Statins Protect the Blood Brain Barrier Acutely after Experimental Intracerebral Hemorrhage

Objectives: The goal of this study was to measure the impact of simvastatin and atorvastatin treatment on blood brain barrier (BBB) integrity after experimental intracerebral hemorrhage (ICH). Methods: Primary ICH was induced in 27 male Wistar rats by stereotactic injection of100mL of autologous blood into the striatum. Rats were divided into three groups (n = 9/group): 1) oral treatment (2 mg/kg) of atorvastatin, 2) oral treatment (2 mg/kg) simvastatin, or 3) phosphate buffered saline daily starting 24-hours post-ICH and continuing daily for the next 3 days. On the fourth day, the animals underwent magnetic resonance imaging (MRI) for measurements of T1sat (a marker for BBB integrity), T2 (edema), and cerebral blood flow (CBF). After MRI, the animals were sacrificed and immunohistology or Western blotting was performed. Results: MRI data for animals receiving simvastatin treatment showed significantly reduced BBB dysfunction and improved CBF in the ICH rim compared to controls (P 0.05) 4 days after ICH. Simvastatin also significantly reduced edema (T2) in the rim at 4 days after ICH (P 0.05). Both statin-treated groups demonstrated increased occludin and endothelial barrier antigen levels within the vessel walls, indicating better preservation of BBB function (P 0.05) and increased number of blood vessels (P 0.05). Conclusions: Simvastatin treatment administered acutely after ICH protects BBB integrity as measured by MRI and correlative immunohistochemistry. There was also evidence of improved CBF and reduced edema by MRI. Conversely, atorvastatin showed a non-significant trend by MRI measurement.

Acute statin treatment improves recovery after experimental intracerebral hemorrhage

Background and Purpose: We have previously demonstrated that 2-week treatment of experimental intracerebral hemorrhage (ICH) with a daily dose of 2 mg/kg statin starting 24 hours post-injury exerts a neuroprotective effect. The present study extends our previous investigation and tests the effect of acute high-dose (within 24 hours) statin therapy on experimental ICH. Material and Methods: Fifty-six male wistar rats were subjected to ICHby stereotactic injection of 100 μl of autologous blood into the striatum. Rats were divided randomly into seven groups: saline control group (n = 8);10, 20 and 40 mg/kg simvastatin-treated groups (n = 8);and 10, 20 and 40 mg/kg atorvastatin-treated groups (n = 8). Simvastatin or atorvastatin were administered orally at 3 and 24 hours after ICH. Neurological functional outcome was evaluated using behavioral tests (mNSS and corner turn test) at multiple time points afterICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. Results: Acute treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg, but not at 40 mg/kg, significantly enhanced recovery of neurological function starting from 2 weeks post-ICH and persisting for up to 4 weeks postICH. In addition, at doses of 10 mg/kg and 20 mg/kg, histological evaluations revealed that simvastatin or atorvastatin reduced tissue loss, increased cell proliferation in the subventricular zone and enhanced vascular density and synaptogenesis in the hematoma boundary zone when compared to salinetreated rats. Conclusions: Treatment with simvastatin or atorvastatin at doses of 10 and 20 mg/kg significantly improves neurological recovery after administration during the first 24 hours after ICH. Decreased tissue loss, increased cell proliferation and vascularity likely contribute to improved functional recovery in rats treated with statins after ICH.

Thymosin <i>β</i>4 Improves Neurological Outcome and Enhances Induced Oligodendrogenesis in the Rat after ICH

Thymosin β4 (Tβ4), a G-actin binding protein, has diverse biological functions. This study tested the effects of Tβ4 on oligodendrogenesis in a rat model of intracerebral hemorrhage (ICH). ICH was induced by stereotactic injection of 100 μm of autologous blood into the striatum in 32 male Wistar rats. The rats were randomly divided into four groups: 1) saline control group (n = 8);2) 3 mg/kg Tβ4-treated group (n = 8);3) 6 mg/kg Tβ4-treated group (n = 8);and 4) 12 mg/kg Tβ4treated group (n = 8). Tβ4 or saline was administered intraperitoneally starting at 24 h post ICH and then every 3 days for 4 additional doses. The neurological functional outcome was evaluated by behavioral tests (i.e., modified Neurological Severity Score and corner turn test) at multiple time points after ICH. Animals were sacrificed at 28 days post ICH, and histological studies were completed. Tβ4 treatment improved neurological functional recovery significantly and increased actively proliferating oligodendrocytic progenitor cells and myelinating oligodendrocytes in the ICH-affected brain tissue, compared with the saline-treated group. The high-dose treatment of Tβ4 showed better restorative effects compared with the low-dose treatment. Tβ4 treatment enhanced ICH-induced oligodendrogenesis that may contribute to the enhanced functional recovery after ICH. Further investigation is warranted to determine the associated underlying mechanisms of Tβ4 treatment for ICH.

Statins enhance expression of growth factors and activate the PI3K/Akt-mediated signaling pathway after experimental intracerebral hemorrhage

Previous studies have demonstrated that statins improve neurological outcome and promote neuro-vascular recovery after ICH. This study is designed to examine whether simvastatin and atorvastatin affect levels of growth factors and activate the Akt signaling pathway during the recovery phase after intracerebral hemorrhage (ICH) in rats. Sixty (60) male Wistar rats were subjected to ICH by stereotactic injecttion of 100 μL of autologous blood into the striatum and were treated with or without simvastatin or atorvastatin. Neurological functional outcome was evaluated by behavioral tests (mNSS and corner turn test) at different time points after ICH. Brain extracts were utilized for Enzyme-linked immunosorbent assay (ELISA) analyses to measure vascular endothelial growth factor (VEGF);brain-derived neurotrophin factor (BDNF) expression, and nerve growth factor (NGF). Western blot was used to measure the changes in the Akt-mediated signaling pathway. Both the simvastatin and atorvastatin-treated animals had significant neurological improvement at 2 weeks post-ICH. Simvastatin and atorvastatin treatment increased the expression of BDNF, VEGF and NGF in both low- and high-dose groups at 7 days after ICH (p < 0.05). Phosphorylation of Akt, glycogen synthase kinase-3β (GSK-3β), and cAMP response element-binding proteins (CREB) were also increased at 7 days after statin treatment. These results suggest that the therapeutic effects of statins after experimental ICH may be mediated by the transient induction of BDNF, VEGF and NGF expression and the activation of the Akt-mediated signaling pathway.