Rosuvastatin Reduces Neuroinflammation in the Hemorrhagic Transformation After rt-PA Treatment in a Mouse Model of Experimental Stroke

Is this just a followup to these much earlier research articles which I bet your stroke hospital never did anything with? If my doctor had been following stroke research at all he could have asked me if I wanted to try statin therapy even though it had only been tested in rats. My stroke was May 2006 so my doctor had been incompetent for three years already.
Statins:
tested in rats from 2003
http://oc1dean.blogspot.com/2011/09/statins-induce-angiogenesis.html 
tested in humans, March, 2011
http://www.medwirenews.com/39/91658/Stroke/Acute_statin_therapy_improves_survival_after_ischemic_stroke.html 

Rosuvastatin Reduces Neuroinflammation in the Hemorrhagic Transformation After rt-PA Treatment in a Mouse Model of Experimental Stroke

Dan Lu^1,2†, Yanfang Liu^1,2†, Hongcheng Mai^1,2, Jiankun Zang^1,2, Lingling Shen^1,2, Yusheng Zhang^1* and Anding Xu^1,2*

• ¹Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
• ²Clinical Neuroscience Institute of Jinan University, Guangzhou, China

Hemorrhagic transformation (HT) is a serious complication that stimulates inflammation during reperfusion therapy after acute ischemic stroke. Rosuvastatin, a 3-hydroxymethyl-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, might improve the outcome of HT by inhibiting neuroinflammation. This study aimed to explore the protective effects of rosuvastatin against HT after recombinant tissue plasminogen activator (rt-PA) treatment in mice with experimental stroke via the attenuation of inflammation. A total of one hundred sixty-nine male BALB/c mice were used in the experiment. HT was successfully established in 70 mice that were subjected to 3 h of middle cerebral artery occlusion (MCAO) followed by a 10 mg/kg rt-PA injection over 10 min and reperfusion for 24 h. The mice were then administered rosuvastatin (1 mg/kg, 5 mg/kg) or saline (vehicle). The brain water content and neurological deficits (wire hang and adhesive removal somatosensory tests) were assessed at 24 h after rt-PA reperfusion following MCAO surgery. The morphology, blood-brain barrier (BBB) permeability and number of astrocytes and microglia were assessed by immunohistochemistry, electron microscopy and western blotting at 24 h after rt-PA reperfusion following MCAO surgery. Rosuvastatin protected against impaired neurological function and reversed the BBB leakage observed in the HT group. The increased activation of astrocytes and microglia and secretion of inflammatory factors caused by HT damage were significantly attenuated by high-dose rosuvastatin treatment vs. normal-dose rosuvastatin treatment. Related inflammatory pathways, such as the nuclear factor kappa B (NF-κB) and mitogen-activated protein kinase (MAPK) pathways, were downregulated in the rosuvastatin-treated groups compared with the HT group. In conclusion, our results indicate that rosuvastatin is a promising therapeutic agent for HT after rt-PA reperfusion following MCAO surgery in mice, as it attenuates neuroinflammation. Additionally, high-dose rosuvastatin treatment could have a greater anti-inflammatory effect on HT than normal-dose rosuvastatin treatment.

Introduction

Hemorrhagic transformation (HT) is a serious complication that occurs after acute ischemic stroke (Álvarez-Sabin et al., 2013; Wang et al., 2015). In clinical practice, after the administration of intravenous recombinant tissue plasminogen activator (IV-rt-PA) within the therapeutic window, the rate of type two parenchymal hemorrhage within 7 days is 6.8%, with a 90-day mortality rate as high as 17.9% (Emberson et al., 2014). Studies have shown that disturbances in the blood-brain barrier (BBB), which is composed mainly of endothelial cells, pericytes and astrocytes, occur throughout the process of HT (Kelly et al., 2006; Mishiro et al., 2012; Ozkul-Wermester et al., 2014). Emerging data have shown that the oxidative stress and overexpression and release of proinflammatory cytokines caused by rt-PA reperfusion are associated with BBB disruption (Wang et al., 2015). Furthermore, increasing studies in the literature have shown that inflammation related to the interaction between microglia and astrocytes but not astrocytes alone contributes to ischemia-induced HT and oedema (del Zoppo et al., 2012).

Statins, also known as 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, are well known for having beneficial effects on vascular events by lowering cholesterol levels (Postmus et al., 2014) and are used as neuroprotectants in experimental brain ischemia (Spence, 2014). In vivo studies have shown that statins induce time- and concentration-dependent reductions in Aβ production, and the reduced production of Aβ has been attributed to reductions in neuroinflammation (Hosaka et al., 2013). One study has suggested that reduced chronic neuroinflammation might be a key mechanism underlying statin-induced neuroprotection (McFarland et al., 2014). Furthermore, statins play a protective role against neurodegenerative conditions, including vascular dementia, Alzheimer’s disease (AD) and Parkinson’s disease (PD; Mandas et al., 2014). However, whether statins protect against HT and the related mechanisms in mice have not been determined.

Rats who were treated with rosuvastatin (a synthetically derived statin) immediately post-spinal cord injury demonstrated reduced inflammatory cell infiltration, tumor necrosis factor alpha (TNF-α) expression, myeloperoxidase activity, nitric oxide levels and caspase-3 activity in caudal spinal cord tissue (Kahveci et al., 2014). Pretreatment with rosuvastatin significantly reduced lipopolysaccharide (LPS)-induced interleukin 1 beta (IL-1β) and TNF-α release (Kahveci et al., 2014). Because the protective effect of rosuvastatin relies on the modulation of several signaling transduction pathways, including the nuclear factor kappa B (NF-κB), phosphatidylinositol 3-kinase and protein kinase B (PI3K/Akt) and c-Jun N-terminal kinase (JNK) pathways (Li et al., 2015; Liu et al., 2017), determining the potential role played by rosuvastatin in neuroinflammation-related diseases is critical.

In this study, experiments were performed to demonstrate our hypothesis that rosuvastatin protects against HT in middle cerebral artery occlusion (MCAO) mice by attenuating inflammation.