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.
Highlights
It has been demonstrated that dysfunctions of glial mechanisms, including self-reinforcing interplay between dysfunctional energy homeostasis, inflammation, and astroglial signaling, play important roles in pathomechanisms of development of several neuropsychiatric disorders, including epilepsy, bipolar disorder, schizophrenia, and chronic pain [1,2,3,4]
Chronic Effects of interferon γ (IFNγ) and tumor necrosis factor α (TNFα) on Basal, amino-3-(3-hydroxy-5-methyl-isoxazol-4-yl)propanoic acid (AMPA), and AdA-Evoked Astroglial L-Glutamate Releases (Study 1). Both clinical and preclinical studies have indicated that proinflammatory cytokines, including IFNγ and TNFα, play important roles in the development of epilepsy and several neuropsychiatric disorders [1,7]
After wash-out at DIV28, astrocytes were incubated in artificial cerebrospinal fluid (ACSF) containing the same cytokine for 30 min, and ACSF was collected for analysis of basal release
Summary
It has been demonstrated that dysfunctions of glial mechanisms, including self-reinforcing interplay between dysfunctional energy homeostasis, inflammation, and astroglial signaling, play important roles in pathomechanisms of development of several neuropsychiatric disorders, including epilepsy, bipolar disorder, schizophrenia, and chronic pain [1,2,3,4]. Proinflammatory cytokines, tumor necrosis factor α (TNFα), and interferon γ (IFNγ) probably contribute to development of epilepsy (epileptogenesis, ictogenesis, and seizure-related brain damages) [7,8], and several neuropsychiatric disorders [1] These cytokines enhance astroglial glutamatergic transmission, which is compensated by anticonvulsant, carbamazepine (CBZ), and levetiracetam [8,9,10], as well as antipsychotics, aripiprazole, and clozapine [11,12,13]. CBZ inhibits voltage-gated sodium channels, therapeutic-relevant concentration of CBZ increased basal releases of GABA, dopamine, serotonin, and acetylcholine without affecting that of L-glutamate by in vivo microdialysis study [17,19,23,24,25]
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