The β-carboline derivative Carbacetam attenuates mortality and neuroendocrine dysfunction in a rodent model of...

Carbacetam is a synthetic β-carboline with clinical neuroprotective potential whose primary targets include quinone reductase 2 (QR2), neuronal L-type calcium channels (Cav1.2), DYRK1A kinase, and the GABA-A receptor. To evaluate whether this polypharmacological profile provides a mechanistic basis for its efficacy, a two-arm study using a standardised weight-drop moderate traumatic brain injury (TBI) model was conducted in 125 male Wistar rats. Subjects received intraperitoneal Carbacetam (5 mg/kg/day) for 10 days, followed by longitudinal assessments of spatial behaviour, neurohumoral dynamics (hypothalamic-pituitary-adrenal, somatotropic, and vasopressinergic axes), neurological deficits, mortality, and predictive molecular docking. Carbacetam significantly attenuated post-traumatic mortality, yielding a 30-day survival probability of 81.2% compared to 33.2% in untreated TBI controls (log-rank χ²(1) = 15.23, p = 9.51 × 10^-5; Cox proportional-hazards ratio = 0.23, 95% CI 0.10-0.51), corresponding to a 3.55-fold reduction in cumulative 30-day mortality incidence (66.8% vs 18.8%). Behaviourally, the treatment reduced early post-traumatic freezing by 39% and increased mobility by 57% at day 7, with subjects converging toward a non-injured behavioural phenotype by day 45. Treatment significantly accelerated the recovery of reflexive capacity by day 7 (p = 0.003). Neurohumorally, acute post-traumatic hypercortisolism was heavily suppressed (p = 0.008); growth hormone and vasopressin concentrations among surviving Carbacetam-treated animals remained comparable to non-injured reference values through day 30. In silico docking predicted that Carbacetam exhibits nanomolar-range QR2 binding affinity via extensive π-π stacking with the FAD cofactor, alongside predicted secondary structural engagements at the Cav1.2 dihydropyridine site, the canonical DYRK1A hinge-region, and the transmembrane GABA-A neurosteroid pocket. This study provides converging behavioural, neuroendocrine, and computational evidence that Carbacetam exerts neuroprotective effects in experimental TBI consistent with a concentration-dependent, multi-target ligand profile, offering a theoretical structural-to-physiological rationale, pending direct mechanistic validation, for its re-evaluation in neurotraumatology.