Courtesy of a colleague
The first thing Debra McVean did when she woke up at the hospital in March 2024 was try to get to the bathroom. But her left arm wouldn’t move; neither would her left leg. She was paralyzed all along her left side.
She had suffered a stroke, her doctor soon explained. A few nights before, a blood clot had lodged in an artery in her neck, choking off oxygen to her brain cells. Now an M.R.I. showed a dark spot in her brain, an eerie absence directly behind her right eye. What that meant for her prognosis, however, the doctor couldn’t say.
“Something’s missing there, but you don’t know what,” Ms. McVean’s husband, Ian, recalled recently. “And you don’t know how that will affect her recovery. It’s that uncertainty, it eats away at you.”
With a brain injury, unlike a broken bone, there is no clear road to recovery. Nor are there medical tools or therapies to help guide the brain toward healing. All doctors can do is encourage patients to work hard in rehab, and hope.
That is why, for decades, the medical attitude toward survivors of brain injury has been largely one of neurological “nihilism,” said Dr. Fernando Testai, a neurologist at the University of Illinois, Chicago, and the editor in chief of the Journal of Stroke and Cerebrovascular Diseases. Stroke, he said, “was often seen as a disease of ‘diagnose and adios.’”
That may be about to change. A few days after Ms. McVean woke up in the Foothills Medical Center in Calgary, she was told about a clinical trial for a pill that could help the brain recover from a stroke or traumatic injury, called Maraviroc. Given her level of physical disability, she was a good candidate for the study.
She hesitated. The pills were large — horse pills, she called them. But she knew the study could help others, and there was a 50 percent chance that she would get a drug that could help her, too.
Eventually, she agreed. “I was game,” she said. “I didn’t want to be in a wheelchair all my life.”
A ‘Harsh Decree’
Dr. S. Thomas Carmichael, the head of neurology at the Geffen School of Medicine at the University of California, Los Angeles, was taught the same thing again and again in his medical training: The brain doesn’t grow back. “Unlike, say, the liver, there is no regenerative capacity,” he recalled being told in the 1990s. “You work with what you’re given.”
In many ways, neuroscience was stuck in the age of Santiago Ramón y Cajal, one of neurology’s greatest minds. Dr. Carmichael’s teachers often quoted Dr. Cajal’s 1928 declaration that, in the adult brain, “the nerve paths are something fixed, ended and immutable. Everything may die, nothing may be regenerated.”
But in his rotation at a rehabilitation center for brain injury survivors, Dr. Carmichael saw evidence to the contrary. His patients relearned how to walk, to grasp, to string words into sentences. Somehow, their brains were healing and adapting.
“There is something happening,” he said. “It just doesn’t get very far.” That something, he learned, was the brain reorganizing.
Against the advice of his thesis advisers, he set out to discover whether the brain could repair itself. What he learned would astonish the field: After injury, healthy neurons far from the site of damage sprouted new axons, the rootlike tentacles that conduct electrical signals.
A stroke does not just kill off part of the brain. It also disrupts a vast network of neurons that exchange messages with far-off regions. The death of one neuron can take thousands of these connections down with it, like downed power lines.
And yet, Dr. Carmichael found, the injury initiates a wave of plasticity and growth throughout the brain, an event previously thought to occur only in development. Neurons come alive again, sprouting new rootlets that poke their way into gray matter and try to re-establish lost connections.
Not many succeed. But it may take only a few to rewire distant parts of the brain. That is most likely how Ms. McVean woke up one morning in a rehab center, a month after her stroke, and found that she could rotate her left thumb. A few days later, she waggled a finger. “That was a big, big deal,” she said.
Therapist Azul Gordiano helped Ms. McVean stretch and move her fingers during an in-home rehabilitation program.Credit...Amber Bracken for The New York Times
While the brain can regenerate, that process is limited. Very few stroke survivors ever achieve close to a full recovery, according to the American Stroke Association. It’s as if, at some point, the brain decides it is done healing and returns to its default state.
Dr. Carmichael wanted to go further, to keep the window of plasticity open longer and allow the brain to heal beyond its natural limits. There was, he recalled, a second half to Dr. Cajal’s statement: “It is for the science of the future to change, if possible, this harsh decree.”
Maybe the science of the future was finally here.
In 2015, Dr. Alcino Silva, a leading memory researcher and colleague at U.C.L.A., was studying “smart” mice — mice with mutations that enhanced their ability to learn and remember. One day, he called Dr. Carmichael over to see a mouse that was smart for an unexpected reason: It was missing an immune gene.
The gene coded for a receptor called CCR5, which, Dr. Silva’s lab had found, seemed to suppress plasticity, memory and learning. He wondered if it might play a role in recovery from stroke, which triggers the immune system to flood the brain with inflammatory cells.
Dr. Carmichael was intrigued. In a healthy human brain, CCR5 was not present in neurons. But after a stroke or other brain injury, the receptor suddenly appeared everywhere in the brain.
The period of initial plasticity following a stroke, he realized, was being cut short by CCR5. Like a dam closing, the receptor seemed to tell the brain: Enough. Let’s lock in what we’ve learned, and call it a day. Maybe this was why stroke survivors rarely fully recovered: The brain was holding itself back.
The mutant mice did not have that safety valve, however. Their window of brain plasticity stayed open longer. After a stroke or traumatic injury, Dr. Carmichael and Dr. Silva found, they recovered faster and more completely.
The next step was to see whether the same was true for humans with the mutation, a group that included Ashkenazi Jews. By this point, the researchers were leading an effort funded by the Adelson Medical Research Foundation to find new approaches to recovery from brain injury.
The foundation connected them to Dr. Einor Ben Assayag, a neurologist at Tel Aviv University in Israel who was tracking a cohort of 600 stroke patients to see which ones developed dementia.
Amazingly, she had kept blood samples of every patient, in addition to cognitive evaluations over time. When she analyzed her data, she found that patients with some form of the CCR5 mutation had better language, memory and attention scores. This was groundbreaking: They had identified the first gene associated with stroke recovery.
But the researchers had more than just a target; they also had a drug that mimicked the mutation. Tawnie Silva, Dr. Silva’s wife and a researcher in his lab, had found it while researching the mutant mouse strain: a little-known H.I.V. treatment that had been approved by the Food and Drug Administration in 2007. It was called Maraviroc.
“I mean, that’s a unicorn kind of thing,” Dr. Silva said. “That’s incredibly rare.”
As it turned out, the CCR5 receptor was also known as the portal that H.I.V. binds to in order to enter cells. In the 2000s, as the deadly virus gained resistance to older medications, Pfizer developed a drug that blocked this portal and protected cells from infection.
But no one had looked at what Maraviroc might be doing in the brain. In 2019, Dr. Carmichael laid out three lines of evidence showing that Maraviroc boosted neuroplasticity after brain injury, and published his findings in a landmark paper in the journal Cell.
As he was sharing his results at a conference later that year, Dr. Sean Dukelow, a Canadian stroke neuroscientist sitting in the back row, grew excited. Dr. Dukelow would become the main investigator conducting the Maraviroc trial at the Foothills Medical Center and across Canada.
When Dr. Dukelow was a teenager, at around the same time that Dr. Carmichael was being taught that the brain was static, he watched his grandfather suffer a mini-stroke at home. Since there were no therapies for brain recovery, all his family doctor could offer was bed rest and an aspirin. Within a year, his grandfather died of a full-blown stroke.
For 70 years, the field had believed the brain could not rewire. Now, “we’re actually on the verge of guiding that rewiring,” Dr. Dukelow said. “Do I wish it would have moved faster? Yes. But it’s actually pretty incredible to have come through and watched it happen, to go from absolutely nothing to now there’s hope.”
Maraviroc is not a perfect drug, Dr. Carmichael said. It does cross the blood-brain barrier, but only in limited amounts. That’s why his allegiance is not to one drug, but to laying the groundwork for future therapies by deepening the understanding of the brain’s recovery systems.
In May, in his office at U.C.L.A., he projected onto the wall an image of what looked like a glowing green centipede covered in knobby legs. This was a dendrite, a branch of a mouse neuron that receives signals from other neurons. The knobs were dendritic spines.
After a stroke, his next image showed, many of these spines disappeared — the centipede lost some legs. But if the mouse was made to perform precise motor tasks for a month, it could actually sprout new ones. “Rehab boosts these,” Dr. Carmichael said. “There are more little green things.”
He recently identified a drug that produced a similar effect in the brain, leading to better motor recovery in mice. While promising, it would take years and “a lot of non-sexy science” to bring this “neurorehabilitation pill” to market, he said.
If any of these therapies make it to F.D.A. approval, it could change not only the way doctors treat brain injury patients, but also the way those patients imagine their own futures.
Ms. McVean still doesn’t know whether she received Maraviroc; the trial won’t be complete for another two years. But she knows her brain is still rewiring, reorganizing and adapting to its new reality, more than a year after her stroke.
Sitting in her folding wheelchair in her kitchen last May, she lifted a one-pound weight with her left hand, a feat that would have been impossible six months ago. She can now wheel from her bed across the kitchen to make herself coffee. She can walk upstairs, tentatively, with a brace. “I count the stairs,” she said. “I know there’s 15.”
Recently, she noticed her fingers on her left hand becoming more mobile. “They don’t feel like they don’t belong to me anymore,” she said.
Whether or not she received the drug, she knows some innate capacity for recovery is there. In their own ways, she and Dr. Carmichael are continuing to challenge Dr. Cajal’s harsh decree.
Rachel E Gross
https://www.nytimes.com/2025/09/04/science/neuroscience-brain-injury-pill.html?unlocked_article_code=1.jU8.xRwZ.N7-CAKaNIdOH&smid=url-share
Joy MT, Ben Assayag E, Shabashov-Stone D, Liraz-Zaltsman S, Mazzitelli J, Arenas M, Abduljawad N, Kliper E, Korczyn AD, Thareja NS, Kesner EL, Zhou M, Huang S, Silva TK, Katz N, Bornstein NM, Silva AJ, Shohami E, Carmichael ST. CCR5 Is a Therapeutic Target for Recovery after Stroke and Traumatic Brain Injury. Cell. 2019 Feb 21;176(5):1143-1157.e13. doi: 10.1016/j.cell.2019.01.044. PMID: 30794775; PMCID: PMC7259116.
Abstract
We tested a newly described molecular memory system, CCR5 signaling, for its role in recovery after stroke and traumatic brain injury (TBI). CCR5 is uniquely expressed in cortical neurons after stroke. Post-stroke neuronal knockdown of CCR5 in pre-motor cortex leads to early recovery of motor control. Recovery is associated with preservation of dendritic spines, new patterns of cortical projections to contralateral pre-motor cortex, and upregulation of CREB and DLK signaling. Administration of a clinically utilized FDA-approved CCR5 antagonist, devised for HIV treatment, produces similar effects on motor recovery post stroke and cognitive decline post TBI. Finally, in a large clinical cohort of stroke patients, carriers for a naturally occurring loss-of-function mutation in CCR5 (CCR5-Δ32) exhibited greater recovery of neurological impairments and cognitive function. In summary, CCR5 is a translational target for neural repair in stroke and TBI and the first reported gene associated with enhanced recovery in human stroke.
Molad J, Hallevi H, Seyman E, Rotschild O, Bornstein NM, Tene O, Giladi N, Hausdorff JM, Mirelman A, Ben Assayag E. CCR5-Δ32 polymorphism-a possible protective factor from gait impairment amongst post-stroke patients. Eur J Neurol. 2023 Mar;30(3):692-701. doi: 10.1111/ene.15637. Epub 2022 Dec 3. PMID: 36380716; PMCID: PMC10107159.
Abstract
Background and purpose: Stroke and small vessel disease cause gait disturbances and falls. The naturally occurring loss-of-function mutation in the C-C chemokine receptor 5 gene (CCR5-Δ32) has recently been reported as a protective factor in post-stroke motor and cognitive recovery. We sought to examine whether it also influences gait and balance measures up to 2 years after stroke.
Method: Participants were 575 survivors of first-ever, mild-moderate ischaemic stroke or transient ischaemic attack from the TABASCO prospective study, who underwent a 3 T magnetic resonance imaging at baseline and were examined by a multi-professional team 6, 12 and 24 months after the event, using neurological, neuropsychological and mobility examinations. Gait rhythm and the timing of the gait cycle were measured by force-sensitive insoles. CCR5-Δ32 status and gait measures were available for 335 patients.
Results: CCR5-Δ32 carriers (16.4%) had higher gait speed and decreased (better) stride and swing time variability 6 and 12 months after the index event compared to non-carriers (p < 0.01 for all). The association remained significant after adjustment for age, gender, education, ethnicity and stroke severity.
Conclusions: Significant associations were found between gait measurements and CCR5-Δ32 loss-of-function mutation amongst stroke survivors. This is the first study showing that genetic predisposition may predict long-term gait function after ischaemic stroke.
Tene O, Molad J, Rotschild O, Alpernas A, Hawwari M, Seyman E, Giladi N, Hallevi H, Assayag EB. Blocking CCR5 activity by maraviroc augmentation in post-stroke depression: a proof-of-concept clinical trial. BMC Neurol. 2024 Jun 6;24(1):190. doi: 10.1186/s12883-024-03683-3. PMID: 38844862; PMCID: PMC11155100.
Abstract
Background: Post-stroke depression (PSD) is a significant impediment to successful rehabilitation and recovery after a stroke. Current therapeutic options are limited, leaving an unmet demand for specific and effective therapeutic options. Our objective was to investigate the safety of Maraviroc, a CCR5 antagonist, as a possible mechanism-based add-on therapeutic option for PSD in an open-label proof-of-concept clinical trial.
Methods: We conducted a 10-week clinical trial in which ten patients with subcortical and cortical stroke, suffering from PSD. were administered a daily oral dose of 300 mg Maraviroc. Participants were then monitored for an additional eight weeks. The primary outcome measure was serious treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation. The secondary outcome measure was a change in the Montgomery-Asberg Depression Rating Scale (MADRS).
Results: Maraviroc was well tolerated, with no reports of serious adverse events or discontinuations due to intolerance. The MADRS scores substantially reduced from baseline to week 10 (mean change: -16.4 ± 9.3; p < 0.001). By the conclusion of the treatment phase, a favorable response was observed in five patients, with four achieving remission. The time to response was relatively short, approximately three weeks. After the cessation of treatment, MADRS scores increased at week 18 by 6.1 ± 9.6 points (p = 0.014).
Conclusions: Our proof-of-concept study suggests that a daily dosage of 300 mg of Maraviroc may represent a well-tolerated and potentially effective pharmacological approach to treating PSD. Further comprehensive placebo-controlled studies are needed to assess the impact of Maraviroc augmentation on PSD.
