Acute statin treatment improves recovery after experimental intracerebral hemorrhage

Abstract

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 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. 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 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. 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.

Statins in Intracerebral Hemorrhage

“…A variety of preclinical studies have shown improved functional outcome, reduced peri-hematomal edema, preserved blood brain barrier, promoted synaptogenesis, and decreased inflammatory reaction and perihematomal cell death in experimental ICH in rodents [47][48][49][50][51][52]. One should keep in mind that in most of these studies, very high dosages of statins are used-that is, dosages that go beyond current recommendations, if translated into the human setting.…”

Intracerebral Hemorrhage: Perihemorrhagic Edema and Secondary Hematoma Expansion: From Bench Work to Ongoing Controversies

“…In animal studies, statins showed less neuronal tissue loss and inflammation; increased cell proliferation, angiogenesis, and synaptogenesis in the perihemorrhagic zone with better functional outcomes (85–87). Statins’ neuroprotective actions may be explained by their ability to induce expression of vascular endothelial growth factor (VEGF), brain-derived neurotrophic factor (BDNF), and nerve growth factor (NGF) (88) to reduce activated microglia, MMP-9 (89), and cytokine-mediated inflammation (less TNF-α and higher interleukin-10 levels) (90, 91).…”

Statin use after intracerebral hemorrhage: a 10‐year nationwide cohort study

“…Another animal study revealed that high‐dose statin use exerted adverse effects on function and tissue recovery and that statin‐induced adverse effects may be dose‐related (Yang et al. 2013a,b). The mechanisms underlying the absence of a therapeutic effect of high‐dose statin use in this ICH model remain unknown.…”

“…2012; Yang et al. 2013a,b). However, statins may also have antithrombotic properties because they can inhibit platelet aggregation and enhance fibrinolysis, which might amplify the risk of ICH (Goldstein 2013).…”