Advances in ischemic stroke treatment: neuroprotective and combination therapies

Abstract

Thrombolysis with intravenous alteplase (recombinant tissue-type plasminogen activator) continues to be the sole recourse for acute ischemic stroke therapy, provided that patients seek treatment preferably within 3 h of stroke onset. The narrow window of efficacy, coupled with the significant risk of hemorrhage and the high mortality rate, preclude the use of alteplase beyond this time frame. Moreover, in part because of safety concerns, only a small percentage (6-15%) of eligible patients is treated with alteplase. Clearly, safer and more effective treatments that focus on improving the shortcomings of the present thrombolysis for stroke need to be identified. Therefore, newer thrombolytics are being developed with the goal of minimizing side effects, while also shortening the time of cerebral reperfusion and extending the therapeutic window of efficacy. Besides thrombolytics, new and potentially useful drugs and devices are also being studied either as monotherapeutic agents or for use in conjunction with alteplase. In animal models of stroke, neuroprotective agents that affect various components of the ischemic injury cascade that results in neurodegeneration have shown promise for the latter. Examples of such agents include spin traps that block oxidative stress, metalloprotease inhibitors that prevent vascular damage, anti-inflammatory drugs that suppress inflammation and transcranial infrared laser irradiation, which promotes recovery of function. Ideally, a successful combination of neuroprotectant (drug or device) and thrombolytic therapy for stroke would minimize the side effects of thrombolysis followed by supplementary neuroprotection thereafter.

A novel approach to screening for new neuroprotective compounds for the treatment of stroke

“…The improvement in behavioral outcome relative to the control rabbits that we observed was better than that seen with the antioxidant ebselen (Lapchak and Zivin, 2003) and similar to that seen with several other compounds including the phenylpropanoid chlorogenic acid (Lapchak, 2007) and the spin trap NXY-059 (Lapchak et al, 2004b). This result further supports the use of the in vitro chemical ischemia assay in combination with the biochemical assays as an initial screen for potential neuroprotective compounds for the treatment of stroke.…”

“…In this experiment, we administered either vehicle (90% β-hydroxypropyl cyclodextrin in PBS containing 10% HPLC-grade dimethylsulfoxide) or bolus injections of fisetin (50 mg/kg) over 1 minute starting 5 minutes following embolization. This dose and treatment schedule were chosen based on earlier studies with the phenylpropanoid chlorogenic acid (Lapchak, 2007) and the free radical trapping spin trap NXY-059 (Lapchak et al, 2004b) using this stroke model. Behavioral analysis was conducted 24 h following treatment, which allowed for the construction of quantal analysis curves.…”

“…Worldwide, approximately 6 million people died of stroke in 2005, with a projected increase over the next decade of 12% (Ingall, 2004). Ischemic stroke occurs when the normal blood supply to the brain is disrupted, usually due to artery blockage by a blood clot, thereby depriving the brain of oxygen and metabolic substrates and hindering the removal of waste products (for review see Lapchak and Araujo, 2007). The nerve cell damage caused by cerebral ischemia results in functional impairment and/or death.…”

“…Finally, flavonoids have been shown to induce neurite outgrowth (Sagara et al, 2004), reduce inflammation (Read, 1995), improve cerebral blood flow (Curin et al, 2006), prevent platelet aggregation (Curin et al, 2006) and enhance cognition , all properties that could have additional benefits for the treatment of stroke. Indeed, the phenylpropanoid chlorogenic acid was recently shown to improve behavioral performance in a rabbit embolic stroke model (Lapchak, 2007). Finally, in animal studies, flavonoids have generally shown low levels of toxicity over a wide range of doses.…”

Sesamol attenuates oxidative stress, apoptosis and inflammation in focal cerebral ischemia/reperfusion injury

“…Previous reports have suggested that several biomechanisms may be associated with the pathology of cerebral ischemic damage, such as ion imbalance, loss of ATP, increased release of excitatory neurochemical transmitters, increased generation of free radicals and apoptosis (1)(2)(3). In the context of stroke, these events may induce irreversible brain damage.…”