Prophylactic but Not Delayed Administration of Simvastatin Protects Against Long-Lasting Cognitive and Morphological Consequences of Neonatal Hypoxic-Ischemic Brain Injury, Reduces Interleukin-1β and Tumor Necrosis Factor-α mRNA Induction, and Does Not Affect Endothelial Nitric Oxide Synthase Expression

Abstract

Background and Purpose-Prophylactic administration of simvastatin has been shown to protect against brain damage and its long-lasting behavioral consequences in neonatal rats. To establish the drug treatment window, we evaluated the effectiveness of simvastatin administered at different intervals before and after stroke. Furthermore, we determined whether simvastatin affected endothelial nitric oxide synthase (eNOS) or inflammatory cytokines in brain tissue or cholesterol levels in serum. Methods-On postnatal day 7, male rats were subjected to hypoxia-ischemia (HI). The experiment included sham-operated controls and HI animals receiving daily saline or activated simvastatin (20 mg/kg) injections from postnatal day 1 to day 7 (HI-simvastatin 1-7 group), from postnatal day 4 to day 11 (HI-simvastatin 4 -11 group), or from postnatal day 7 to day 14 (HI-simvastatin 7-14 group). The neuroprotective effect of simvastatin was evaluated at adulthood by means of behavioral and histological analyses. Cytokines and eNOS expression were assessed by reverse transcriptasepolymerase chain reaction and Western blotting. Results-Animals in both the HI-simvastatin 1-7 and HI-simvastatin 4 -11 groups performed better than HI rats in either the T-maze or the circular water maze and showed significantly attenuated brain damage. Expression of interleukin-1␤ and tumor necrosis factor-␣ mRNA in cortex was significantly increased in HI but not in HI-simvastatin 1-7 animals. In the same brain area, simvastatin treatment did not affect the increase of eNOS expression observed after HI. Conclusions-These findings indicate that prophylactic but not delayed administration of simvastatin improves functional outcome in neonatal rat stroke. The reduced induction of cytokines suggests that the neuroprotective effect of simvastatin may be related to a dampening of the inflammatory response. (Stroke.

Multitargeted Effects of Statin-Enhanced Thrombolytic Therapy for Stroke With Recombinant Human Tissue-Type Plasminogen Activator in the Rat

“…However, studies in postnatal rats subjected to hypoxia-ischemia showed that prophylactic administration of simvastatin reduced brain injury and improved functional recovery and that this prophylactic effect was associated with a reduction in cytokine expression but did not affect eNOS expression. 20 In parallel, our data demonstrate that administration of atorvastatin after stroke extended the therapeutic window of rht-PA by enhancement of cerebral microvascular patency and integrity, primarily by decreasing thrombosis. Combination treatment did not increase eNOS levels, and blocking NOS activity with the NOS inhibitor L-NAME did not abolish the beneficial effects of combination treatment on stroke.…”

Anti-Inflammatory Effects of AT1 Receptor Blockade Provide End-Organ Protection in Stroke-Prone Rats Independently from Blood Pressure Fall

“…Total RNA was prepared by guanidium thiocyanate denaturation from frozen kidney collected from vehicle-and valsartan (10 mg/kg/day)-treated rats sacrificed after 6 weeks of dietary treatment. The expression of MCP-1, TGF-␤1, and IL-1␤ was measured by semi-quantitative RT-PCR (Balduini et al, 2003). GAPDH was amplified as a standard.…”

Activation of autophagy and Akt/CREB signaling play an equivalent role in the neuroprotective effect of rapamycin in neonatal hypoxia-ischemia

“…Positive cells were counted using the NIH-Image software in three separate fields of the cerebral cortex in slices cut at the level A 3750 of the Koning and Klippel stereotaxic atlas. 30 Five animals for each group were analyzed. Assessment of brain damage.…”