For most stroke patients, surviving an attack on the brain is just the beginning. The majority of stroke survivors go on to face a range of chronic problems caused by the deaths of millions of neurons and the breakdown of neural connections throughout the brain. The aftermath of a stroke often brings sensorimotor problems, including the inability to control movements or position a limb in space and diminished sensations of touch, pain, and temperature (1,2).
To curb the early damage and save as many neurons as possible after a stroke, clinicians administer medications to thin the blood and break up clots. But after the first few days have passed, there are no pharmacological therapeutics to help the brains of stroke survivors continue to recover and reverse common sensorimotor problems.
Tadeusz Wieloch, a neuroscientist at Lund University, wants to change that. In a new paper published in BRAIN, Wieloch and his collaborators reported that drugs that block the activity of the metabotropic glutamate receptor 5 (mGluR5) neuronal receptor led to rapid restoration of brain circuitry and sensorimotor functions in mice and rats after stroke (3).
There's really nothing that exists on the market that's in this category of 'here's something you can take temporarily after a stroke to accelerate brain recovery.'
– Joshua Siegel, Washington University School of Medicine
Wieloch and his team hope that the mGluR5-blocking drugs known as negative allosteric modulators (NAM) will become the first ever treatment to restore neural circuitry and reverse sensorimotor deficits in human stroke patients. Others in the field view the study as a significant step in that direction. "When I saw the work in this paper, I was excited because the idea is very promising and has a lot of logic and sense behind it," said Joshua Siegel, a neuropsychopharmacologist at Washington University School of Medicine who was not involved in the study but has previously collaborated with study coauthor Adam Bauer, a neuroscientist at Washington University in St. Louis. "There's really nothing that exists on the market that's in this category of 'here's something you can take temporarily after a stroke to accelerate brain recovery.'"
Wieloch first happened upon the idea to test mGluR5 NAM for stroke recovery in 2009 while attending a conference in the picturesque hilltop town of Taormina, Italy. There, he learned about a clinical trial where researchers used a NAM drug to block mGluR5 activity in patients with Parkinson’s disease. To explore the drug’s applications for stroke, Wieloch joined forces with Bauer and Ferdinando Nicoletti of the Sapienza University of Rome. The team hypothesized that while mGluR5 helps modulate the strength of neural connections in healthy brains, its activity might become maladaptive and counteract this neuroplasticity during a stroke.
To test the potential for NAM drugs to block mGluR5 activity and help the post-stroke brain to reorganize, Wieloch's team induced strokes in male and female mice and rats. They then waited two days before providing the treatment, allowing time for the area of dead tissue in each of their brains to stop growing. In mice treated with mGluR5 NAM, several behavioral tests demonstrated rapid recovery of motor abilities and sense of touch. For example, rodents given the mGluR5-blocking drugs regained sensation in their paws within a matter of hours. Wieloch noted that one of the most exciting parts of the study was watching the movement of a paw that had been paralyzed just moments before.
To find out what happened within the rodents’ brains to cause the rebound in behavior, the researchers analyzed the brains using optical intrinsic signal imaging and observed restoration of connectivity among regions of the sensorimotor and visual cortices. They also found that the sensorimotor deficits came back when the drug wore off, so they repeated the treatment for 12 days and soon saw sustained improvements. "You have to repeat it so that the plasticity kicks in and [connections] will be restored again on the synaptic level. So, that told us that actually, we have the circuitry; it's just inhibited by mGluR5," said Wieloch.
This discovery supports the idea that mGluR5 activity becomes maladaptive after stroke and blocks the plasticity mechanisms that would usually allow restoration of brain circuitry. Upon treatment with mGluR5 NAM, mGluR5 can no longer inhibit these plasticity mechanisms, allowing the neurons to reconnect.
The researchers also combined their drug therapy with rehabilitative therapy, which further enhanced the improvements in post-stroke sensorimotor behaviors. They placed their rodents in enriched sensory environments that challenged them to retrain their motor and sensory networks, similar to the process of physical therapy in stroke patients. "That's one of the indicators that this has a greater potential of being useful in humans in the sense that [the drug can] enhance the benefit of physical therapy and other interventions that are already happening after stroke," said Siegel.
I see it almost as an obligation, whenever possible, to move the discovery from the bench to bed.
- Tadeusz Wieloch, Lund University
Dale Corbett, a neuroscientist studying stroke recovery and plasticity at the University of Ottawa who was not involved in the study, agreed that the new work is impressive and has the potential to one day provide a treatment for post-stroke sensorimotor problems in humans. But before mGluR5 NAM drugs enter a clinical trial for this purpose, Corbett would first like to see evidence that the drug could treat older populations who most commonly experience stroke (4). "We know that the plasticity mechanisms in older animals are not identical to those in younger animals. So, what I would want to see is does this work at least in middle-aged animals?" said Corbett.
Wieloch’s team indeed plans to further test mGluR5 NAM in older animals along with animal models of other stroke risk factors such as hypertension, obesity, and diabetes. Looking further ahead, the researchers are cautiously optimistic that they will be able to design a trial to test mGluR5 NAM as the first treatment for post-stroke sensorimotor deficits. One of the NAM drugs tested in the present study, AFQ056, has already entered clinical trials to treat addiction and neurodevelopmental disorders (5).
With mGluR5 receptors so widely distributed throughout many regions of the brain, the team also hopes that these drugs may be able to treat a variety of other post-stroke problems such as fatigue, depression, and loss of language and memory.
“Anybody who does drug development understands that there is a long way to go… but you have to do it," said Wieloch. “I see it almost as an obligation, whenever possible, to move the discovery from the bench to bed.”
- Carey, L.M. & Matyas, T.A. Frequency of discriminative sensory loss in the hand after stroke in a rehabilitation setting. J Rehabil Med 43, 257-263 (2011).
- Connell, L.A., Lincoln, N.B., & Radford, K.A. Somatosensory impairment after stroke: frequency of different deficits and their recovery. Clin Rehabil 22, 758-767 (2008).
- Hakon, J. et al. Inhibiting metabotropic glutamate receptor 5 after stroke restores brain function and connectivity. Brain (2023).
- Feigin, V.L., Lawes, C.M., Bennett, D.A., & Anderson, C.S. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2, 43-53 (2003).
- Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials. Sci Transl Med 8, 321ra5 (2016).