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Post-Stroke Gabapentin Promotes Plasticity and Regained Forelimb Function in Mice

Adult mice given the drug gabapentin regained skilled control of their forelimbs and had improvements in their structural and functional neuroplasticity, according to a study published May 23 in the journal Brain.

“These observations highlight the strong potential for repurposing gabapentinoids as a promising treatment strategy for stroke repair," wrote first author Andrea Tedeschi, PhD, assistant professor in the department of neuroscience at The Ohio State University, and colleagues.

To test the treatment, the researchers first induced a photothrombotic cortical stroke in adult mice, after which they administered gabapentin or saline as a control within either one hour or one day. Treatment with the drug or saline continued for six weeks.

Gabapentin had no effect on vascular occlusion, hemodynamic changes, or survival of corticospinal neurons within the ipsilateral sensory-motor cortex during the acute stage of the stroke.

However, the group used a combination of tract tracing, electrical stimulation, and functional connectivity mapping to find significant neuroplasticity in the contralateral side of the brain.

Corticospinal axons originating from that side extended many collaterals, formed new synaptic contacts, and better integrated within spinal circuits that control forelimb muscles.

At the same time, maladaptive plasticity in the mice treated with gabapentin was dampened by reducing the excitability of spinal motor circuitry, the paper reported.

The recovery of skilled upper extremity function persisted after the six-week treatment ended.  

Gabapentin or saline were administered at a rate of 46 mg per kg of body weight, delivered three times a day for the first week and two times a day for the remaining five weeks. In the mice given gabapentin or saline 24 hours after the induced stroke, treatment ended at 43 days, and behavioral data were collected for the following two weeks.

To explore the mechanism by which gabapentin was conferring its benefits, the investigators chemo-genetically silenced the cortical projections originating from the contralateral side of the brain. As a result, recovery in the mice administered gabapentin temporarily paused. This finding, the study authors wrote, supports the conclusion that “gabapentin-dependent reorganization of spared cortical pathways drives functional recovery after stroke."

The researchers became intrigued by the potential of gabapentin after discovering in an earlier study that the α2δ2 subunit of the voltage gated calcium channel “acts as a developmental switch that suppresses axon growth and regeneration in the adult CNS," they wrote. By blocking α2δ2 with gabapentin or pregabalin in mice with a spinal cord injury, they found, axon sprouting was restored, as was regeneration of sensory ascending and descending corticospinal pathways.

The paper noted that gabapentinoids are already being studied for promoting neurological recovery after severe traumatic brain injuries.

“As gabapentinoids are clinically approved drugs prescribed for a wide range of neurological disorders, our findings highlight the strong potential for repurposing GBP as a promising treatment strategy for stroke repair," the study concluded.

The study was supported by the National Institute of Neurological Disorders and Stroke, as well as by a grant from the Chronic Brain Injury Discovery Theme at The Ohio State University. The authors reported no competing interests. 

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Tedeschi A, Larson JE, Xouridakis A, et al. Harnessing cortical plasticity via gabapentinoid administration promotes recovery after stroke. Brain 2022: awac103.

Sun W, Larson MJ, Kiyoshi CM, et al. Gabapentinoid treatment promotes corticospinal plasticity and regeneration following murine spinal cord injury. J Clin Invest 2020;130(1):345-358.