Simvastatin acutely reduces ischemic brain damage in the immature rat via Akt and CREB activation.
We have previously shown that simvastatin (Sim) has long-lasting neuroprotective effects in a neonatal model of hypoxia-ischemia. Herein we evaluated the neuroprotective effect of different doses and duration of Sim treatment and further addressed its mechanism of action. Neonatal rats were subjected to occlusion of the right carotid artery followed by 2.5 h hypoxia (hypoxia-ischemia, HI). Sim was given at the dose of 10 or 5 mg/kg, s.c. from postnatal day 1 (PN1) to PN7, or at 20 mg/kg from PN4 to PN7, or at 20 mg/kg in a single administration 18 h before the onset of the ischemic procedure. Low-dose treatments or a single administration of the drug were effective in reducing HI-induced brain damage and its behavioural outcomes. Sim increased both Akt and CREB phosphorylation in neuronal cells and treatment with wortmannin completely blocked neuroprotection and p-Akt. These data demonstrate that even a single prophylactic Sim administration protects from hypoxic ischemic brain damage and that neuroprotection is in part obtained by preserving Akt and stimulating CREB phosphorylation in neuronal cells. Prophylactic Sim administration set in motion biochemical events that are known to increase brain tolerance to harmful factors, suggesting that the drug may exert neuroprotection by inducing pharmacological preconditioning.
Carloni
Silvia
S
Institute of Pharmacology and Pharmacognosy, University of Urbino "Carlo Bo", Urbino, Italy.
Girelli
Silvia
S
Buonocore
Giuseppe
G
Longini
Mariangela
M
Balduini
Walter
W
D000367:Age Factors; D000375:Aging / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016893:Carotid Stenosis / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D017362:Cyclic AMP Response Element-Binding Protein / Q000187:drug effects* / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D020925:Hypoxia-Ischemia, Brain / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D018696:Neuroprotective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D051057:Proto-Oncogene Proteins c-akt / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D017362:Cyclic AMP Response Element-Binding Protein; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D019821:Simvastatin; D051057:Proto-Oncogene Proteins c-akt