Neuroprotection for ischemic stroke: Past, present and future

Abstract

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. Rigorously conducted experimental studies in animal models of brain ischemia provide incontrovertible proof-of-principle that high-grade protection of the ischemic brain is an achievable goal. Nonetheless, many agents have been brought to clinical trial without a sufficiently compelling evidence-based pre-clinical foundation. At this writing, around 160 clinical trials of neuroprotection for ischemic stroke have been initiated. Of the approximately 120 completed trials, two-thirds were smaller early-phase safetyfeasibility studies. The remaining one-third were typically larger (>200 subjects) phase II or III trials, but, disappointingly, only fewer than one-half of these administered neuroprotective therapy within the 4-6 hour therapeutic window within which efficacious neuroprotection is considered to be achievable. This fact alone helps to account for the abundance of "failed" trials.This review presents a close survey of the most extensively evaluated neuroprotective agents and classes and considers both the strengths and weakness of the pre-clinical evidence as well as the results and shortcomings of the clinical trials themselves. Among the agent-classes considered are calcium channel blockers; glutamate antagonists; GABA agonists; antioxidants/radical scavengers; phospholipid precursor; nitric oxide signal-transduction down-regulator; leukocyte inhibitors; hemodilution; and a miscellany of other agents. Among promising ongoing efforts, therapeutic hypothermia, high-dose human albumin therapy, and hyperacute magnesium therapy are considered in detail. The potential of combination therapies is highlighted. Issues of clinical-trial funding, the need for improved translational strategies and clinical-trial design, and "thinking outside the box" are emphasized. Part I: Neuroprotection -from Past to the PresentNeuroprotection for ischemic brain injury has emerged only recently as a topic of serious biomedical inquiry. A MEDLINE survey (PubMed, 2007) reveals virtually no publications on this topic until the early 1990's but a remarkable surge in publications over the past 10 years Correspondence and reprint requests to:

Microglial Activation in Stroke: Therapeutic Targets

“…1,2 The inflammatory response can also impair neurogenesis and other postischemic changes that are thought to contribute to functional recovery after stroke. [3][4][5] Several interventions have been shown to reduce acute ischemic cell death in animal models of stroke, 6 but these are generally ineffective if not initiated very soon after onset of ischemia. These interventions have consequently been difficult to put into clinical practice, because the vast majority of stroke patients do not present for medical care until many hours after symptom onset.…”

Ischémie cérébrale

“…Ces traitements adjuvants pourraient aussi être des agents neuroprotecteurs, c'est-à-dire des agents capables de retarder ou de prévenir la mort neuronale : leur recherche a débuté dans les années 1980 mais reste aujourd'hui infructueuse en dépit du nombre de molécules testées tant au plan expérimental que clinique depuis une vingtaine d'années [3]. Ces échecs répétés conduisent aujourd'hui à développer des stratégies pharmacologiques aux mécanismes pléiotropes et ciblant l'ensemble de l'unité neurovasculaire.…”

“…Au cours des six dernières années, 1 000 articles expérimentaux et 400 articles cliniques ont été publiés dans ce domaine [3]. La neuroprotection peut être définie comme une stratégie ou une combinaison de stratégies qui peuvent inhiber, interrompre ou ralentir les événements moléculaires et cellulaires qui conduisent à des lésions ischémiques irréversibles ; elle exclue les thérapeutiques visant à agir directement sur l'obstruction artérielle elle-même.…”

Supportive or detrimental roles of P2Y receptors in brain pathology?—The two faces of P2Y receptors in stroke and neurodegeneration detected in neural cell and in animal model studies

“…Necrosis in brain occurs after traumatic injury or in the core of stroke tissue, where occlusions lead to stark limitation in supply of oxygen and glucose. Breakdown of ion gradients causes osmotic swelling and finally permeabilization of cells and subsequent inflammation [21][22][23]. Apoptosis leads to controlled degradation of cells and avoids further damage in the surrounding area by inflammation.…”