Abstract
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. Fifty-six male Wistar rats were subjected to ICH by 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 after ICH. Animals were sacrificed at 28 days after treatment, and histological studies were completed. 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 post ICH. 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 saline-treated rats. 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.
Highlights
Intracerebral hemorrhage (ICH) is a devastating form of stroke subtype with high rates of mortality and morbidity [1,2]
Effects of Statins on Neurological Functional Recovery. As evaluated by both modified neurological severity score (mNSS) and corner turn tests, all intracerebral hemorrhage (ICH)-induced rats had similar neurological impairments prior to and at one week after ICH (Figure 1). Rats treated with both statins at doses of 10 and 20 mg/kg showed significant improvements in mNSS and corner turn test starting at 2 weeks, and persisting up to 4 weeks post ICH
Both the simvastatin- and atorvastatin-treated groups at doses of 10 mg/kg and 20 mg/kg showed significantly reduced tissue loss compared to control at 4 weeks after ICH
Summary
Intracerebral hemorrhage (ICH) is a devastating form of stroke subtype with high rates of mortality and morbidity [1,2]. Statins, which are HMG-CoA reductase inhibitors, are widely prescribed as cholesterol-lowering medications and have been shown to exert beneficial pleiotropic effects on neurological diseases [4,9,10,11]. These effects include reduction of neuroinflammation and oxidative stress, improvement of vascular endothelial function, and enhancement of synaptogenesis [11,12,13,14]. 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 ad-
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