Signaling, delivery and age as emerging issues in the benefit/risk ratio outcome of tPA For treatment of CNS ischemic disorders

Abstract

Abbreviations used: BBB, blood-brain barrier; ERK, extracellular signal related kinase; ET, endothelin; FPI, fluid percussion brain injury; ICH, intracerebral hemorrhage; JNK, c-Jun-N-terminal kinase; LRP, low-density receptor-related protein; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NVU, neurovascular unit; PA, plasminogen activator; PAI-1, PA inhibitor I; RBC, red blood cells; TBI, traumatic brain injury; tPA, tissue-type plasminogen activator; uPA, urokinase plasminogen activator. AbstractStroke is a leading cause of morbidity and mortality. While tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for ischemic stroke, clinical use of tPA has been constrained to roughly 3% of eligible patients because of the danger of intracranial hemorrhage and a narrow 3 h time window for safe administration. Basic science studies indicate that tPA enhances excitotoxic neuronal cell death. In this review, the beneficial and deleterious effects of tPA in ischemic brain are discussed along with emphasis on development of new approaches toward treatment of patients with acute ischemic stroke. In particular, roles of tPA-induced signaling and a novel delivery system for tPA administration based on tPA coupling to carrier red blood cells will be considered as therapeutic modalities for increasing tPA benefit/ risk ratio. The concept of the neurovascular unit will be discussed in the context of dynamic relationships between tPA-induced changes in cerebral hemodynamics and histopathologic outcome of CNS ischemia. Additionally, the role of age will be considered since thrombolytic therapy is being increasingly used in the pediatric population, but there are few basic science studies of CNS injury in pediatric animals. Keywords: cerebral ischemia, neurovascular unit, pediatric, signaling, stroke, tissue plasminogen activator. BackgroundThe Word Health Organization defines stroke as 'rapidly developing signs of focal or global disturbance of cerebral function, with symptoms lasting 24 h or longer leading to death, with no apparent cause other than that of vascular origin'. Stroke is the third leading cause of morbidity and mortality after heart disease and cancer. Surviving stroke victims often face serious long-term disability and constitute a significant familial and societal economic burden. Stroke can be classified broadly into ischemic or hemorrhagic, with the former comprising 80% of cases. Ischemic stroke, in turn, can be further subclassified as thrombotic or embolic in origin. Thrombotic stroke occurs when a clot forms in an artery located within the brain whereas an embolic stroke results from a clot formed elsewhere in the body that is subsequently transported to the brain. Hemorrhagic stroke results from the disruption of vascular integrity or aneurysm sufficient to cause bleeding within the brain. Generally speaking, three major approaches have been used in the treatment of acute stroke: neuroprotection, thrombolysis, and clot removal. To date, neuroprotection ha...

Astragaloside IV reduces cerebral edema post-ischemia/reperfusion correlating the suppression of MMP-9 and AQP4

“…Tissue-type plasminogen activator (tPA) remains the only FDA-approved treatment for acute ischemic stroke, because intravenous thrombolysis with tPA is an approved and effective therapy for acute ischemic stroke within the first 3 h from onset (Armstead et al, 2010). However, cerebral edema is an uncommon but potentially lethal complication postintravenous thrombolysis in addition to the risk of cerebral hemorrhage (Cruz-Flores et al, 2001).…”

Effects of skilled reach training with affected forelimb and treadmill exercise on the expression of neurotrophic factor following ischemia-induced brain injury in rats

“…In general, treadmill exercise is commonly applied to stroke patients thanks to its beneficial effect on neuroprotection11, 12 ) . To date, the only therapy approved by FDA has been thrombolytic tissue plasminogen activator (tPA) although approximately 80% of human strokes are classified into ischemic stroke13,14,15 ) . It is suggested that continuous researches via experimental ischemic stroke models should be performed to develop novel, proper, and helpful solutions for patients with ischemic stroke.…”

Neuroprotective effects of lycopene pretreatment on transient global cerebral ischemia-reperfusion in rats: The role of the Nrf2/HO-1 signaling pathway

“…In addition, the mechanisms underlying stroke include oxidative stress, blood-brain barrier dysfunction, neuronal apoptosis and inflammation (5,6). Although tissue-type plasminogen activator is used clinically and remains the only FDA-approved treatment for ischemic stroke, it is not so effective for all patients and only a small number of patients recover as a result of the reperfusion injury and a narrow 3 h time-window for safe administration (7). Therefore, other effective therapeutic agents are required to assist the patients with their diseases.…”