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- Title
Hyperlipidemia in Stroke Pathobiology and Therapy: Insights and Perspectives.
- Authors
Menet, Romain; Bernard, Maxime; ElAli, Ayman
- Abstract
Stroke constitutes a major cause of death and disability of the adults in the industrialized world. Ischemic stroke accounts for the majority of cases (Dirnagl, 2012). Interruption of the blood supply triggers the ischemic cascade leading to cell death and inflammation (Dirnagl et al., 1999; Lo, 2008). Our understanding for the molecular mechanisms underlying neuronal death has tremendously advanced in the last decade, leading to the development of several neuroprotective agents (Moskowitz et al., 2010). Although neuroprotection was successful in experimental studies, it failed to achieve clinical benefits in acute stroke patients (Gladstone et al., 2002; Lo, 2008). Currently, tissue plasminogen activator (tPA)-induced thrombolysis is the only Food and Drug Administration (FDA)-approved treatment used in clinics to restore the cerebral blood flow (CBF) (Wardlaw et al., 2014). Nonetheless, less than 5% of stroke patients can benefit from thrombolysis, as tPA should be administered within a narrow therapeutic time window of 4.5 h after onset (Wang et al., 2004). Endovascular mechanical embolectomy has emerged as a therapeutic option when thrombolysis is unsuccessful or cannot be applied (Smith et al., 2005). Beyond neuroprotection in the acute phase, there is a growing interest in neurorestoration that aims to promote brain remodeling in the post-acute phase (Gladstone and Black, 2000; Gladstone et al., 2002). The interest has emerged from the overwhelming experimental and clinical findings suggesting that the brain is actively trying to recover after stroke by repairing itself (Chopp et al., 2009). The neurorestorative processes include coordinated neurogenic and angiogenic responses, which aim to improve functional recovery (Ohab et al., 2006; Zhang et al., 2008; Chopp et al., 2009; Chen et al., 2014). Until now, no clinically validated neurorestorative approach exists, and cognitive/motor rehabilitation remains the only approach used in clinics in the post-stroke phase. Evidence fromclinical trials suggests that saving neurons alone after strokemay not be sufficient to develop clinically viable therapies (Gladstone et al., 2002; Lo, 2008). Neuronal survival narrowly depends upon integrity of themicrovasculature, which regulates oxygen and nutrients delivery. The functional interaction between the neuronal and vascular systems is governed by the neurovascular unit, which comprises sealed endothelial cells forming the blood-brain barrier (BBB), pericytes, astrocytes, microglia, and neurons (Hermann and ElAli, 2012). As such, it is well established that any clinically viable therapies must succeed to restore the neurovascular unit by stabilizing the microvasculature, while limiting neuronal loss and stimulating neuronal plasticity. Moreover, preclinical investigations use essentially healthy animals, which do not adequately translate the clinical setup in which stroke patients usually present several vascular risk factors, namely atherosclerosis associated to hyperlipidemia (Gladstone et al., 2002; ElAli et al., 2011). This aspect must be adequately and systemically addressed in the pre-clinical context.
- Subjects
STROKE treatment; CEREBRAL ischemia; STROKE risk factors; BLOOD circulation disorders; TISSUE plasminogen activator
- Publication
Frontiers in Physiology, 2018, p1
- ISSN
1664-042X
- Publication type
Article
- DOI
10.3389/fphys.2018.00488