Glibenclamide ameliorates cerebral edema and improves outcomes in a rat model of status epilepticus.

Glibenclamide (GBC), a sulfonylurea receptor 1 blocker, emerges recently as a promising neuron protectant in various neurological disorders. This study aimed to determine whether GBC improves survival and neurological outcome of status epilepticus (SE). Male Sprague-Dawley rats successfully undergoing SE for 2.5 h (n = 134) were randomly assigned to GBC or vehicle group. Rats in the GBC group received a loading dose of 10 μg/kg of GBC, followed by 1.2 μg/6 h for 3 days, while same dose of vehicle was used as control. The 28-day survival rate in the GBC group (11/23) was significantly higher than that in the vehicle group (8/36). In addition, the frequency and duration of spontaneous recurrent seizures in SE rats were profoundly reduced by GBC but not by vehicle treatment. Moreover, cognitive impairment was observed in the SE rats at day 28, which was reversed by GBC treatment. Meanwhile, cerebral edema, as well as neuronal loss, was decreased in several brain areas in the GBC group. Additionally, on the molecular basis, the subunits of sulfonylurea receptor 1/transient receptor potential M4 (SUR1-TRPM4) heterodimer were both strongly upregulated after SE but partly suppressed by GBC treatment. Furthermore, gene knockdown of Trpm4 in SE rats reduced BBB disruption and neuronal loss, similar to the inhibitory effects with GBC treatment. Taken together, GBC treatment markedly improved survival and neurologic outcomes after SE. The salutary effects of GBC were correlated to the alleviation of cerebral edema and reduction in neurological injury via down-regulation of SUR1-TRPM4 channel.

Lin Z ，Huang H ，Gu Y ，Huang K ，Hu Y ，Ji Z ，Wu Y ，Wang S ，Yang T ，Pan S ... -  《-》

Role of Glibenclamide in Brain Injury After Intracerebral Hemorrhage.

Jiang B ，Li L ，Chen Q ，Tao Y ，Yang L ，Zhang B ，Zhang JH ，Feng H ，Chen Z ，Tang J ，Zhu G ... -  《-》

Glibenclamide, a Sur1-Trpm4 antagonist, does not improve outcome after collagenase-induced intracerebral hemorrhage.

Wilkinson CM ，Brar PS ，Balay CJ ，Colbourne F ... -  《PLoS One》

Glibenclamide Is Comparable to Target Temperature Management in Improving Survival and Neurological Outcome After Asphyxial Cardiac Arrest in Rats.

We previously have shown that glibenclamide (GBC), a sulfonylurea receptor 1-transient receptor potential M4 (SUR1-TRPM4) channel inhibitor, improves survival and neurological outcome after asphyxial cardiac arrest and cardiopulmonary resuscitation (ACA/CPR). Here, we further compare the efficacy of GBC with target temperature management (TTM) and determine whether the efficacy of GBC is affected by TTM. Male Sprague-Dawley rats (n=213) subjected to 10-minute ACA/CPR were randomized to 4 groups after return of spontaneous circulation (ROSC): normothermia control (NT); GBC; TTM; and TTM+GBC. Survival, neurodeficit scores, histological injury, as well as the expressions of SUR1 and TRPM4 were evaluated. The 7-day survival rate was 34.4% (11 of 32) in the NT group, 65% (13 of 20) in the GBC group, 50% (10 of 20) in the TTM group, and 70% (14 of 20) in the TTM+GBC group. Rats that received either GBC, TTM alone, or in combination showed less neurological deficit than NT control at 24, 48, and 72 hours and 7 days after ROSC. Moreover, TTM or GBC ameliorated neuronal degeneration and glial activation in the hippocampal CA1 region with similar efficacy, whereas the combination of them had a trend toward better effect. The subunits of SUR1-TRPM4 heterodimers were both strongly upregulated after ACA/CPR and expressed in multiple types of brain cells, but partly suppressed by TTM. GBC is comparable to TTM in improving survival and neurological outcome after ACA/CPR. When GBC is given along with TTM, less histological injury tended to be achieved.

Huang K ，Wang Z ，Gu Y ，Hu Y ，Ji Z ，Wang S ，Lin Z ，Li X ，Xie Z ，Pan S ... -  《-》

Knockout of Transient Receptor Potential Melastatin 4 Channel Mitigates Cerebral Edema and Neuronal Injury After Status Epilepticus in Mice.

This study aimed to evaluate whether the knockout of transient receptor potential melastatin 4 (TRPM4) could reduce cerebral edema and improve neurologic outcome in a mouse model of status epilepticus (SE). Wild-type (WT) (n = 61) and Trpm4-/- mice (n = 61) with behavioral seizures induced by lithium (10 mEq/kg) and pilocarpine (30-40 mg/kg) were terminated 2.5 hours after the onset of SE. After SE, 28 WT-SE and 27 Trpm4-/--SE mice were observed for 28 days and assessed for survival and cognitive function; the others were killed after 24 hours, 72 hours, or 7 days, and evaluated for cerebral edema and histological injury. In comparison to WT-SE mice, the mortality and cognitive deficit for Trpm4-/--SE mice following SE after 28 days were significantly ameliorated. Trpm4-/--SE mice also showed less water content and cerebral edema assessed by magnetic resonance imaging, and decreased blood-brain barrier breakdown after SE. Moreover, Trpm4 deficiency significantly mitigated neuronal loss, cellular necrosis and apoptosis in the hippocampus and piriform cortex and mitigated astrocytosis and microgliosis. In conclusion, this study suggests that Trmp4 may represent a new target for improving outcomes after SE.

Chen X ，Liu K ，Lin Z ，Huang K ，Pan S ... -  《-》