The drug gabapentin, which is currently prescribed to control seizures and reduce neural pain.
By helping neurons on the undamaged side of the brain take over the signaling job of lost cells. Photo: Shutterstock.
The Ohio State University team discovered that gabapentin blocks the activity of a protein that, when expressed at high levels after brain or spinal cord injury, hinders the regrowth of axons, the long and thin extensions of nerve cell bodies that transmit messages.
“When this protein is elevated, it interferes with neurological recovery,” explains lead author Andrea Tedeschiassociate professor of neuroscience at the Ohio State College of Medicine.
“Imagine that this protein is the brake pedal and recovery is the accelerator,” he continues. “Put on the brakes and keep pressing the accelerator, you can speed up recovery a lot. We think that this is the effect of gabapentin on neurons, and that there is a contribution from non-neuronal cells that take advantage of this process and make it even more efficient.” , stands out.
The main focus of treatment after an ischemic stroke is to restore blood flow to the brain as quickly as possible, but this research suggests that gabapentin has no role in that acute stage: Recovery outcomes were similar whether the treatment was started an hour or a day after the stroke.
Experiments performed on mice, and published in Brain, mimicked the stroke ischemic in humans. The results showed that daily treatment with gabapentin for six weeks after stroke restored fine motor functions in the upper limbs of animals. The researchers found that functional recovery also continued after discontinuation of treatment.
Instead, the drug’s effects are manifested in specific motor neurons whose axons carry signals from the central nervous system to the body that tell muscles to move.
The researchers found that after strokeneurons on the uninjured side of the brain began to sprout axons that re-established signals for voluntary movement in the upper extremities that had been silenced by neuron death after injury. stroke. This is an example of plasticity, that is, the ability of the central nervous system to repair damaged structures, connections and signals.
“The mammalian nervous system has a certain intrinsic capacity for self-repair,” explains Tedeschialso a member of Ohio State Chronic Brain Injury Program–. But we found that this increased spontaneous plasticity was not enough to drive recovery. Functional deficits are not as severe in this experimental model of stroke ischemic, but they are persistent.
Neurons after injury have a tendency to “overexcited,” causing excessive signaling and muscle contractions that can lead to uncontrolled movement and pain. While the neural receptor protein alpha2delta2 contributes to central nervous system development, its overexpression after neuronal damage means that it stunts axon growth at inopportune times and contributes to this problematic hyperexcitability.
This is where gabapentin does its job: by inhibiting the alpha2delta1/2 subunits and allowing post-stroke central nervous system repair to progress in a coordinated fashion. “We block the receptor with the drug and ask ourselves: will it produce even more plasticity? The answer is yes,” he stresses. Tedeschi.
Since a technique that temporarily silenced the new circuits reversed the behavioral signs of recovery, Tedeschi highlights that the findings suggest that the drug normalizes conditions in the damaged nervous system to promote cortical reorganization in a functionally meaningful way.
Compared to control mice that did not receive the drug, mice that received six weeks of daily gabapentin treatment recovered fine motor function in their forelimbs. The researchers noted that, two weeks after stopping treatment, the functional improvements persisted. “This confirmed that functional changes are solidified in the nervous system,” he concludes. Tedeschi.
Gabapentin also seemed to have an effect on the brain affected by stroke in non-neuronal cells that influence the timing of message transmission. Examination of their activity after drug treatment suggested that these cells may dynamically change their behavior in response to variations in synaptic communication, allowing smooth sprouting of axons that compensate for lost neurons.
The team continues to study the mechanisms underlying the recovery of the strokebut Tedeschi states that the results suggest that gabapentin holds promise as a treatment strategy for repair of stroke.
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