Acute post-injury blockade of α2δ-1 calcium channel subunits prevents pathological autonomic plasticity after spinal cord injury

• Published in: Cell reports (Cambridge) 2021-01, Vol.34 (4), p.108667-108667, Article 108667
• Main Authors: Brennan, Faith H., Noble, Benjamin T., Wang, Yan, Guan, Zhen, Davis, Hayes, Mo, Xiaokui, Harris, Clay, Eroglu, Cagla, Ferguson, Adam R., Popovich, Phillip G.
• Format: Article
• Language: English
• Subjects: Animals; autonomic dysreflexia; Autonomic Dysreflexia - pathology; Autonomic Dysreflexia - therapy; axon sprouting; Calcium Channel Blockers - pharmacology; Calcium Channel Blockers - therapeutic use; dysautonomia; Excitatory Amino Acid Antagonists - pharmacology; Excitatory Amino Acid Antagonists - therapeutic use; Gabapentin - pharmacology; Gabapentin - therapeutic use; Humans; immune suppression; lymphopenia; Male; Mice; neuroplasticity; neurotrauma; Spinal Cord Injuries - pathology; Spinal Cord Injuries - therapy; spinal cord injury; synaptogenesis
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.108667

After spinal cord injury (SCI), normally innocuous visceral or somatic stimuli can trigger uncontrolled reflex activation of sympathetic circuitry, causing pathological dysautonomia. We show that remarkable structural remodeling and plasticity occur within spinal autonomic circuitry, creating abnormal sympathetic reflexes that promote dysautonomia. However, when mice are treated early after SCI with human-equivalent doses of the US Food and Drug Administration (FDA)-approved drug gabapentin (GBP), it is possible to block multi-segmental excitatory synaptogenesis and abolish sprouting of autonomic neurons that innervate immune organs and sensory afferents that trigger pain and autonomic dysreflexia (AD). This “prophylactic GBP” regimen decreases the frequency and severity of AD and protects against SCI-induced immune suppression. These benefits persist even 1 month after stopping treatment. GBP could be repurposed to prevent dysautonomia in at-risk individuals with high-level SCI. [Display omitted] •Prophylactic GBP blocks synaptogenesis and autonomic fiber sprouting after SCI in mice•Prophylactic GBP prevents autonomic dysreflexia and immune suppression•Benefits of prophylactic GBP persist at least 1 month after treatment withdrawal•Syndromic analyses predict spinal sympathetic reflex pathology and GBP efficacy Brennan et al. show that α2δ-1 calcium channel subunits drive remarkable structural reorganization of autonomic circuitry and autonomic dysfunction after spinal cord injury. Early (prophylactic) post-injury treatment with gabapentin, an FDA-approved drug, prevents α2δ-1-dependent structural changes and autonomic dysfunction. Prophylactic gabapentin could be repurposed clinically for at-risk individuals.