Minocycline improves functional outcomes, memory deficits, and histopathology after endovascular perforation-induced subarachnoid hemorrhage in rats.
Subarachnoid hemorrhage (SAH) results in significant long-lasting cognitive dysfunction. Therefore, evaluating acute and long-term outcomes after therapeutic intervention is important for clinical translation. The aim of this study was to use minocycline, a known neuroprotectant agent, to evaluate the long-term benefits in terms of neurobehavior and neuropathology after experimental SAH in rats, and to determine which neurobehavioral test would be effective for long-term evaluation. SAH was induced by endovascular perforation in adult male Sprague-Dawley rats (n=118). The animals were treated with intraperitoneal injection of minocycline (45 mg/kg or 135 mg/kg) or vehicle 1 h after SAH induction. In the short-term, animals were euthanized at 24 and 72 h for evaluation of neurobehavior, brain water content, and matrix metalloproteinase (MMP) activity. In the long-term, neurobehavior was evaluated at days 21-28 post-SAH, and histopathological analysis was done at day 28. High-dose but not low-dose minocycline reduced brain water content at 24 h, and therefore only the high-dose regimen was used for further evaluation, which reduced MMP-9 activity at 24 h. Further, high-dose minocycline improved spatial memory and attenuated neuronal loss in the hippocampus and cortex. The rotarod, T-maze, and water maze tests, but not the inclined plane test, detected neurobehavioral deficits in SAH rats at days 21-28. This study demonstrates that minocycline attenuates long-term functional and morphological outcomes after endovascular perforation-induced SAH. Long-term neurobehavioral assessments using the rotarod, T-maze, and water maze tests could be useful to evaluate the efficacy of therapeutic intervention after experimental SAH.
Department of Physiology, Loma Linda University, School of Medicine, Loma Linda, California 92354, USA.
Prativa
P
Sherchan
Tim
T
Lekic
Hidenori
H
Suzuki
Yu
Y
Hasegawa
William
W
Rolland
Kamil
K
Duris
Yan
Y
Zhan
Jiping
J
Tang
John H
JH
Zhang
D000818:Animals; D002536:Cerebral Arteries / Q000293:injuries*; D057510:Endovascular Procedures / Q000009:adverse effects*; D007274:Injections, Intraperitoneal; D008297:Male; D008569:Memory Disorders / Q000188:drug therapy* / Q000469:parasitology / Q000473:pathology; D008911:Minocycline / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects* / Q000502:physiology; D013345:Subarachnoid Hemorrhage / Q000188:drug therapy* / Q000473:pathology / Q000523:psychology
D008911:Minocycline