Steps Toward Stroke Recovery

Mouse brain neurons (green) and inflammatory cells (red). Blocking CCR5 gene expression reduces the intensity of the latter.

Mary Teena Joy

No medical therapies currently exist to reduce long-term cognitive and motor disabilities caused by strokes and other traumatic brain injuries. In some cases, however, natural recovery is possible when the brain creates new connections after losing functions in damaged areas—a process that parallels memory formation through learning. In 2016, a University of California, Los Angeles (UCLA) research team found that turning down the expression of the C-C chemokine receptor 5 (CCR5) gene in laboratory mice improved their learning and memory. Building on this finding, multiple studies in mice and humans have examined the potential role of CCR5 in stroke recovery.

A research team led by UCLA neurologist S. Thomas Carmichael traced which parts of the mouse brain expressed CCR5 before and after an induced stroke. They found that this gene’s signaling moved from immune cells in the healthy brain to its nerve cells, or neurons, shortly following stroke.

Next, the team tested how reducing CCR5 expression in mice affected recovery from stroke and traumatic brain injury. In one set of studies, they knocked down neuronal CCR5 expression using a virus. In a parallel set of studies, they used daily injections of an FDA-approved HIV drug, maraviroc, to block CCR5 signaling starting one day after stroke or traumatic brain injury and continuing for either three or nine weeks.

Across the board, mice with reduced CCR5 expression—induced either virally or after maraviroc treatment—saw significant improvements in early and late phases after stroke or traumatic brain injury. Mice with reduced CCR5 expression made fewer post-stroke stepping errors when walking across an uneven grid of metal rungs and showed less stroke-induced asymmetry in paw use, demonstrating improved motor function. Reduced CCR5 expression was also associated with improved cognitive function following traumatic brain injury, as measured by mouse memory tests. The researchers were able to pinpoint the molecular pathways involved in this recovery, which allow mouse brains to rewire and form new connections.

The research team collaborated with several Israeli institutions (lack of the CCR5 gene is more common in Ashkenazi Jews) to conduct an examination of nearly 450 human patients with mild stroke. They found that those born without CCR5 showed greater recovery in mobility, memory, and language. “This is the first time that a human gene has been linked to a better recovery from stroke,” said Carmichael. Next up is a clinical trial testing how stroke patients with CCR5 respond to maraviroc treatment. (Cell)