Rapamycin Exacerbates Cardiovascular Dysfunction after Complete High-Thoracic Spinal Cord Injury

Khalid C. Eldahan, David H. Cox, Jenna L. Gollihue, Samir P. Patel, Alexander G. Rabchevsky

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Autonomic dysreflexia (AD) is a potentially life-threatening syndrome in individuals with spinal cord injury (SCI) above the T6 spinal level that is characterized by episodic hypertension in response to noxious stimuli below the lesion. Maladaptive intraspinal plasticity is thought to contribute to the temporal development of AD, and experimental approaches that reduce such plasticity mitigate the severity of AD. The mammalian target of rapamycin (mTOR) has gained interest as a mediator of plasticity, regeneration, and nociceptor hypersensitivity in the injured spinal cord. Based on our preliminary data that prolonged rapamycin (RAP) treatment markedly reduces mTOR activity in the cord weeks after high-thoracic (T4) spinal transection, we sought to determine whether RAP could modulate AD development by impeding intraspinal plasticity. Naïve and injured rats were administered RAP or vehicle every other day, beginning immediately after injury for four weeks, and hemodynamic monitoring was conducted to analyze the frequency of spontaneously occurring AD, as well as the severity of colorectal distention (CRD) induced AD. Results showed that after SCI, RAP significantly exacerbated sustained body weight loss and caused a marked elevation in resting blood pressure, with average daily blood pressure rising above even normal naïve levels within one week after injury. Moreover, RAP significantly increased the frequency of daily spontaneous AD and increased the absolute blood pressure induced by CRD at three weeks post-injury. These dynamic cardiovascular effects were not, however, correlated with changes in the density of nociceptive c-fibers or c-Fos+ neurons throughout the spinal cord, indicating that intraspinal plasticity associated with AD was not altered by treatment. These findings caution against the use of RAP as a therapeutic intervention for SCI because it evokes toxic weight loss and exacerbates cardiovascular dysfunction perhaps mediated by increased peripheral nociceptor sensitivity and/or vascular resistance.

Original languageEnglish
Pages (from-to)842-853
Number of pages12
JournalJournal of Neurotrauma
Volume35
Issue number6
DOIs
StatePublished - Mar 15 2018

Bibliographical note

Funding Information:
Special thanks to Dr. Richard Kryscio (University of Kentucky) for expert assistance in statistical analysis and Jensen Goh for assistance with immunohistochemistry procedures. This study was supported by 5T32 NS077889 (KCE), Craig H. Neilsen Foundation (AGR), SCoBIRC Chair Endowment (AGR), National Institutes of Health/National Institute of Neurological Disorders and Stroke P30 NS051220.

Publisher Copyright:
© Copyright 2018, Mary Ann Liebert, Inc.

Keywords

  • autonomic
  • mammalian target of rapamycin
  • plasticity
  • sprouting
  • sympathetic

ASJC Scopus subject areas

  • Clinical Neurology

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