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Acute Post-Injury Blockade of α2δ-1 Receptors Prevents Pathological Autonomic Plasticity after Spinal Cord Injury

45 Pages Posted: 18 Oct 2019 Publication Status: Published

See all articles by Faith H. Brennan

Faith H. Brennan

Ohio State University (OSU) - Department of Neuroscience

Benjamin T. Noble

Ohio State University (OSU) - Department of Neuroscience

Yan Wang

Ohio State University (OSU) - Department of Neuroscience

Zhen Guan

Ohio State University (OSU) - Department of Neuroscience

Hayes Davis

Ohio State University (OSU) - Department of Neuroscience

Xiaokui Mo

Ohio State University (OSU) - Center for Biostatistics

Clay Harris

Ohio State University (OSU) - Department of Chemistry and Biochemistry

Cagla Eroglu

Duke University - Duke Institute for Brain Sciences

Phillip G. Popovich

Ohio State University (OSU) - Department of Neuroscience

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Abstract

Spinal cord injury (SCI) damages supraspinal control over spinal autonomic circuitry. As a result, normally innocuous visceral or somatic stimuli (e.g. distended bladder or bowel) trigger pathological dysautonomia caused by uncontrolled reflex activation of sympathetic circuitry. In this report we show that remarkable structural remodeling and synaptic plasticity occurs within spinal autonomic circuitry and that this increases the frequency of autonomic dysreflexia (AD), a life-threatening condition of episodic vascular hypertension that develops progressively in SCI animals and people. We also prove that maladaptive plasticity can be prevented if SCI mice are treated with human equivalent doses of the FDA-approved drug, gabapentin (GBP) before the onset of plasticity. Although GBP is used clinically to treat pain or spasticity after symptom onset, we tested the hypothesis that GBP would prevent maladaptive plasticity if it were used as a prophylactic therapy, starting before the onset of a critical period of enhanced synaptogenesis with maintenance dosing continued for up to 35d post-injury.  Using this novel treatment regimen, we show that prophylactic GBP successfully blocks multi-segmental excitatory synaptogenesis within spinal autonomic lamina, abolishes sprouting of autonomic neurons that innervate immune organs and also the sensory afferents that trigger pain and AD. Functionally, this treatment protocol delays the onset and decreases the frequency of spontaneous AD, confers resistance to experimentally induced AD, and protects mice from SCI-induced immune suppression. These data show that GBP could be repurposed as a prophylactic therapy in at-risk individuals with a high-level SCI to prevent the pathological effects of autonomic dysfunction.

Keywords: Spinal cord injury, autonomic dysreflexia, immune suppression, neuroplasticity, synaptogenesis

Suggested Citation

Brennan, Faith H. and Noble, Benjamin T. and Wang, Yan and Guan, Zhen and Davis, Hayes and Mo, Xiaokui and Harris, Clay and Eroglu, Cagla and Popovich, Phillip G., Acute Post-Injury Blockade of α2δ-1 Receptors Prevents Pathological Autonomic Plasticity after Spinal Cord Injury (October 15, 2019). Available at SSRN: https://ssrn.com/abstract=3470401 or http://dx.doi.org/10.2139/ssrn.3470401
This version of the paper has not been formally peer reviewed.

Faith H. Brennan

Ohio State University (OSU) - Department of Neuroscience ( email )

United States

Benjamin T. Noble

Ohio State University (OSU) - Department of Neuroscience

United States

Yan Wang

Ohio State University (OSU) - Department of Neuroscience

United States

Zhen Guan

Ohio State University (OSU) - Department of Neuroscience

United States

Hayes Davis

Ohio State University (OSU) - Department of Neuroscience ( email )

United States

Xiaokui Mo

Ohio State University (OSU) - Center for Biostatistics ( email )

United States

Clay Harris

Ohio State University (OSU) - Department of Chemistry and Biochemistry ( email )

Blankenship Hall-2010
901 Woody Hayes Drive
Columbus, OH 43210
United States

Cagla Eroglu

Duke University - Duke Institute for Brain Sciences ( email )

Box 91003
450 Research Drive
Durham, NC 27708
United States

Phillip G. Popovich (Contact Author)

Ohio State University (OSU) - Department of Neuroscience ( email )

United States

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