gms | German Medical Science

Objective: Cerebral ischemia due to vasospasm is a highly frequent complication after primary subarachnoidal hemorrhage (SAH). Prophylactic administration of Nimodipin reduces vasospasm and improves outcome. However, the therapy is limited in its efficacy and goes along with temporary hypotension. Nicardipin promotes cerebral as well as coronary vasodilation and can be administered continuously intravenously in critically ill patients. Recently Nicardipine was shown to inhibit neuroinflammation. An intraoperative subarachnoid pellet implantation in patients suffering from SAH could be a possibility to locally induce vessel dilatation and reduce vasospasm without systemic side effects. Our study aimed to investigate the in vitro release dynamics of Nicardipine-pellets (NicaPlant®) as well as in vivo vascular and inflammatory reaction to the calcium channel blocker in the murine brain.

Methods: We tested the in vitro dissolution for 21 days using artificial cerebrospinal fluid. For in vivo observation, a cranial window preparation in C57BL/6 mice was performed. NicaPlant® slices were placed in proximity of the exposed cerebral vasculature. Epi-fluorescence video microscopy was performed on day 0, 3 and day 7 after implantation. Vessel diameter, vessel permeability, vessel configuration and leukocyte-endothelial interaction were quantified. Immunohistochemistry was performed to analyze inflammatory reactions after pellet implantation.

Results: The in vitro analysis showed a 80% release of NicaPlant® after 15 days and full release after 21 days. Implantation of the NicaPlant® slices could be performed without any complications such as cortical injury or bleeding. In the Nica group the arterial vessel diameter was significantly higher due to vessel dilatation (arterial Dcontrol group= 17,8 +/- 1,5 µm; arterial DNica group 21,6 +/- 2,6 µm, p<0,0001). Neither an increased vessel permeability nor an increased leukocyte-endothelial interaction could be detected after implantation. Histological analysis did not show a microglial activation or accumulation. No structural neuronal changes or degeneration of neurons could be observed.

Conclusion: NicaPlant® shows a continuous local drug delivery over 21 days. A subarachnoid implantation of NicaPlant® in mice results in vasodilation of cortical arteries without inducing neuroinflammation or neuronal damage. This topical therapy is a promising tool to prevent patients from cerebral vasospasm without systemic side effects.