topiramate and Subarachnoid-Hemorrhage

Early brain injury (EBI) following aneurysmal subarachnoid haemorrhage (SAH) insults contributes to the poor prognosis and high mortality observed in SAH patients. Topiramate (TPM) is a novel, broad-spectrum, antiepileptic drug with a reported protective effect against several brain injuries. The current study aimed to investigate the potential of TPM for neuroprotection against EBI after SAH and the possible dose-dependency of this effect. An endovascular perforation SAH model was established in rats, and TPM was administered by intraperitoneal injection after surgery at three different doses (20mg/kg, 40mg/kg, and 80mg/kg). The animals' neurological scores and brain water content were evaluated, and ELISA, Western blotting and immunostaining assays were conducted to assess the effect of TPM. The results revealed that TPM lowers the elevated levels of myeloperoxidase and proinflammatory mediators observed after SAH in a dose-related fashion, and the nuclear factor-kappa B (NF-κB) signalling pathway is the target of neuroinflammation regulation. In addition, TPM ameliorated SAH-induced cortical neuronal apoptosis by influencing Bax, Bcl-2 and cleaved caspase-3 protein expression, and the effect of TPM was enhanced in a dose-dependent manner. Various dosages of TPM also upregulated the protein expression of the γ-aminobutyric acid (GABA)-ergic signalling molecules, GABAA receptor (GABAAR) α1, GABAAR γ2, and K(+)-Cl(-) co-transporter 2 (KCC2) together and downregulated Na(+)-K(+)-Cl(-) co-transporter 1 (NKCC1) expression. Thus, TPM may be an effective neuroprotectant in EBI after SAH by regulating neuroinflammation and neuronal cell death.

Topics: Animals; Brain; Brain Edema; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Fructose; Ion Channels; Male; Neuroimmunomodulation; Neurons; Neuroprotective Agents; NF-kappa B; Random Allocation; Rats, Sprague-Dawley; Severity of Illness Index; Subarachnoid Hemorrhage; Topiramate

The aim of this study was to investigate the ability of topiramate (TPM) to prevent neural injury in a rabbit model of subarachnoid hemorrhage (SAH). The effect of TPM on cerebral vasospasm was also evaluated.. Fifty-three New Zealand white rabbits were allocated into three groups randomly. SAH was induced by injecting autologous blood into the cisterna magna. The treatment groups were as follows: (1) sham operated (no SAH (n=18); (2) SAH only (n=17); (3) SAH + TPM (n=18). Hippocampal sections were evaluated for neural tissue degeneration, using the previously described neural degeneration scoring system. The ApopTag peroxidase in situ apoptosis detection kit (Serologicals Corp., former Intergen) was used to assess apoptosis in the hippocampal sections and the effect of TPM on the apoptotic response. Basilar artery lumen areas and arterial wall thickness were also measured in all groups.. There was a statistically significant difference between the mean degeneration scores of the control and SAH only groups (p<0.05). The level of neural degeneration in TPM treated group was significantly lower compared with SAH only group (p<0.05), but not significantly higher than the control group (p>0.05). There were no statistically significant differences between arterial cross-sectional area and arterial wall thickness measurements of the SAH group and SAH + TPM group.. These findings demonstrate that TPM has marked neuroprotective effect in an experimental model of SAH in rabbits. This observation may have clinical implications suggesting that this antiepileptic drug could be used as a possible neuroprotective agent in patients without major adverse effects.

Topics: Animals; Apoptosis; Basilar Artery; Disease Models, Animal; Fructose; Hippocampus; Immunohistochemistry; Male; Neuroprotective Agents; Rabbits; Subarachnoid Hemorrhage; Topiramate