Convergence of stroke and Alzheimer's neurovascular research

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Science Translational Medicine  27 May 2015:
Vol. 7, Issue 289, pp. 289ec87
DOI: 10.1126/scitranslmed.aac5829

Alzheimer’s disease (AD) and stroke are the two leading causes of long-term neurological disability in our aging population. Tissue plasminogen activator (tPA) is currently the only FDA-approved drug available in the United States for acute ischemic stroke, but numerous other drugs decrease the long-term risk of stroke and are used prophylactically. In stark contrast, AD still exists in a therapeutic void, with no proven disease-modifying therapies. Now, an Asian-Australian group builds upon a promising stroke drug (edaravone) by testing its neuroprotective effects in a preclinical model of AD and shows some promising effects.

The hope has been that drugs can be used to protect neurons from degeneration, but so far there have been no definitive successes in either stroke or neurodegenerative diseases. One candidate neuroprotective drug is edaravone, which was approved in 2001 for stroke therapy in Japan on the basis of promising preclinical research and three small randomized clinical trials. Edaravone is widely used throughout Asia and is currently undergoing larger Phase 3 trials in China. Additional stroke trials have been proposed in conjunction with tPA, since preliminary data from Japan suggest a lower post-tPA hemorrhage risk with edaravone pretreatment. The drug is thought to protect from stroke damage through its powerful antioxidant action, which prevents secondary ischemic injury by quenching hydroxyl radicals and blocking lipid peroxidation.

Jiao et al. report that when edaravone was administered to the APP/PS1 mouse model of AD, it revealed multiple mechanisms of action directly relevant to Alzheimer's. In line with its antioxidant properties, edaravone suppressed inflammation and neuronal apoptosis while preserving synaptic proteins and dendritic spine integrity. Moreover, the drug bound specifically to amino acids 13-18 of Aβ and prevented aggregation of toxic oligomers while decreasing cerebral amyloid angiopathy, a hallmark of both Alzheimer's and microvascular disease in stroke. Edaravone rescued Alzheimer's learning and memory deficits before or after the onset of Aβ deposition and suppressed Aβ burden by up to 50% through dose-dependent inhibition of an APP cleaving enzyme, while potentiating the beneficial α-secretase processing of APP. Edaravone also reduced tau pathology by 40% through attenuation of phosphorylation by GSK-3β.

Because diverse pathways were targeted, the authors propose edaravone as a compelling candidate for fast-track clinical trials for AD. Yet these impressive preclinical results should be tempered by the failure of other high-profile antioxidant drugs (such as NXY-069) in clinical trials for stroke, as well as a recently published study by the Edaravone-ALS Study Group, which failed to show efficacy in a cohort of over 200 patients with ALS. The Stroke Treatment Academic Industry Roundtable (STAIR) guidelines for preclinical studies require testing of multiple species and different routes of administration, and using a clinically useful therapeutic window, among other recommendations. Work on edaravone for AD should follow these guidelines prior to human experimentation.

Altered metabolic states and secondary oxidative injury that aggravate synaptic injury and cell death may occur in both stroke and AD. The broad effects of edaravone on oxidative stress, cerebral amyloidosis, and tau phosphorylation suggest that these processes may be productive targets for both diseases. More investment will be crucial for developing new multitargeted therapies for stroke and AD.

S.-S. Jiao et al., Edaravone alleviates Alzheimer's disease-type pathologies and cognitive deficits. Proc. Natl. Acad. Sci. U.S.A. 112, 5225–5230 (2015). [Full Text]

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