PMID- 29205090
OWN - NLM
STAT- MEDLINE
DCOM- 20190902
LR  - 20190902
IS  - 1557-9042 (Electronic)
IS  - 0897-7151 (Print)
IS  - 0897-7151 (Linking)
VI  - 35
IP  - 6
DP  - 2018 Mar 15
TI  - Rapamycin Exacerbates Cardiovascular Dysfunction after Complete High-Thoracic 
      Spinal Cord Injury.
PG  - 842-853
LID - 10.1089/neu.2017.5184 [doi]
AB  - 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. Naive 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 naive 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.
FAU - Eldahan, Khalid C
AU  - Eldahan KC
AD  - 1 Department of Physiology, University of Kentucky , Lexington, Kentucky.
AD  - 2 Spinal Cord and Brain Injury Research Center, University of Kentucky , 
      Lexington, Kentucky.
FAU - Cox, David H
AU  - Cox DH
AD  - 1 Department of Physiology, University of Kentucky , Lexington, Kentucky.
FAU - Gollihue, Jenna L
AU  - Gollihue JL
AD  - 1 Department of Physiology, University of Kentucky , Lexington, Kentucky.
AD  - 2 Spinal Cord and Brain Injury Research Center, University of Kentucky , 
      Lexington, Kentucky.
FAU - Patel, Samir P
AU  - Patel SP
AD  - 1 Department of Physiology, University of Kentucky , Lexington, Kentucky.
AD  - 2 Spinal Cord and Brain Injury Research Center, University of Kentucky , 
      Lexington, Kentucky.
FAU - Rabchevsky, Alexander G
AU  - Rabchevsky AG
AD  - 1 Department of Physiology, University of Kentucky , Lexington, Kentucky.
AD  - 2 Spinal Cord and Brain Injury Research Center, University of Kentucky , 
      Lexington, Kentucky.
LA  - eng
GR  - T32 AG057461/AG/NIA NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20180129
PL  - United States
TA  - J Neurotrauma
JT  - Journal of neurotrauma
JID - 8811626
RN  - 0 (Immunosuppressive Agents)
RN  - W36ZG6FT64 (Sirolimus)
SB  - IM
MH  - Animals
MH  - Autonomic Dysreflexia/*etiology
MH  - Blood Pressure/drug effects
MH  - Female
MH  - Immunosuppressive Agents/*pharmacology
MH  - Male
MH  - Neuronal Plasticity/drug effects
MH  - Rats
MH  - Sirolimus/*pharmacology
MH  - Spinal Cord Injuries/*complications
MH  - Thoracic Vertebrae
MH  - Weight Loss/drug effects
PMC - PMC5863090
OTO - NOTNLM
OT  - autonomic
OT  - mammalian target of rapamycin
OT  - plasticity
OT  - sprouting
OT  - sympathetic
COIS- No competing financial interests exist.
EDAT- 2017/12/06 06:00
MHDA- 2019/09/03 06:00
PMCR- 2019/03/15
CRDT- 2017/12/06 06:00
PHST- 2017/12/06 06:00 [pubmed]
PHST- 2019/09/03 06:00 [medline]
PHST- 2017/12/06 06:00 [entrez]
PHST- 2019/03/15 00:00 [pmc-release]
AID - 10.1089/neu.2017.5184 [pii]
AID - 10.1089/neu.2017.5184 [doi]
PST - ppublish
SO  - J Neurotrauma. 2018 Mar 15;35(6):842-853. doi: 10.1089/neu.2017.5184. Epub 2018 
      Jan 29.