Simvastatin and atorvastatin improve neurological outcome after experimental intracerebral hemorrhage.
OBJECTIVE
This study investigates the effects of statin treatment on experimental intracerebral hemorrhage (ICH) using behavioral, histological, and MRI measures of recovery.


METHODS
Primary ICH was induced in rats. Simvastatin (2 mg/kg), atorvastatin (2 mg/kg), or phosphate-buffered saline (n=6 per group) was given daily for 1 week. MRI studies were performed 2 to 3 days before ICH, and at 1 to 2 hours and 1, 2, 7, 14, and 28 days after ICH. The ICH evolution was assessed via hematoma volume measurements using susceptibility-weighted imaging (SWI) and tissue loss using T2 maps and hematoxylin and eosin (H&E) histology. Neurobehavioral tests were done before ICH and at various time points post-ICH. Additional histological measures were performed with doublecortin neuronal nuclei and bromodeoxyuridine stainings.


RESULTS
Initial ICH volumes determined by SWI were similar across all groups. Simvastatin significantly reduced hematoma volume at 4 weeks (P=0.002 versus control with acute volumes as baseline), whereas that for atorvastatin was marginal (P=0.09). MRI estimates of tissue loss (% of contralateral hemisphere) for treated rats were significantly lower (P=0.0003 and 0.001, respectively) than for control at 4 weeks. Similar results were obtained for H&E histology (P=0.0003 and 0.02, respectively). Tissue loss estimates between MRI and histology were well correlated (R2=0.764, P<0.0001). Significant improvement in neurological function was seen 2 to 4 weeks post-ICH with increased neurogenesis observed.


CONCLUSIONS
Simvastatin and atorvastatin significantly improved neurological recovery, decreased tissue loss, and increased neurogenesis when administered for 1 week after ICH.
Karki
Kishor
K
Department of Neurology, Henry Ford Hospital, Detroit, MI 48202, USA.
Knight
Robert A
RA
Han
Yuxia
Y
Yang
Dongmei
D
Zhang
Jianfeng
J
Ledbetter
Karyn A
KA
Chopp
Michael
M
Seyfried
Donald M
DM
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D000069059:Atorvastatin; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000503:physiopathology / Q000517:prevention & control; D001973:Bromodeoxyuridine; D002543:Cerebral Hemorrhage / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D038524:Diffusion Magnetic Resonance Imaging; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D006538:Heptanoic Acids / Q000627:therapeutic use*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000378:metabolism; D009410:Nerve Degeneration / Q000188:drug therapy / Q000503:physiopathology / Q000517:prevention & control; D055495:Neurogenesis / Q000187:drug effects / Q000502:physiology; D009473:Neuronal Plasticity / Q000187:drug effects / Q000502:physiology; D009479:Neuropeptides / Q000032:analysis / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use; D011758:Pyrroles / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D012038:Regeneration / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000627:therapeutic use*; D016896:Treatment Outcome
D015415:Biomarkers; C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D006538:Heptanoic Acids; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D011758:Pyrroles; D000069059:Atorvastatin; D019821:Simvastatin; D001973:Bromodeoxyuridine