AAccording to a study published in PLOS Biology last week (September 20).
The spinal cord is made up of bundles of long axons that carry either movement information from the brain to the muscles via descending axons, or sensory information from the body to the brain. In both mice and humans, spinal cord injury causes spasticity, pain and loss of voluntary movement below the site of injury. For years, researchers have searched for a way to reconnect severed neural connections above and below the injury, both immediately and long after damage appears. the cavity that forms after a spinal cord injury,” says the study’s co-author Simone Di Giovanni, a neuroscientist at Imperial College London. “And hopefully restore function.”
But so far, few effective treatments exist. The new study reveals that activation of CREB-binding protein (CBP) and a related protein called p300 can promote regeneration of axons at the injury site long after the initial injury. CBP/p300 are histone acetyltransferases, meaning they can modify histones and unwind DNA, promoting transcription of a number of genes, including those associated with growth, making them more physically accessible to the cellular machinery. But the study, which involved treating mice with a drug that activates CBP/p300, did not find that the effects of the proteins led to an improvement in the mice’s ability to move or walk.
Fluorescence image of a spinal cord lesion with axons in green
“In the field of spinal cord injury, we generally consider two groups of patients: those who are in the early and acute stage of the disease and those who are in the chronic stage of the disease, that is to say a long after sustaining the injury,” says Monica Sousa, a neuroscientist from the University of Porto in Portugal who was not involved in the study. “And we think therapeutic strategies . . . will work best in acute patients [because] once the injury has set in, there is nothing more to be done. This study suggests otherwise, and “In that sense, it’s an excellent finding.
Prior to this study, Di Giovanni and colleagues reported that CBP/p300 stimulates axonal outgrowth in the spinal cord of partially injured mouse, and improves the transcription of several genes associated with regeneration. But this is the first study to show that epigenetic activation can stimulate neuronal growth in nearly complete spinal injury long after the initial injury.
The team caused injuries in the upper back (thoracic) part of the spinal cord of mice. Almost all of the spine nerves of the animals were destroyed due to the injury. A week after inducing a spinal cord injury, the researchers placed the mice in what they called a enriched environment, where the mice have access to wheels, toys and tubes. Researchers previously found that this enriched environment also improved mice recovery after partial spinal cord injury, although Di Giovanni says he doesn’t know how much mice with near-total injury can take advantage of their environment, considering due to their limited mobility.
Twelve weeks after the injury, researchers began treatment. Once a week for 10 weeks, one group of mice was injected with CSP-TTK21, a molecule that activates the natural protein pair CBP/p300, while another group remained untreated.
After 22 weeks, the researchers looked for signatures of neuronal regeneration and synaptic plasticity – the ability of neuronal connections to strengthen or weaken over time – throughout the spinal cord. Such regeneration could fill the void left by the injury, and these stronger connections, the researchers believe, would allow the mice to have better control over their limbs. Using fluorescent markers, the team labeled descending and ascending axons from the motor cortex in the brain and from the spinal cord respectively, both of which had been severed by the injury. Looking through a microscope, the team found that in mice that received CBP/p300, the few undamaged axons at the site of injury began to regenerate and sprout more connections. “We saw an increase in sprouting around the spare piece of tissue present in the lesion,” says Di Giovanni. In particular, he and his team saw more sprouting of serotonin-containing axons, which Di Giovanni says are important for locomotion. No such regrowth was observed in mice that received no treatment.
The study also found a significant increase in the plasticity of excitatory synapses, says Di Giovanni: After administration of TTK21, motor neurons that control the lower back of injured mice had higher levels of specific neurotransmitter receptors which are known to increase in number after logins. between neurons reinforce each other.
The researchers also assessed the mice’s ability to walk and perform sensorimotor tasks, but found no difference between the CBP/p300-treated group and controls. They say that although the treatment is not enough to restore function, it begins to provide connection and structural support through the cavity caused by the injury, which could lead to functional recovery in combination with other therapies. .
“It’s a very nice paper,” says Martin Oudéga, a neuroscientist at Northwestern University who was not involved in the study. While it’s “unfortunate” that promoting axon growth isn’t enough to promote functional recovery, he says more steps – a more complicated experimental process – are likely needed to ensure new growth is “integrated into the circuits” of the central nervous system. He suggests that one way to achieve this could be targeted therapy of the forelimbs or hindlimbs.
In the future, Di Giovanni says he hopes to study other treatments in combination with CBP/p300, such as administering other pharmaceuticals or implanting biomaterials to close the gap between severed nerves, in the goal of inducing “much better growth and functional recovery”. Another question for future research is how CBP/p300 affects the environment around growing axons, which are typically stunted and retract after injury.
“Most patients are in the chronic stage of the disease,” says Sousa. “In most spinal cord injury articles, most therapies are given shortly after or at the same time as the injury. And that’s not what patients need.