gms | German Medical Science

Objective: Under hypoxic conditions Sulfonylurea receptor 1 (SUR1) regulated non-selective cation channels are generated in astrocytes, neurons and endothelial cells. ATP depletion causes depolarization and opening of these channels leading to cytotoxic edema. Blocking of SUR1 with low-dose glibenclamide reduces edema, contusion volume and mortality rate in models of experimental cerebral stroke and spinal cord injury. Therefore, glibenclamide might also prevent the development of secondary brain damage after experimental traumatic brain injury (TBI).

Method: Experimental TBI was performed by a controlled cortical impact injury (CCI) in 68 Sprague-Dawley rats. Glibenclamide or vehicle was administered as a subcutaneous bolus 15 min after CCI and via diffusion pumps over 7 days. Acute (patho-) physiological changes (ICP, cerebral metabolism, EEG activity) were monitored over 180 min following trauma. 24 h after CCI brain water content was assessed gravimetrically. Contusion volume depicted by MRI scans and neurological function were quantified 8 h, 48 h, 72 h and 7 days following CCI.

Results: In comparison to baseline levels ICP increased significantly after trauma. Extracellular (ec) glucose concentrations dropped to a “close to zero” level 30 min after CCI, but recovered subsequently. L/P ratio and glutamate concentrations (ec) rose significantly during the observation time. In EEG monitoring average frequency was significantly decreased after CCI compared to sham-operated animals. Number and duration of epileptic seizures were declined in glibenclamide treated animals, but these results did not reach significance. Due to the administration of glibenclamide brain water content was reduced significantly 24 h after TBI (80.47 ± 0.37% vs. 80.83 ± 0.44%, p<0.05). Contusion volumes increased continuously within the first 72 h and diminished 7 days after CCI. At each point in time contusion volume could be decreased significantly in rats treated with glibenclamide compared to controls (8h: 158.0 ± 36.8 mm³ vs. 264.1 ± 44.4 mm³, p<0.001; 24h: 172.5 ± 38.7 mm³ vs. 299.2 ± 64.0 mm³, p<0.001; 72h: 211.1 ± 41.0 mm³ vs. 309.8 ± 64.4 mm³, p<0.001; 7d: 107.1 ± 21.3 mm³ vs. 164.0 ± 29.0 mm³, p<0.005). Neurological function, however, was not influenced by glibenclamide during the first 7 days following CCI.

Conclusions: In summary, treatment with glibenclamide could significantly reduce brain edema and contusion volume after CCI. Therefore, it might offer a promising treatment option for patients with TBI.