Current Topics in Medicinal Chemistry - Volume 9, Issue 14, 2009

“Time Is Brain”, this is the guide principle of American Guidelines of Stroke Management [1]. This principle derives from the notion that neurons die within a few minutes of oxygen deprivation. Thus, some neuronal death occurs in areas of no blood flow within minutes of stroke onset. Around such areas of necrosis exist regions of hypoperfused, electrically silent tissue that barely receives enough blood flow to keep neurons alive. This tissue area is called the “ischemic penumbra”. A major goal of acute stroke management is resuscitation of the ischemic penumbra. If reperfusion of the penumbra occurs expeditiously, neurons recover and the patient improves; with no reperfusion, a time-related attrition converts ailing neurons to frank infarction. Because of the time-dependent death of neurons in the ischemic penumbra, emphasis should be placed on the earliest possible intervention. Due to the complexity of the brain and the heterogenicity of the disease, ischemic stroke (IS) treatment has been known to be challenging and risky. Current therapies to treat IS are severely limited and most treatments have a narrow therapeutic window after the onset of the disease and often lead to severe side effects such as internal bleeding. Nevetheless, ischemic stroke is a potential treatable disease. Because of the limited treatment options currently available and significant unmet medical needs, opportunities exist for the development of novel, safer, more effective IS treatments with a broader therapeutic window. Possible therapeutic targets in acute stroke treatment are: Neuron damage (neuroprotection) Lysing the thrombus Inflammation (immuno-inflammatory activation of the acute phase) High arterial blood pressure of the acute phase to blood pressure of the acute phase High glucose blood levels of the acute levels High cholesterol plasma levels Platelet hyperactivity

Animal models of focal ischaemia induced by middle cerebral artery occlusion (MCAO) provide most evidence for cellular inflammatory responses in stroke. Permanent MCAO results in a modest neutrophil infiltration at 24 h after ischaemia, predominantly around arterial vessels at the margins of infarction, whereas MCAO with subsequent reperfusion is associated with substantial infiltration by neutrophils throughout the entire infarct. Several studies show that C-reactive protein (CRP), an inflammatory marker, is associated with stroke outcomes and future vascular events. Several drugs, especially hydroxymethylglutaryl coenzyme A reductase inhibitors (statins), have been demonstrated to reduce hsCRP levels independently of their effects on plasma cholesterol. Various cytokines were shown to be expressed in the injured brain. Recent investigations demonstrated that mRNAs of above cytokines were induced in the ischemic rat brain. TNF-α is a pleiotropic cytokine that mediates key roles in many physiological and pathological cellular processes including acute and chronic inflammation, programmed cell death or apoptosis, anti-tumor responses, and infection. Pharmaceutical industry to search a small molecule TNF Inhibitor have taken multiple strategies. Significant protection after in vivo oral use of SB-239063 from brain injury and neurological deficits was observed in one study. In the same study significant protection from brain injury and neurological deficits was also demonstrated due to i.v post-stroke treatment with the same compound. Leukocyte-endothelial adhesion process consists of several steps, beginning with rolling of the leukocyte on the endothelial surface until it has slowed down to such a degree that it sticks to the endothelium. Treatment with a murine anti-ICAM-1 antibody (enlimomab) has been investigated in patients with acute ischemic stroke in the Enlimomab Acute Stroke Trial (EAST). Unfortunately, the case fatality rate in this trial was significantly higher in the enlimomab patient group than in the placebo group. Furthermore, experimental data have shown that focal cerebral ischemia induces a time-dependent activation of granulocytes, lymphocytes, and macrophages. Dissipation of ATP by CD39 reduced P2X7 receptor stimulation and thereby suppressed baseline leukocyte alphaMbeta2-integrin expression. As alphaMbeta2-integrin blockade reversed the postischemic, inflammatory phenotype of Cd39-/- mice, these data suggest that phosphohydrolytic activity on the leukocyte surface suppresses cellcell interactions that would otherwise promote thrombosis or inflammation.

Ischaemic stroke is extremely common in western societies contributing to 70-85% of strokes, one of the leading causes of mortality and long-term disability. Despite advancement in preventive measures, the total number of strokes is set to rise in the future due to increasing numbers of aging populations across the world. Diabetes as a risk factor for stroke has been well established. There are also emerging evidence to suggest glucose level management in acute stroke phase as a therapeutic target may be beneficial, albeit remains controversial. One of the issues in difficulty in interpreting study findings is their heterogeneity. In this article, we provide epidemiological, basic science, clinical observational and trial evidence leading to the current practice of regarding blood glucose as the therapeutic target in acute ischaemic stroke setting.

Stroke, as a clinical manifestation of the cardiovascular diseases, is one of the leading causes of death and disability in both developed and developing countries. Hypertension is by far, the most important risk factor for stroke. Epidemiological data indicate that the risk of stroke increases with both systolic and diastolic blood pressure elevation, from levels of 115/75 mmHg. It is also evident that most adults worldwide have values above these limits, thus emphasizing the importance of blood pressure as a risk factor for stroke. Clinical trials of antihypertensive treatment, both in studies that have compared active drugs against placebo or in those comparing different types of drugs have clearly demonstrated a protective effect of blood pressure reduction in the prevention of stroke. The degree of protection is directly related to blood pressure reduction and, the lower the level, the better the prognosis. Although data on secondary stroke prevention are scarcer, studies also seem to indicate that lowering blood pressure with antihypertensive treatment protects against stroke recurrence. At the present moment there is still uncertainty on 2 different aspects regarding the relationship between antihypertensive treatment and stroke. First, the blood pressure management during acute stroke has not adequately investigated in clinical trials. Second, the possibility of a protective role of specific types of antihypertensive drugs beyond blood pressure reduction is a matter of debate. Independently of these unresolved issues, prevention of hypertension development by lifestyle changes and adequate treatment and control to the hypertensive population will be a very effective measure in reducing stroke incidence, stroke recurrence, and stroke mortality.

In the last decennium, thrombolytic therapy has changed the management of acute ischemic stroke. Randomized clinical studies have demonstrated that intravenous thrombolysis with tissue plasminogen activator improves functional outcomes. Recently the time window for intravenous thrombolysis has been extended from 3 to 4.5 hours after stroke onset, which will allow more stroke patients to benefit from this treatment. Currently several studies are investigating how to improve recanalization rates of thrombolytic therapy. In this review several aspects of intravenous and intra-arterial thrombolysis are discussed.

Ischemic stroke is a major cause of morbidity and mortality. Whereas dyslipidemia is a major risk factor for coronary heart disease (CHD), its role in the pathogenesis of ischemic stroke is less clear. Epidemiological studies have provided conflicting findings regarding the association of dyslipidemia with ischemic stroke. Overall, elevated LDL-C levels appear to increase the risk of ischemic stroke. Low HDL-C levels also appear to be associated with a greater risk whereas the importance of high triglyceride levels is less clear. The discordant results of observational studies might result from the heterogeneity of stroke, since dyslipidemia is less likely to play a major role in the pathogenesis of some ischemic stroke subtypes (e.g. lacunar and cardioembolic strokes) and elevated LDL-C levels might increase the risk of hemorrhagic stroke. In clinical trials, statins consistently reduced the risk of ischemic stroke in patients with or without CHD whereas the data on the effects of other lipid modifying drugs on stroke risk are limited. In patients with a previous stroke, statins reduce the risk of both ischemic stroke and other vascular events but also increase the risk of hemorrhagic stroke. Accordingly, current guidelines recommend the same lipid targets for the primary and secondary prevention of both stroke and CHD. In addition, stroke and transient ischemic attacks of carotid origin are considered CHD risk equivalents. Nevertheless, more trials are required to identify which patients with stroke but without CHD will benefit more from statin treatment.

Antiplatelets represent a diverse group of agents that share the ability to reduce platelet activity through a variety of mechanisms. Antithrombotic agents are effective in the secondary prevention of ischemic strokes. Most strokes are caused by a sudden blockage of an artery in the brain (called an ischaemic stroke) that is usually due to a blood clot. Immediate treatment with antiplatelet drugs such as aspirin may prevent new clots from forming and hence improve recovery after stroke. Several studies have evaluated the role of one antiplatelet agent, aspirin, in reducing stroke severity. The International Stroke Trial (IST) of 20,000 patients with acute stroke from other countries. In this study there was a significant 14% proportional reduction in mortality during the scheduled treatment period (343 [3.3%] deaths among aspirin-allocated patients vs 398 [3.9%] deaths among placebo-allocated patients; 2p = 0.04). There were significantly fewer recurrent ischaemic strokes in the aspirin-allocated than in the placebo-allocated group (167 [1.6%] vs 215 [2.1%]; 2p = 0.01) but slightly more haemorrhagic strokes (115 [1.1%] vs 93 [0.9%]. Few studies examined the role of ticlopidin in acute stroke setting the results showed treatment with ticlopidine improved the neurologic outcome. In the Examining the Safety of Loading of Aspirin and Clopidogrel in Acute Ischemic Stroke and TIA (LOAD) study, 40 consecutive ischemic stroke patients were treated with 325 mg of aspirin and 375 mg of clopidogrel within 36 hours of symptom onset. Overall, 37.5% (n = 15) of the patients had an improvement of 2 or more points on the NIHSS 24 hours after antiplatelet administration. The antiplatelet efficacy of aspirin in preventing secondary stroke was established by three studies conducted in the late 1980s and early 1990s: the Swedish Aspirin Low-dose Trial (SALT) trials have demonstrated that aspirin-even in doses as low as 30 mg/day-reduces secondary stroke, MI, or vascular death in patients with. Clopidogrel and aspirin have been used in combination in patients with diverse arterial vascular diseases However, combinations of antithrombotic agents do not necessarily improve clinical efficacy and are typically associated with increased toxicity.

Involvement of various neurotransmitters and neuromodulators have been shown to contribute to the ischemic injury and neuronal death associated with stroke Role of excitatory amino acid receptor activation, calcium overload, nitric oxide, and oxidative stress in the pathogenesis of ischemic brain damage is well established. Several new strategies are currently emerging, based on recent advances in our understanding of molecular pathways that could be considered as potential therapeutic targets. For example reactive oxygen species (ROS) are important contributors to the secondary injury cascade following traumatic brain injury (TBI), and ROS inhibition has consistently been shown to be neuroprotective following experimental TBI and brain ischemia. Furthermore, more recently, some authors concluded that nonanticoagulant 3K3A-APC exhibits greater neuroprotective efficacy with no risk for bleeding compared with drotrecogin-alfa activated, a hyperanticoagulant form of APC. Excessive calcium entry into depolarized neurons contributes significantly to cerebral tissue damage after ischemia. Included in the sequence of events leading to neuronal death in ischemic tissue following stroke is an excessive and toxic rise in the intracellular Ca(2+)-concentration, predominantly due to an influx of Ca2+ through nonselective cation-channels as well as Ca(2+)-channels. Some authros conducted a study to investigate whether the enhancement of GABA receptor activity could inhibit NMDA receptor-mediated nitric oxide (NO) production by neuronal NO synthase (nNOS) in brain ischemic injury. The results showed that both the GABA(A) receptor agonist muscimol and the GABA(B) receptor agonist baclofen had neuroprotective effect, and the combination of two agonists could significantly protect neurons against death induced by ischemia/reperfusion. On this basis we conclude that neuroprotection for ischemic stroke refers to strategies, applied singly or in combination, that antagonize the injurious biochemical and molecular events that eventuate in irreversible ischemic injury. There has been a recent explosion of interest in this field, with over 1000 experimental papers and over 400 clinical articles appearing within the past 6 years. These studies, in turn, are the outgrowth of three decades of investigative work to define the multiple mechanisms and mediators of ischemic brain injury, which constitute potential targets of neuroprotection.