ReviewThe development of stroke therapeutics: Promising mechanisms and translational challenges
Section snippets
Introduction to ischemic stroke
Stroke ranks second to ischemic heart disease as a cause of death and long-term disability with 4,000,000 new cases per year worldwide. The incidence is predicted to grow with the increasing age of the population (Donnan et al., 2008). Ischemic strokes constitute ∼75–85% of all strokes while hemorrhagic strokes amount to ∼15–20% of the acute stroke incidence. Stroke is a rapidly developing cerebrovascular event triggered by a thrombus or embolism in an extraparenchymal cerebral vessel (commonly
The current gold standard
The rationale for administering a thrombolytic to a stroke patient is to achieve reperfusion by breaking up an occluding thrombus and reestablishing cerebral blood flow. Treatment of patients with rt-PA (0.9 mg/kg, with a maximum dose of 90 mg) within 3 h of the onset of acute ischemic stroke has been shown to improve recovery in two clinical phase III trials on the basis of which rt-PA gained approval in the United States and most of Europe (Schellinger et al., 2001). Recent results from ECASS
Advances from neuroimaging
Advances in magnetic resonance (MR) imaging such as diffusion/perfusion (DWI/PWI) mismatch (see later) have been used as surrogate markers for detecting and estimating the volume of penumbra and applied to pre-selecting patients that may benefit from thrombolysis beyond the 3-h window (Muir et al., 2006). Two phase II studies (DIAS and DEDAS) for Desmoteplase, a fibrin selective agent originally isolated from bat saliva with a longer half-life than rt-PA, showed that: (i) early reperfusion
Intrinsic repair in the ischemic brain
The intrinsic adaptive response of the brain to ischemic injury promotes at least two obvious modes of tissue repair: cell replacement and structural plasticity. Firstly, an increased rate of neurogenesis and the directed migration of stem cells to sites of injury have been observed in several animal models of ischemic stroke. Genetic marking studies have demonstrated that endogenous precursor cells arising from the subventricular zone (SVZ) generate new neurons in the striatum and the cortex (
Translating pre-clinical research
At first sight, given the common mechanisms involved in cell death across species and the ability to occlude blood flow in a manner comparable to that seen in the patient, one might guess that stroke research is amenable to accurate translation from the laboratory to the clinic. This is clearly not the case. Drug development for stroke is a very high-risk endeavor with countless large and very expensive clinical failures exemplified over the past two decades (Ford, 2008, Green, 2008, Pangalos
Drug development
Clinical development can be improved in at least two respects: (i) patient selection to maximize for patients capable of showing a treatment response, and (ii) clinical endpoints in early development to improve the specificity and accuracy of clinical outcomes in larger trials. The use of diffusion/perfusion MR “mismatch” imaging to identify patients with “salvageable” brain tissue (or “penumbra”) that could more likely benefit from neuroprotective drugs has been the subject of much debate and
Conclusion
Over the past two decades, significant learning has been gained both from unsuccessful clinical trials and neutral or positive proof of concept studies in humans. Advancements in neuroimaging have established prolonged existence of salvageable penumbral brain tissue. Future research directions should focus on deepening our understanding of the biological pathways driving tissue to transition from injury to repair and the appropriate temporal therapeutic windows for targeting specific
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