Astaksantyna poprawiła skuteczność karbamazepiny i komorbidności nastroju u szczurów z epilepsją poprzez wzmocnienie szlaku sygnalizacji GABAergicznej

Abstract Background and aims: Epilepsy is a prevalent neurological disorder characterized by recurrent seizures and frequently accompanied by cognitive and psychiatric comorbidities. A key mechanism underlying epileptogenesis is disruption of the excitation–inhibition (E/I) balance, driven by excessive glutamatergic activity and impaired gamma-aminobutyric acid (GABA)-mediated inhibition. Although carbamazepine (CBZ) is a first-line agent for the treatment of focal and generalized seizures, its clinical utility is often limited by dose-dependent adverse effects and suboptimal seizure control. Astaxanthin (AXT), a lipophilic carotenoid with anti-inflammatory and neuroprotective properties, has demonstrated potential anti-seizure effects, including modulation of GABAergic signaling. This study aimed to evaluate whether co-administration of AXT enhances CBZ efficacy in a pentylenetetrazol (PTZ)-kindling model and to identify an optimal CBZ dose within a dose-response framework. Experimental procedure: Adult male Wistar rats (250–300 g) were randomly assigned to seven groups (n = 6/group): Sham, PTZ, PTZ + AXT (4 mg/kg/day, oral), PTZ+CBZ25, PTZ+CBZ75, PTZ+CBZ25 + AXT, and PTZ+CBZ75 + AXT. PTZ (35 mg/kg, i.p.) was administered on alternate days for 4 weeks. CBZ (25 or 75 mg/kg, i.p.) was administered 30 min prior to each PTZ injection. Seizure severity was assessed using a standard 0–6 scoring scale, and seizure latency was recorded. Anxiety- and depressive-like behaviors were evaluated. Expression levels of the GABA_A receptor and GAD65 in the somatosensory cortex and hippocampal subfields were assessed using immunofluorescence and Western blotting. Data were analyzed using one-way ANOVA or two-way repeated-measures ANOVA followed by Tukey’s post hoc test, with p considered statistically significant. Key results: Co-administration of AXT and CBZ produced a pronounced anticonvulsant effect compared with monotherapy. Across the 4-week PTZ protocol, combined treatment with AXT and CBZ (25 and 75 mg/kg) significantly prolonged seizure latency and reduced seizure severity scores relative to both the PTZ group and the corresponding CBZ monotherapy groups. In contrast, AXT alone and CBZ monotherapy at either dose failed to provide adequate seizure control, indicating that the anticonvulsant effect was primarily attributable to the combined regimen. Conclusion: These findings suggest that AXT may serve as a low-risk adjunct to CBZ, enhancing its anticonvulsant efficacy and improving affective outcomes. The observed effects are likely mediated, at least in part, through restoration of GABAergic inhibitory signaling.