LOS ANGELES – Efforts to develop a drug to enhance poststroke recovery yielded promising results in a recent study in mice.
Dr. Marion Buckwalter of Stanford (Calif.) University and her colleagues found that a synthetic compound that mimics the positive effects of brain-derived neurotrophic factor (BDNF) significantly improved motor function and increased neurogenesis in mice when given 3 days after a stroke.
“An ideal pro-recovery agent would be something that didn't need to be given within the first 3 or 4.5 or 6 hours but could be given days after a stroke,” Dr. Buckwalter said at the conference, sponsored by the American Heart Association.
Although little is known about how the brain recovers from stroke at cellular and molecular levels, Dr. Buckwalter said the process “might include neurogenesis, the formation of new connections between neurons, and the strengthening of existing, useful synapses.”
BDNF is critical for synaptic plasticity and learning, especially motor learning and memory. It has been shown to be involved in the enlargement of motor maps during learning, in the promotion of neurogenesis, and in axonal and dendritic sprouting.
BDNF binds to two different receptors, TrkB and p75. Activation of TrkB is neuroprotective, promotes neurogenesis and axonal and dendritic sprouting, and is essential for learning and synaptic plasticity; p75 activation is known to increase neuropathic pain.
One of Dr. Buckwalter's coauthors at Stanford, Dr. Frank M. Longo, worked around the problem of p75 activation in an earlier study by designing a compound that would activate only TrkB. Dr. Longo and his associate, Dr. Stephen M. Massa, wrote a computer program that sifted through a library of compounds that might theoretically bind and activate TrkB. They found that one of the compounds in the library, called LM22A-4, activated TrkB without activating other Trk receptors or p75.
In subsequent experiments, Dr. Buckwalter and her associates randomized mice to 10 weeks of daily intranasal administration of LM22A-4 or placebo, beginning 3 days after stroke. They found that after 3 weeks, the compound significantly improved gait accuracy and increased the speed of their use of the contralateral paw, based on ladder and catwalk testing, in comparison with saline-treated mice. These results were comparable to those obtained with sham-treated mice given saline. The rate of neurogenesis of both mature and immature neurons more than doubled in regions near the stroke in mice treated with LM22A-4, compared with saline-treated mice after stroke.
The study was funded by the National Institute for Neurological Disorders and Stroke and the Stanford Stroke Center. Dr. Buckwalter had no relevant financial disclosures. Dr. Longo is the founder of PharmatrophiX, a company focused on the development of small-molecule ligands for neurotrophin receptors.
Unique Targeted Approach
Endogenous growth factor ligands and their receptors have a lot to teach us about physiology, development, and repair mechanisms. Much research has shown that BDNF exerts effects that could be beneficial in a variety of neurologic disease categories, including degenerative, ischemic, and traumatic conditions.
BDNF itself has been an impractical and ineffective agent in the few trials that have utilized it, because of both its inability to cross the blood-brain barrier and its short half life.
The exciting study by Dr. Buckwalter and her colleagues was made possible by Dr. Stephen Massa and his associates' groundbreaking discovery of LM22A-4. They showed that TrkB activation with LM22A-4 resulted in protection against neurodegeneration in in vitro models and against traumatic brain injury in an in vivo model (J. Clin. Invest. 2010;120:1774-85).
Just as Dr. Massa and his colleagues considered what properties a BDNF-like ligand required to achieve practical utility, so too did Dr. Buckwalter and her coauthors consider what clinical parameters would be useful to show that a neurotrophic strategy could enhance clinical outcomes after stroke. The administration of LM22A-4 on day 3 following ischemic injury was one such consideration, although it is premature to extrapolate from mouse models to humans based on that.
While TrkB activation may prevent neurodegeneration and promote neurogenesis, it also appears to be oncogenic (Blood 2009;113:2028-37). Therefore, oncologists are not in search of TrkB activators but rather TrkB inhibitors (Mol. Cancer Ther. 2009;8:1818-27).
Dr. Buckwalter and her coauthors found no evidence of angiogenesis, glial scar formation, or contralateral neurogenesis, which provides some reassurance, but clearly more work is needed.
How soon we might see clinical trials is not clear. To date, there are no drugs with an indication for poststroke recovery that have been approved by the Food and Drug Administration. An agent that promotes recovery on a cellular level but also results in clinical improvement would be a milestone.