Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice

How fucking long before this is tested in humans?  Don't try this on your own, you have no clue how to translate mice body size and amount of resveratrol to human size and then convert that to bottles of red wine. Our fucking failures of stroke associations will do nothing with this, just like they always do nothing with promising research.

Resveratrol Attenuates Neurodegeneration and Improves Neurological Outcomes after Intracerebral Hemorrhage in Mice

Front. Cell. Neurosci., 08 August 2017 | https://doi.org/10.3389/fncel.2017.00228

Frederick Bonsack, Cargill H. Alleyne Jr. and Sangeetha Sukumari-Ramesh^*

• Department of Neurosurgery, Medical College of Georgia, Augusta University, Augusta, GA, United States

Intracerebral hemorrhage (ICH) is a devastating type of stroke with a substantial public health impact. Currently, there is no effective treatment for ICH. The purpose of the study was to evaluate whether the post-injury administration of Resveratrol confers neuroprotection in a pre-clinical model of ICH. To this end, ICH was induced in adult male CD1 mice by collagenase injection method. Resveratrol (10 mg/kg) or vehicle was administered at 30 min post-induction of ICH and the neurobehavioral outcome, neurodegeneration, cerebral edema, hematoma resolution and neuroinflammation were assessed. The Resveratrol treatment significantly attenuated acute neurological deficits, neurodegeneration and cerebral edema after ICH in comparison to vehicle treated controls. Further, Resveratrol treated mice exhibited improved hematoma resolution with a concomitant reduction in the expression of proinflammatory cytokine, IL-1β after ICH. Altogether, the data suggest the efficacy of post-injury administration of Resveratrol in improving acute neurological function after ICH.

Introduction

Intracerebral hemorrhage (ICH) is a catastrophic type of stroke caused by bleeding within the brain parenchyma (Leclerc et al., 2015). Approximately, 10–15% of strokes are caused by ICH. Despite recent advances in clinical and preclinical research, the one-month mortality rate of ICH is 40% and only about 20% of the survivors with spontaneous ICH regain functional independence at 6 months (Flemming et al., 2001; Qureshi et al., 2001; Gebel et al., 2002; Flaherty et al., 2006; Ke et al., 2015). Primary as well as secondary brain damage is involved in the pathological processes of ICH. The primary damage usually occurs within minutes to hours and is mainly caused by mechanical disruption resulting from the mass effect of hematoma, whereas the cytotoxicity of blood, excitotoxicity, oxidative stress, and inflammation together result in secondary brain damage, causing severe disability or death (Xi et al., 2006; Aronowski and Zhao, 2011). Notably, there is no effective therapeutic or surgical treatment for ICH and the current treatment options even in dedicated stroke centers are limited to supportive care. Therefore, finding new treatment regimens that could provide safety and neuroprotection to patients suffering from ICH is critical.

Resveratrol (3,5,4′-trihydroxystilbene) is a naturally occurring polyphenolic compound and the content of Resveratrol in major dietary sources such as grapes and red wine ranges from 0.16 to 3.54 μg/g and 0.1 to 14.3 mg/L, respectively (Mark et al., 2005; Baur and Sinclair, 2006; Mukherjee et al., 2010). Resveratrol is associated with anti-inflammatory, anti-oxidant, anti-apoptotic properties (Narayanan et al., 2015; Taguchi et al., 2015; Tellone et al., 2015; Tsai et al., 2015; Gwak et al., 2016; Hoda et al., 2016) and is able to cross the blood–brain barrier (BBB) making it an ideal candidate to be tested for its role in neuropathological conditions. In addition, Resveratrol has been tested for the treatment of various neuroinflammatory and neurodegenerative diseases such as stroke, spinal cord injury, epilepsy, Huntington's disease and Alzheimer's disease (Gupta et al., 2001, 2002; Wang et al., 2002; Yang and Piao, 2003; Kiziltepe et al., 2004; Kaplan et al., 2005; Parker et al., 2005; Ates et al., 2006; West et al., 2007; Wu et al., 2009; Li et al., 2014; Shao et al., 2014; Lopez et al., 2015), and it was well tolerated in preclinical animal models. However, the neuroprotective efficacy of Resveratrol after ICH remains largely unstudied. Further, to date, very few studies have reported whether post-injury administration of resveratrol can protect against brain injury. Therefore, the main objective of the present study is to evaluate whether the post-treatment with Resveratrol confers neuroprotection in a pre-clinical model of ICH.

Neurological Outcome

Neurobehavioral outcome (n = 9–13/group) was estimated by an independent researcher blinded to the experimental groups using a composite neurological test, as detailed previously by our laboratory and others (Rosenberg et al., 1990; Clark et al., 1998; King et al., 2011; Sukumari-Ramesh and Alleyne, 2016; Sukumari-Ramesh et al., 2016). This 24-point scale composite test that determines the sensorimotor deficits associated with intrastriatal ICH, is comprised of six neurobehavioral sub-tests (climbing, circling, compulsory circling, whisker response, bilateral grasp, and beam walking; Rosenberg et al., 1990; Clark et al., 1998; King et al., 2011; Sukumari-Ramesh and Alleyne, 2016; Sukumari-Ramesh et al., 2016). Briefly, the climbing ability of the mouse was assessed using a gripping surface kept at 45° angle and the circling behavior was tested on an open bench top. To assess compulsory circling, mouse was placed on its front limbs on a bench and held suspended by its tail and the whisker response was evaluated with a gentle touch to its whisker using a swab. The bilateral grasp assessed the strength to hold onto a steel grip-bar with forepaws and the beam walking was graded by evaluating the ability of a mouse to traverse a narrow beam. Each sub-test was scored from 0 (performs with no impairment) to 4 (severe impairment) and the individual subtest scores are provided as Supplementary Data-Table 1. A composite score was calculated as the sum of the scores on all the six sub-tests, establishing a maximum neurological deficit score of 24.

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