Local delivery of nimodipine by prolonged-release microparticles-feasibility, effectiveness and dose-finding in experimental subarachnoid hemorrhage.
OBJECTIVE
To investigate the effect of locally applied nimodipine prolonged-release microparticles on angiographic vasospasm and secondary brain injury after experimental subarachnoid hemorrhage (SAH).


METHODS
70 male Wistar rats were categorized into three groups: 1) sham operated animals (control), 2) animals with SAH only (control) and the 3) treatment group. SAH was induced using the double hemorrhage model. The treatment group received different concentrations (20%, 30% or 40%) of nimodipine microparticles. Angiographic vasospasm was assessed 5 days later using digital subtraction angiography (DSA). Histological analysis of frozen sections was performed using H&E-staining as well as Iba1 and MAP2 immunohistochemistry.


RESULTS
DSA images were sufficient for assessment in 42 animals. Severe angiographic vasospasm was present in group 2 (SAH only), as compared to the sham operated group (p<0.001). Only animals within group 3 and the highest nimodipine microparticles concentration (40%) as well as group 1 (sham) demonstrated the largest intracranial artery diameters. Variation in vessel calibers, however, did not result in differences in Iba-1 or MAP2 expression, i.e. in histological findings for secondary brain injury.


CONCLUSIONS
Local delivery of high-dose nimodipine prolonged-release microparticles at high concentration resulted in significant reduction in angiographic vasospasm after experimental SAH and with no histological signs for matrix toxicity.
Department of Neurosurgery, Heinrich-Heine-University, Düsseldorf, Germany. daniel.haenggi@uni-duesseldorf.de
Daniel
D
Hänggi
Jason
J
Perrin
Sven
S
Eicker
Kerim
K
Beseoglu
Nima
N
Etminan
Marcel Alexander
MA
Kamp
Hi-Jae
HJ
Heiroth
Nadia
N
Bege
Stephan
S
Macht
Katrin
K
Frauenknecht
Clemens
C
Sommer
Thomas
T
Kissel
Hans-Jakob
HJ
Steiger
D015901:Angiography, Digital Subtraction; D000818:Animals; D001921:Brain / Q000098:blood supply / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000473:pathology; D002135:Calcium-Binding Proteins / Q000235:genetics; D003692:Delayed-Action Preparations / Q000008:administration & dosage* / Q000737:chemistry; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D015870:Gene Expression / Q000187:drug effects; D007150:Immunohistochemistry; D007275:Injections, Intravenous; D019344:Lactic Acid / Q000008:administration & dosage* / Q000737:chemistry; D008297:Male; D008840:Microfilament Proteins / Q000235:genetics; D008869:Microtubule-Associated Proteins / Q000235:genetics; D009553:Nimodipine / Q000494:pharmacology / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000008:administration & dosage* / Q000737:chemistry; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D051381:Rats; D017208:Rats, Wistar; D013345:Subarachnoid Hemorrhage / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use*; D020301:Vasospasm, Intracranial / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology
C100745:Aif1 protein, rat; D002135:Calcium-Binding Proteins; D003692:Delayed-Action Preparations; C489787:MAP2 protein, rat; D008840:Microfilament Proteins; D008869:Microtubule-Associated Proteins; D014665:Vasodilator Agents; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D009553:Nimodipine