In humans, acute ischemic stroke is the primarily result of a blood-clot that moves toward the brain and blocks one or more important blood vessels that supply blood, oxygen, and nutrients to brain tissue (Fig. 1), causing brain tissue death. Now there are 2 methods to remove this block: the Genentech Inc. drug tissue plasminogen activator (tPA) that “dissolves” the clot and endovascular procedures to physically remove the clot. Both are beneficial to stroke patients, but cannot be used on all stroke patients. Thus, this creates the need for stroke research and funding.

For the development of new stroke treatments, guidelines need to be established to best utilize abysmally low funding for stroke research from government agencies, and to guarantee that research is being conducted in a strict manner aligned with the standards of the research community.

Fig. 1. blockage of a brain vessel with a blood clot: Courtesy of Blausen Medical Communications, Inc.

Surprisingly, even though acute ischemic stroke is the result of a blood clot, many stroke studies are not utilizing clinically relevant blood clot-induced stroke models (i.e.: embolic stroke), but are focused on “ischemia” models where a suture is moved into an important vessel to produce a block.

In 2017, a workshop was held at National Institute of Neurological Disorders and Stroke (NINDS) in an attempt to discuss and establish acceptable guidelines for stroke research so that a therapy can be developed. The workshop was diffuse, with many diverse scientific opinions from invitees and attendees. The result was a set of recommendations that can be applied to stroke research.

First, researchers should apply RIGOR guidelines to all studies to include Power analysis, blinding, randomization, and statistical analysis. All studies should be completely transparent with full documentation in dated notebook, and the data should be counter-signed and trackable). This is just good laboratory practice- GLP.

Thefirst phaseproof of concept study should be conducted in a single species and a single gender (Note: the species is not defined). Attendees were well aware of the limitations of young rodents to conduct translational research, because rodents (rats and mice) are overly adaptive to stroke manipulations. An additional option for a research model includes the standardized rabbit embolic stroke model used in the development of tPA, the only Food and Drug Administration approved drug therapy for stroke.

Thesecond phaseshould incorporate gender analysis (male/female subjects) and aged animals and should be conducted in multiple species. This study will be more practical and incorporate dose-response and therapeutic window analysis and will be the basis for dose and timing estimation in humans.

Thethird phasewill be a randomized multi-site study with large numbers of animals so that meta-analysis can be conducted.

[All stages of development should be conducted using ateam approach, including basic researchers, translational researchers and clinicians].

• 委员会成员还建议过高ly expensive aged animals be used for stroke research, and co-morbid conditions (diabetes and hypertension) need to be included. There was an important idea to ensure that doses are adjusted for efficacy responses in aged animals and rodents with co-morbid conditions because the same low dose may not be optimally effective in aged animals/co-morbid animals as in young animals.

• Committee member emphasized that data should be reproduced by independent research groups, and that there should be auditing of data from laboratories if funded by the National Institutes of Health. Oversight of all aspects of translational stroke research is the ultimate goal.

In conclusion, since acute ischemic stroke is the primary cause of disability in the United States with an estimated cost of $68.9 billion annually, and the fifth leading cause of death, there is a need for focused, rapid development of new therapies. The development plan should incorporate multiple “stroke” models in multiple species (i.e: rat/mouse and rabbit, or possibly non-human primate) in multiple laboratories to ensure reproducibility and so thevisionof developing a new stroke therapy is not a lostopportunitybecause of failure or futility when ultimately tested in stroke victims. Each year there are approximately 800,000 new stroke victims in the USA; this number has now been stable for many years. Stroke does kill 130,000 of its victims annually!

Now with established transparency and therapy development guidelines for researchers to use in their work, there is a need for increased funding support to allow us to efficiently test new strategies and approaches to treat stroke.

Paul A. Lapchak
Department of Neurology & Neurosurgery, Advanced Health Sciences Pavilion, Los Angeles, CA, USA

Publication

Translational Stroke Research Opportunities and a Strategy to Develop Effective Cytoprotection.
Lapchak PA
Transl Stroke Res. 2017 Aug

Read offline:

Related Articles:

	Investigating SOCS3 as a new target for drugs to treat…Pulmonary arterial hypertension (PAH) is a fatal disease caused by the walls of the small blood vessels that supply the lungs walls becoming thicker (Fig. 1) and unable to adapt…
	Microalgae-based wastewater treatment for nutrients recoveryThe world may face deficits of water supplies in the decades ahead, for both potable water and water for irrigation, due to human population growth, droughts and floods due to…
	Excess nutrients cause environmental deterioration in the…The introduction of excess nutrients (i.e., nitrogen and phosphorus) to coastal areas can have a series of impacts. One of the most common is eutrophication—the enrichment of water with surplus…
	Gas types affect stability of microbubbles and ultrasound…Ultrasound (US) is used for clinical diagnosis and therapy. Microbubbles (MBs) as US-contrast agents are applied to detect micro blood flow or specific lesions. Recently, the combination of MBs and…
	WRGSD: improving reliability and efficiency for coastal…Water-quality response grid-based sampling design (WRGSD) using optimization and multi-factors assessment can reliably detect a variety of the impact of human activities. The sampling design are optimized by clustering and…
	Soil and water bioengineering – Sustainable erosion…Accelerated soil erosion and loss is a serious environmental problem, particularly for the Mediterranean region, due to its long history of human pressures, seasonally contrasting climate and rugged topography. Anthropogenic…