Gabapentin Promotes Beneficial Neuroplasticity in a Stroke Model

 

This from 2002 I'm sure never got to being a protocol:

Central post-stroke pain syndrome: yet another use for gabapentin?

Maybe because of this?

Gabapentin linked to increased risk of opioid-related death

Be careful out there.

The latest here:

Gabapentin Promotes Beneficial Neuroplasticity in a Stroke Model

By Richard Robinson

July 7, 2022

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Article In Brief

In a rat model, gabapentin promoted recovery after stroke, unleashing plasticity in the corticospinal tract to improve motor function. Independent experts said the finding is promising for potential clinical applications in the future.

Gabapentin increased neuroplasticity and corticospinal tract axonal sprouting, and improved fine motor function, in a rat model of stroke, according to a study published May 23 in the journal Brain.

The findings point toward a potential clinical role in stroke rehabilitation for this widely used drug and expand the number of strategies for harnessing the nervous system's own regenerative potential after it suffers damage.

“Gabapentin is widely used, and the preclinical data in this study suggest it may have efficacy in unleashing the plasticity in the corticospinal tract to improve motor function,” commented Michael Chopp, PhD, vice chair for research of the department of neurology and scientific director of the Henry Ford Neuroscience Institute of Henry Ford Health in Detroit, who was not involved in the study. “That is very positive.”

The discovery of this new role for gabapentin came about through the search for ways to unblock the regenerative capacity of the adult central nervous system, said lead study author Andrea Tedeschi, PhD, assistant professor of neuroscience at the Ohio State College of Medicine in Columbus.

“We were investigating how neurons in the central nervous system lose the ability to regrow, and we found that a key inhibitory role was played by the alpha2-delta2 subunit of the voltage-gated calcium channel, which acts as a developmental switch to suppress axonal growth and regeneration,” he said.

Gabapentinoids (gabapentin and pregabalin) block this subunit, and Dr. Tedeschi and colleagues have shown in models of spinal cord injury that dosing one or the other leads to axonal sprouting and regeneration of corticospinal pathways in injured mice.

“This was very exciting, and so the natural next step was to look at the potential of gabapentin in stroke,” Dr. Tedeschi said.

Study Details

To do that, the team, including co-principal investigator Wenjing Sun, PhD, research assistant professor of neuroscience, induced a unilateral “photothrombotic” cortical stroke, in which mice were first injected with a photosensitive compound, and then received precisely delivered transcranial illumination to the sensory-motor cortex. Absorption of light by the compound causes excitation and localized tissue damage. This technique restricts damage to the illuminated area, Dr. Sun explained, causing highly reproducible behavioral impairments; in these experiments, they consisted of fine motor actions of the forelimb.

The research team administered gabapentin beginning one hour after injury, three times a day for the first week, then twice a day until the end of the study, four to six weeks post-injury.

Compared with mice that did not receive gabapentin, those that did had enhanced collateral sprouting of adult corticospinal axons in the sensory-motor cortex on the side opposite the stroke. These new sprouts integrated into existing spinal networks with the formation of new excitatory synaptic contacts.

Treated mice had improved forelimb function, with better stepping behavior and restored forelimb symmetry when rearing. Those improvements could be blocked by injection of the contralateral forelimb sensory-motor cortex with an agent that reduced synaptic firing, indicating the importance of the contralateral side in the observed recovery.

Because the one-hour post-stroke time window for beginning gabapentin may be restrictive in clinical practice, the team examined whether waiting 24 hours after injury to begin treatment was also effective. They found that both forelimb placement and symmetry improved compared with untreated mice, and in fact continued to improve beyond the six weeks of treatment, with performance returning almost to baseline at the end of nine weeks.

Current indications for gabapentin include chronic treatment of neuropathic pain and reduction of seizures. Dr. Tedeschi noted that in these conditions, “the pathology is already embedded in the system, and the only thing the drug can do is dampen down some of the comorbidities that develop. Our approach is very different. We don't administer at the chronic or pathologic state, but rather shortly after injury, to push the system towards an adaptive response, rather than allowing the system to choose to develop a maladaptive response.”

While it is still unknown how long the window for treatment remains open, Dr. Tedeschi noted it may at least be longer than the window for tissue plasminogen activator (tPA), which, according to its label, must be given within three hours of the stroke.

“This might give the patient a second chance,” after the window for tPA treatment has closed.

It is not clear whether the benefit seen in mice can translate to humans, Dr. Tedeschi cautioned, although given the long safety record of the drug, it should be possible to test it quickly. Dr. Sun noted that retrospective data on patients taking gabapentin for neuropathic pain or seizures, who then experienced a stroke, may be available, and could offer some insight into potential benefits.

Assuming benefit can be demonstrated, the most promising scenario is likely to be using gabapentin in combination with other post-injury approaches, including physical rehabi litation. “The key may be to combine drug treatment with targeted activities in order to drive recovery toward a specific goal,” Dr. Tedeschi said. “I think this is achievable.”

Expert Commentary

Martin Schwab, PhD, professor of neuroscience at ETH Zurich in Switzerland, commented, “In this model, enhanced compensatory growth of intact, spared fibers was seen, paralleled by a certain degree of functional recovery of skilled forelimb movements in the stroke mice. It is, therefore, conceivable that one effect of longer-term use of these drugs could be increased regenerative axonal growth and circuit plasticity, which would then be a substrate for enhanced recovery of functions lost after a central nervous system injury. Dose, time window, treatment duration and safety of such a therapy must be tested, however, in future clinical trials.”