Effects of Pravastatin on neuroprotection and neurogenesis after cerebral ischemia in rats.
OBJECTIVE
Statins inhibit hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase activity and lower total serum cholesterol levels. We investigated the effects of Pravastatin on neuroprotection and neurogenesis in the dentate gyrus (DG), subventricular zone (SVZ) and striatum after cerebral ischemia in rats.


METHODS
The filament method was used for temporary middle cerebral artery occlusion (tMCAO). Pravastatin or saline post-ischemically were administered at subsequent time points: 6 h after tMCAO, and then on every subsequent day up to day 14 after tMCAO. Neurological outcome was investigated by using a neuroscore, the beam balance test and the rotarod test. Cholesterol and triglycerides levels were determined by blood sample analysis prior to sacrifice. Infarct area was calculated by microtubule-associated protein 2 (MAP2) staining. Neurogenesis was evaluated by triple staining with bromodeoxyuridine (BrdU), doublecortin (DCX), and neuronal nuclei (NeuN).


RESULTS
Compared with the control groups, Pravastatin treated animals were significantly improved in neurological outcome in rotarod test, with smaller infarct size. Pravastatin increased BrdU-positive cells number in the DG (P = 0.0029) and the SVZ (P = 0.0280) but not in the striatum (P = 0.3929). Furthermore, Pravastatin increased BrdU-labeled DCX positive cells number in the DG (P = 0.0031), SVZ (P = 0.0316) and striatum (P = 0.0073). We also observed a DCX-positive cells stream from the SVZ to the striatum, suggesting a migration route of those immature neurons. No significant differences of total serum cholesterol and triglycerides were observed between groups.


CONCLUSIONS
The Pravastatin administration strategy is safe and could promote neurological recovery in ischemic stroke. Pravastatin induces neurogenesis in the DG and SVZ, and increases the number of migration cells in the striatum. These effects are independent of the cholesterol-lowering property of Pravastatin.
Zheng
Zhao
Z
Burns Center, Xijing Hospital, The Fourth Military Medical University, Xi'an, China. zz73553@fmmu.edu.cn
Chen
Bi
B
D000818:Animals; D002545:Brain Ischemia / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D001973:Bromodeoxyuridine / Q000378:metabolism; D002452:Cell Count / Q000379:methods; D049109:Cell Proliferation / Q000187:drug effects*; D004195:Disease Models, Animal; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism; D009460:Neurologic Examination / Q000379:methods; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009479:Neuropeptides / Q000378:metabolism; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D010751:Phosphopyruvate Hydratase / Q000378:metabolism; D017035:Pravastatin / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D013997:Time Factors
C000714848:Dcx protein, rat; D000089622:Doublecortin Domain Proteins; D000089662:Doublecortin Protein; D008869:Microtubule-Associated Proteins; D009479:Neuropeptides; D018696:Neuroprotective Agents; D010751:Phosphopyruvate Hydratase; D001973:Bromodeoxyuridine; D017035:Pravastatin