Investigation of the effects of lacosamide on ischaemic tissue injury in an experimental subarachnoi̇d haemorrhage model

Early brain injury (EBI) after subarachnoid haemorrhage (SAH) arises from the simultaneous activation of hypoxia–ischaemia, oxidative stress, inflammation and caspase-mediated apoptosis, thereby laying the foundation for long-term neurological sequelae. The present thesis evaluates the neuroprotective actions of the antiepileptic drug lacosamide (LCM) on the neuron–glia–vascular unit in an experimental SAH model. Forty-six male Wistar-Albino rats were assigned to Control, Sham, SAH, SAH + LCM (20 mg kg⁻¹ i.p.) and LCM groups. SAH was induced by injecting 0.3 mL autologous arterial blood into the cisterna magna; the Sham group received an equal volume of sterile physiological saline. LCM therapy was initiated within the first hour and continued as a single daily dose for four days. On day four the rats were sacrificed; cortico-hippocampal blocks were graded histopathologically with the Extended Subarachnoid Assessment Score (ESAS) and immunostained for brain-derived neurotrophic factor (BDNF), myelin basic protein (MBP), synaptophysin (SYP), vascular endothelial growth factor (VEGF) and caspase-3 (CAS-3). Total antioxidant status (TAS) and total oxidant status (TOS) were determined spectrophotometrically and the oxidative stress index (OSI) calculated. Finally, transcripts for interleukin-6 (IL-6), signal transducer and activator of transcription-3 (STAT-3) and hypoxia-inducible factor-1α (HIF-1α) were quantified by RT-qPCR. Histology revealed diffuse oedema, haemorrhage and neuronal loss in the SAH group, whereas LCM halved ESAS values and preserved morphology. Immunohistochemically, SAH produced marked reductions in BDNF and MBP, a 75 % loss of SYP and strong CAS-3/VEGF positivity; LCM reversed all changes and limited blood–brain-barrier injury. Biochemically, SAH doubled TOS and OSI while lowering TAS; LCM reduced TOS-OSI by 58 % and restored TAS. RT-qPCR showed excessive activation of the IL-6/STAT-3/HIF-1α axis after SAH, which LCM suppressed by ≥ 60 %. These findings demonstrate that LCM preserves neuronal, glial and vascular integrity by simultaneously dampening inflammatory, hypoxic, oxidative and apoptotic signalling during the early phase of SAH. Despite its short half-life, once-daily dosing effectively covered the early brain injury window; nevertheless, optimisation of dose–timing and assessment of long-term neurobehavioural outcomes are required before clinical application in aneurysmal SAH.