Less progress has been made in the area of neuroprotection, and while there are many factors that may explain the gap between observations in preclinical studies and clinical trials, one important feature is that many laboratory models have not historically taken into account the many comorbidities suffered by patients who are at risk for or suffer stroke. Laboratory studies often use healthy young male animals, but stroke typically occurs in patients of both genders with risk factors such as advanced age, atherosclerosis, diabetes, hypertension and other conditions. Thus, translating a potential therapy observed in the laboratory could be limited when moved to clinical trials. With this in mind, investigations have now turned to models of disease comorbidities in order to simulate a more realistic clinical scenario. By studying models of diabetes, hypertension and other conditions, it is now possible to extend testing of certain therapeutics that appear promising in healthy animals to those with relevant disease. Further, it is well known that gender can influence outcome from stroke as well as response to treatment, and these disparities should be studied and determined. Here, we review the clinical perspective of stroke and how this might drive experimental studies. At the clinical level, the most effective treatment for stroke is prevention. Prevention is thought to entail reduction of stroke risk factors, but also prevention of future strokes once an initial stroke occurs . After an acute stroke happens, there are few clinically proven acute treatments. Pharmacological thrombolysis and mechanical thrombectomy are currently the only widely accepted interventions. Pharmacological thrombolysis, typically with recombinant tissue plasminogen activator is restricted to patients that can be treated within 4.5 hours of symptom onset, while those who meet criteria for mechanical thrombectomy may receive this intervention out to 24 hours.Unfortunately, these treatments are still limited to a relatively short time frame with only about 6% of acute stroke patients eligible for intravenous t-PA and about 10% eligible for mechanical thrombectomy.Aside from offering acute intervention, it is important to identify the underlying cause of the stroke,grow rack vertical also referred to as the stroke mechanism. Typical causes include atherosclerotic disease of the cerebral vessels or underlying cardiac disease which can predispose to thrombi that can then embolize.

A third type of cerebrovascular disease involving the small end vessels of the brain is another common cause of ischemic stroke, and this is often observed in the setting of poorly controlled hypertension and diabetes. Finally, cryptogenic strokes, which include embolic strokes of undetermined sources , constitute a substantial proportion of all strokes.Thus, an important part of the clinical management of stroke patients revolves around determining the cause of the stroke and modifying risk factors to prevent future occurrences. Age is a major risk factor for IS. IS risk increases after the age of 45 years, and over 70% of strokes occur after the age of 65. Elderly patients also have several comorbid risk factors for IS which not only increase stroke risk, but also increases risk for bad outcome.These include hypertension , diabetes mellitus , dyslipidemia, tobacco use, and obesity/ metabolic syndrome, and recreational drug use.There are also numerous genetic factors that increase stroke risk, some of which can be identified, and many others that are unknown. This review will focus on those which are generally thought to be modifiable either through lifestyle changes and/or pharmacological treatment.While hypertension is a major stroke risk factor at the clinical level, few preclinical studies of acute neuroprotection studied potential stroke treatments in hypertensive animals. However, some animal studies have been carried out in hypertensive animals. In a metaanalysis by O’Collins et al , an exhaustive review of over 3,000 animal studies and over 500 potential treatments. Amongst the studies reviewed, the authors found that only 10% of studies addressed the role of hypertension. Overall, the authors failed to find any direct neuroprotective effect of the hypertensive agents studied, but also that hypertensive animals sometimes responded differently to potential therapies, compared to normotensive animals. While many of potential neuroprotective treatments were ineffective in hypertensive animals, the authors also found divergent responses, where certain potential therapies were only effective in normotensive models , while other strategies were actually more effective in hypertensive models . Thus, hypertension should be considered in preclinical translational studies of stroke. A few clinical trials have also attempted to clarify a neuroprotective effect of antihypertensive agents in acute stroke, but have yet to demonstrate any efficacy. Early trials of calcium channel blockers such as nimodipine failed to show any neurological improvement,although these studies were criticized for initiating treatment rather late .

More recently, the Superselective Administration of VErapamil During Recanalization in Acute Ischemic Stroke study assess the therapeutic potential of verapamil.In this early phase I clinical trial, combined therapy of verapamil given immediately following thrombectomy in AIS patients was shown to be both safe and feasible, without significantly increasing intracranial hemorrhage or other adverse events, but failed to show any benefit with respect to improved neurological outcome. Hyperglycemia is well known to exacerbate stroke outcome,and diabetes is a common comorbidity in stroke patients. Hyperglycemia has also been shown to increase inflammatory responses through the fueling of the NADPH oxidase proinflammatory pathway and exacerbating oxidative stress through generation of superoxide. It has also been shown to exacerbate inflammatory responses in experimental diabetic stroke models and in stroke amongst patients with diabetes. Compared to the normoglycemic state, the expression of several inflammatory molecules including proinflammatory cytokines, cell adhesion molecules , chemokines, inducible nitric oxide synthase , cyclooxygenase-2 , NOX, and NF-κB were increased by hyperglycemia. This also led to increased leukocyte infiltration of the ischemic brain and activation of microglia. High serum levels of high mobility group box-1 was also observed in diabetic rats and correlated to worse stroke outcomes.In a clinical study, elevated serum HMGB1 levels has been associated with poor outcome in IS patients with DM.Since glucose is required in order for NOX to generate superoxide, hyperglycemia itself can lead to increased oxidative stress.Hyperglycemia is also known to increase brain hemorrhage in IS following treatment with tissue plasminogen activator .However, at the clinical level, intensive glucose control in the acute setting has not been shown to improve outcome from IS.Yet, treatments for long term glucose control in diabetes have shown some benefit in lowering stroke risk and improving stroke outcome. The UK Prospective Diabetes Study showed that metformin reduced the incidence of large vessel events, compared to other treatments.The PROactive study showed that pioglitazone, a peroxisome proliferator-activated receptor γ agonist, reduced recurrent stroke risk significantly in patients with type 2 diabetes.PPARγ agonists not only decrease serum glucose levels, but also inhibit inflammation. PPARγ activation in monocyte-derived macrophages is thought to influence macrophage polarization through an alternative or anti-inflammatory mechanism.PPARγ agonists has also been shown to reduce ischemia-induced inflammation and hemorrhagic transformation in experimental models.Further, pioglitazone has also been shown to possess antioxidant and anti-apoptotic effects in experimental stroke models of diabetes.Recent novel agents to treat diabetes such as dipeptidyl peptidase-4 inhibitor, glucagon like peptide-1 receptor agonist,and sodium glucose cotransporter 2 inhibitor may also have a role in secondary prevention in large vessel diseases.In particular, the DPP-4 inhibitor is thought to have pleiotropic effects against ischemic injury.

In a recent study, sitagliptin administration has shown to suppress the pro-inflammatory NF-κB signaling pathway,as well as anti-inflammatory, antioxidant, and anti-apoptotic effects in stroke models with diabetes.To date,grow racking the neuroprotective effects of these diabetes treatments have not been assessed in clinical trials, although the GLP-1 receptor analogues are thought to reduce IS risk. The SGLT2 and DPP-4 inhibitors have not been shown to be efficacious in recent clinical studies.Hyperlipidemia is another major comorbidity contributing to stroke risk. Elevated serum lipid levels can lead to atherosclerosis and narrowing or occlusion of the cerebral arteries. Lipid-lowering-therapy can significantly lower IS risk.3-Hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors are frequently used for treatment of dyslipidemia and are nearly routinely prescribed for secondary stroke prevention. The Stroke Prevention by Aggressive Reduction in Cholesterol Levels study showed that atorvastatin treatment led to 16% relative risk reduction from IS. Although the benefit of IS risk reduction with statins was not achieved with LDL-C levels < 120mg/dl in a previous study, aggressive targeted LLT to reduce LDL-C levels to less than 70mg/dl led to 22% relative cardiovascular disease risk reduction.Thus, statins have been the preferred lipid lowering agent for primary and secondary IS prevention.Statins are also thought to have pleiotropic effects, in addition to their lipid lowering effects. Statins have been thought to have anti-thrombotic, anti-inflammatory, anti-oxidant, and neuroprotective effects.Specifically, statins have been shown to up-regulate endothelial NOS through the inhibition of isoproterinoids.A variety of statins have been shown to reduce infarct volume and improve neurological deficit in experimental stroke. Rosuvastatin was also shown to reduce ischemic injury by inhibiting oxidative stress and inflammatory responses by reducing superoxide and NOX, inhibiting microglial activation, and downregulating inflammatory molecules .Recently, ezetimibe and a PCSK9 inhibitor have been also shown to have efficacy in combination with statins in cardiovascular disease;however, its benefit in IS prevention and neuroprotection is still unclear. In addition to LLT, ω3-polyunsaturated fatty acid supplementation as an addition to statin therapy may also prove beneficial in stroke prevention. In particular, eicosapentaenoic acid has shown some benefit at the clinical level. The Japan EPA Lipid Intervention Study demonstrated the efficacy of EPA when added to statins pravastatin or simvastatin. In this study, investigators reported a 20% relative reduction in recurrent IS with EPA treatment among patients with a prior history of IS.Its beneficial effect is thought to be through esolvin and protectin, both ω3-PUFA metabolites, which have anti-inflammatory and anti-oxidant properties. Tobacco use is another significant risk factor which contributes to vascular disease, including stroke. A dose-response relationship between tobacco use in young IS patients has been described, although, interestingly, the relationship is less strong in older adults. Tobacco use leads to vascular endothelial damage and dysfunction through generation of ROS and activation of inflammation, both of which can increase atherosclerotic risk. Not only does tobacco use increase ROS generation, but it can also weaken antioxidant defense systems. Tobacco use promotes pro-inflammatory responses including leukocyte infiltration and activation of matrix metallo proteinases via cytokine signaling. Further, tobacco use can induce BBB dysfunction and worsen loss of cerebral blood flow during IS. In clinical studies, tobacco us was found to increase not only the incidence IS, but also HTf in the setting of anticoagulant use.Recently, current tobacco use has also been reported to increase the incidence of HTf in young patients with IS who have non-valular atrial fibrillation.Recreational drug use, while a significant public health problem for many reasons, is also associated with IS, particularly cocaine, methamphetamine, and cannabis.The toxicity of these drugs can induce not only IS but also hemorrhagic stroke. Hemorrhagic stroke via cocaine and/or methamphetamine use may lead to hypertension, vascular fatigue as a consequence of hypertension and tachycardia, and necrotising angiitis.In addition to chronic vascular damage and acceleration of atherosclerosis, use of these substances can lead to IS from acute cerebral vasospasm and vasculitis.Cannabis-associated stroke has been also reported, where most cases occurred after cannabis exposure or subsequent reexposure.While half of these cases had concomitant risk factors such as tobacco and alcohol,major causes of cannabis-related IS were thought to be due to acute cerebral angiopathy and vasospasm. Stroke prevention can be broadly categorized into primary and secondary prevention. Primary prevention refers to a series of lifestyle modifications and treatments in patients who have stroke risk factors but have not suffered stroke. Secondary prevention refers to similar changes and treatments but applied to patients who have already suffered stroke or transient ischemic attack . Many of these interventions overlap and will be discussed together. Lifestyle changes that can reduce stroke risk include modifications in diet, exercise, tobacco and elicit drug use cessation.For primary stroke prevention, cessation of smoking, regular physical activity , a healthy diet, moderate alcohol consumption, and maintaining a body mass index ＜ 25kg/m2 has been shown to reduce stroke risk by as much as 80% compared to no lifestyle modifications.In contrast, the effectiveness of these modifications for secondary stroke prevention seems less robust.