PMID- 31463438
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20240204
IS  - 2572-1143 (Electronic)
IS  - 2572-1143 (Linking)
VI  - 1
IP  - 1
DP  - 2018 Mar
TI  - Link N as a therapeutic agent for discogenic pain.
PG  - e1008
LID - 10.1002/jsp2.1008 [doi]
LID - e1008
AB  - Neurotrophins (NTs) are the major contributors of sensory axonal sprouting, 
      neural survival, regulation of nociceptive sensory neurons, inflammatory 
      hyperalgesia, and neuropathic pain. Intervertebral disc (IVD) cells 
      constitutively express NTs. Their expression is upregulated by proinflammatory 
      cytokines present in the IVD during degeneration, which can promote peripheral 
      nerve ingrowth and hyperinnervation, leading to discogenic pain. Currently, there 
      are no targeted therapies that decrease hyperinnervation in degenerative disc 
      disease. Link N is a naturally occurring peptide with a high regenerative 
      potential in the IVD. Therefore, the suitability of Link N as a therapeutic 
      peptide for suppressing NTs, which are known modulators and mediators of pain, 
      was investigated. The aim of the present study is to determine the effect of Link 
      N on NTs expression, nerve growth factor (NGF), brain-derived neurotrophic factor 
      (BDNF), and their cognate receptors TrkA and TrkB as they are directly correlated 
      with symptomatic back pain. Furthermore, the neurotransmitter (substance P) was 
      also evaluated in human annulus fibrosus (AF) cells stimulated with cytokines. 
      Human AF cells isolated from normal IVDs were stimulated with interleukin-1beta 
      (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) in the presence or absence of Link N. 
      NGF release in the media was evaluated by Western blotting. Total RNA was 
      isolated and gene expression was measured using real-time PCR. Gene expression of 
      NGF, BDNF, TrkA, and TrkB significantly decreased in human disc cells stimulated 
      with either IL-1beta or TNF-alpha supplemented with Link N when compared to the cells 
      stimulated only with IL-1beta or TNF-alpha. NGF protein expression was also suppressed 
      in AF cells coincubated with Link N and IL-1beta when compared to the cells 
      stimulated only with IL-1beta. Link N can suppress the stimulation of NGF, BDNF, and 
      their receptors TrkA and TrkB in AF cells in an inflammatory milieu. Thus, 
      coupled with previous observations, this suggests that administration of Link N 
      has the potential to not only repair the discs in early stages of the disease but 
      also suppress pain.
FAU - Noorwali, Hussain
AU  - Noorwali H
AD  - Division of Orthopaedic Surgery McGill University Montreal QC Canada.
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
AD  - Division of Orthopaedic Surgery King Abdulaziz University Jeddah Saudi Arabia.
FAU - Grant, Michael P
AU  - Grant MP
AUID- ORCID: 0000-0003-3758-5009
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
FAU - Epure, Laura M
AU  - Epure LM
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
FAU - Madiraju, Padma
AU  - Madiraju P
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
FAU - Sampen, Hee-Jeong
AU  - Sampen HJ
AD  - Department of Biochemistry Rush University Medical Center Chicago Illinois.
FAU - Antoniou, John
AU  - Antoniou J
AD  - Division of Orthopaedic Surgery McGill University Montreal QC Canada.
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
FAU - Mwale, Fackson
AU  - Mwale F
AD  - Division of Orthopaedic Surgery McGill University Montreal QC Canada.
AD  - SMBD-Jewish General Hospital Lady Davis Institute for Medical Research Montreal 
      QC Canada.
LA  - eng
GR  - R01 AR062136/AR/NIAMS NIH HHS/United States
GR  - R21 AR067935/AR/NIAMS NIH HHS/United States
PT  - Journal Article
DEP - 20180315
PL  - United States
TA  - JOR Spine
JT  - JOR spine
JID - 101722350
PMC - PMC6686832
OTO - NOTNLM
OT  - Link N
OT  - discogenic pain
OT  - intervertebral disc
OT  - low back pain
COIS- The authors declare no potential conflict of interests.
EDAT- 2018/03/15 00:00
MHDA- 2018/03/15 00:01
PMCR- 2018/03/15
CRDT- 2019/08/30 06:00
PHST- 2018/01/15 00:00 [received]
PHST- 2018/02/19 00:00 [revised]
PHST- 2018/02/19 00:00 [accepted]
PHST- 2019/08/30 06:00 [entrez]
PHST- 2018/03/15 00:00 [pubmed]
PHST- 2018/03/15 00:01 [medline]
PHST- 2018/03/15 00:00 [pmc-release]
AID - JSP21008 [pii]
AID - 10.1002/jsp2.1008 [doi]
PST - epublish
SO  - JOR Spine. 2018 Mar 15;1(1):e1008. doi: 10.1002/jsp2.1008. eCollection 2018 Mar.