy of polydeoxyribonucleotide (PDRN), a biologic A 2A R agonist, in an experimental model of psoriasis-like dermatitis [22].…”