PMID- 29939872
OWN - NLM
STAT- MEDLINE
DCOM- 20190222
LR  - 20240328
IS  - 1473-558X (Electronic)
IS  - 0959-4965 (Print)
IS  - 0959-4965 (Linking)
VI  - 29
IP  - 12
DP  - 2018 Aug 15
TI  - Homocysteine sensitizes the mouse neuromuscular junction to oxidative stress by 
      nitric oxide.
PG  - 1030-1035
LID - 10.1097/WNR.0000000000001073 [doi]
AB  - Homocysteine (HCY), a redox-active metabolite of the methionine cycle, is of 
      particular clinical interest because of its association with various 
      neurodegenerative diseases including amyotrophic lateral sclerosis. It has been 
      previously established that HCY exacerbates damage to motor neurons from reactive 
      oxygen species (ROS) such as hydrogen peroxide. To assess the role of HCY at the 
      mammalian neuromuscular junction, neurotransmission was monitored by 
      electrophysiology at the mouse epitrochleoanconeus muscle. Preparations were 
      preincubated in HCY before inducing ROS and recordings were taken before and 
      after ROS treatment. In this study, HCY was observed to sensitize the 
      neuromuscular junction to ROS-induced depression of spontaneous transmission 
      frequency, an effect we found to be mediated by a N-methyl-D-aspartate receptor 
      (NMDAR) and nitric oxide (NO). The NMDAR antagonist D, 
      L-2-amino-5-phosphonopentanoic acid prevented the HCY-induced sensitization to 
      oxidative stress. Disrupting NO activity with either the nitric oxide synthase I 
      antagonist Nomega-nitro-L-arginine methyl ester hydrochloride or the NO scavenger 
      2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide potassium salt 
      also prevented sensitization. Moreover, replacing HCY with the exogenous NO donor 
      Diethylamine NONOate diethylammonium was sufficient to reconstitute the effects 
      of HCY-induced sensitization to ROS. Interestingly, a novel secondary effect was 
      observed where HCY itself depresses quantal content, an effect found to be 
      mediated by NMDARs independently of nitric oxide and ROS. Collectively, these 
      data present a novel model of two distinct pathways through which HCY alters 
      neurotransmission at the neuromuscular junction. Characterizing HCY's mechanism 
      of action is of particular clinical relevance as many treatments for amyotrophic 
      lateral sclerosis are centered on mitigating HCY-induced pathologies.
FAU - Wang, John S
AU  - Wang JS
AD  - Department of Biology, Grinnell College, Grinnell, Iowa, USA.
FAU - Bojovic, Danica
AU  - Bojovic D
FAU - Chen, Yang
AU  - Chen Y
FAU - Lindgren, Clark A
AU  - Lindgren CA
LA  - eng
GR  - R15 NS072735/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - England
TA  - Neuroreport
JT  - Neuroreport
JID - 9100935
RN  - 0 (Nitric Oxide Donors)
RN  - 0 (Reactive Oxygen Species)
RN  - 0LVT1QZ0BA (Homocysteine)
RN  - 31C4KY9ESH (Nitric Oxide)
SB  - IM
MH  - Animals
MH  - Excitatory Postsynaptic Potentials/drug effects/physiology
MH  - Homocysteine/*pharmacology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Neuromuscular Junction/drug effects/*metabolism
MH  - Nitric Oxide/agonists/antagonists & inhibitors/*metabolism
MH  - Nitric Oxide Donors/pharmacology
MH  - Organ Culture Techniques
MH  - Oxidative Stress/drug effects/*physiology
MH  - Reactive Oxygen Species/metabolism
PMC - PMC6044473
MID - NIHMS972467
COIS- There are no conflicts of interest.
EDAT- 2018/06/26 06:00
MHDA- 2019/02/23 06:00
PMCR- 2019/08/15
CRDT- 2018/06/26 06:00
PHST- 2018/06/26 06:00 [pubmed]
PHST- 2019/02/23 06:00 [medline]
PHST- 2018/06/26 06:00 [entrez]
PHST- 2019/08/15 00:00 [pmc-release]
AID - 10.1097/WNR.0000000000001073 [doi]
PST - ppublish
SO  - Neuroreport. 2018 Aug 15;29(12):1030-1035. doi: 10.1097/WNR.0000000000001073.