Chronic gabapentin prevents maladaptive plasticity after high-level spinal cord injury in mice
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Date
2019-03
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Abstract
Autonomic dysreflexia (AD) is a potentially fatal condition of episodic vascular hypertension that develops in animals and people when a traumatic spinal cord injury (SCI) occurs above the major sympathetic outflow (spinal level T5). In most cases, the frequency of AD increases over time after SCI, indicating that progressive reorganization of intraspinal circuitry and new synapse formation below the level of injury causes the exaggerated spinal autonomic reflexes that define AD. A strict bladder/bowel care regimen and anti-hypertensive medications can help reduce the incidence of AD but prevention of AD may only be possible with new interventions that block or reverse the formation of structural plasticity in the spinal cord below the level of injury. Thrombospondins (TSPs) are glial-derived proteins that promote excitatory synaptogenesis by binding neuronal α2δ1 receptors. Recent data show that gabapentin (GBP), a drug commonly used to treat neuropathic pain, binds to neuronal α2δ-1 receptors and can reduce the formation of new synapses. Here, we tested the hypothesis that chronic treatment with GBP would limit maladaptive post-injury synaptogenesis and reduce the severity or frequency of AD and associated immune suppression after SCI. In mice with a complete T3 SCI, chronic GBP blocks excitatory synaptogenesis within spinal autonomic lamina, reduces sprouting of both autonomic interneurons that control immune organs, and sensory afferents that have been implicated in nociceptive triggering of AD reflexes. In vivo radio-telemetry revealed chronic GBP delayed the onset and decreased the frequency of spontaneous AD, and reduced the severity of experimentally induced AD. Chronic GBP also protected mice from SCI-induced immune depression. These data show GBP could be repurposed as a prophylactic therapy in at-risk SCI patients to prevent maladaptive anatomical reorganization, AD, and immunosuppression.
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Poster Division: Biological Sciences: 2nd Place (The Ohio State University Edward F. Hayes Graduate Research Forum)
Keywords
Spinal Cord Injury, Autonomic Dysreflexia, Neuroplasticity, Gabapentin