PMID- 29029315
OWN - NLM
STAT- MEDLINE
DCOM- 20190128
LR  - 20240313
IS  - 1096-0929 (Electronic)
IS  - 1096-6080 (Print)
IS  - 1096-0929 (Linking)
VI  - 161
IP  - 1
DP  - 2018 Jan 1
TI  - From the Cover: 7,8-Dihydroxyflavone Rescues Lead-Induced Impairment of Vesicular 
      Release: A Novel Therapeutic Approach for Lead Intoxicated Children.
PG  - 186-195
LID - 10.1093/toxsci/kfx210 [doi]
AB  - Childhood lead (Pb2+) intoxication is a public health problem of global 
      proportion. Lead exposure during development produces multiple effects on the 
      central nervous system including impaired synapse formation, altered synaptic 
      plasticity, and learning deficits. In primary hippocampal neurons in culture and 
      hippocampal slices, Pb2+ exposure inhibits vesicular release and reduces the 
      number of fast-releasing sites, an effect associated with Pb2+ inhibition of NMDA 
      receptor-mediated trans-synaptic Brain-Derived Neurotrophic Factor (BDNF) 
      signaling. The objective of this study was to determine if activation of TrkB, 
      the cognate receptor for BDNF, would rescue Pb2+-induced impairments of vesicular 
      release. Rats were chronically exposed to Pb2+ prenatally and postnatally until 
      50 days of age. This chronic Pb2+ exposure paradigm enhanced paired-pulse 
      facilitation of synaptic potentials in Schaffer collateral-CA1 synapses in the 
      hippocampus, a phenomenon indicative of reduced vesicular release probability. 
      Decreased vesicular release probability was confirmed by both mean-variance 
      analysis and direct 2-photon imaging of vesicular release from hippocampal slices 
      of rats exposed to Pb2+in vivo. We also found a Pb2+-induced impairment of 
      calcium influx in Schaffer collateral-CA1 synaptic terminals. Intraperitoneal 
      injections of Pb2+ rats with the TrkB receptor agonist 7,8-dihydroxyflavone 
      (5 mg/kg) for 14-15 days starting at postnatal day 35, reversed all Pb2+-induced 
      impairments of presynaptic transmitter release at Schaffer collateral-CA1 
      synapses. This study demonstrates for the first time that in vivo pharmacological 
      activation of TrkB receptors by small molecules such as 7,8-dihydroxyflavone can 
      reverse long-term effects of chronic Pb2+ exposure on presynaptic terminals, 
      pointing to TrkB receptor activation as a promising therapeutic intervention in 
      Pb2+-intoxicated children.
CI  - (c) The Author 2017. Published by Oxford University Press on behalf of the Society 
      of Toxicology. All rights reserved. For Permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Zhang, Xiao-Lei
AU  - Zhang XL
AD  - Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New 
      York 10595.
FAU - McGlothan, Jennifer L
AU  - McGlothan JL
AD  - Department of Environmental & Occupational Health, Robert Stempel College of 
      Public Health & Social Work, Florida International University, Miami, Florida 
      33199.
FAU - Miry, Omid
AU  - Miry O
AD  - Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New 
      York 10595.
FAU - Stansfield, Kirstie H
AU  - Stansfield KH
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032.
FAU - Loth, Meredith K
AU  - Loth MK
AD  - Department of Environmental & Occupational Health, Robert Stempel College of 
      Public Health & Social Work, Florida International University, Miami, Florida 
      33199.
AD  - Department of Environmental Health Sciences, Mailman School of Public Health, 
      Columbia University, New York, New York 10032.
FAU - Stanton, Patric K
AU  - Stanton PK
AD  - Department of Cell Biology & Anatomy, New York Medical College, Valhalla, New 
      York 10595.
FAU - Guilarte, Tomas R
AU  - Guilarte TR
AD  - Department of Environmental & Occupational Health, Robert Stempel College of 
      Public Health & Social Work, Florida International University, Miami, Florida 
      33199.
LA  - eng
GR  - R01 ES006189/ES/NIEHS NIH HHS/United States
GR  - R01 ES020465/ES/NIEHS NIH HHS/United States
GR  - T32 ES007322/ES/NIEHS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PL  - United States
TA  - Toxicol Sci
JT  - Toxicological sciences : an official journal of the Society of Toxicology
JID - 9805461
RN  - 0 (6,7-dihydroxyflavone)
RN  - 0 (Flavones)
RN  - 2P299V784P (Lead)
SB  - IM
MH  - Animals
MH  - CA1 Region, Hippocampal/drug effects/physiopathology
MH  - Calcium Signaling/drug effects
MH  - Disease Models, Animal
MH  - Evoked Potentials/drug effects
MH  - Female
MH  - Flavones/*pharmacology
MH  - Lead/blood/*toxicity
MH  - Lead Poisoning, Nervous System, Childhood/*prevention & control
MH  - Neuronal Plasticity/drug effects
MH  - Patch-Clamp Techniques
MH  - Presynaptic Terminals/*drug effects/ultrastructure
MH  - Pyramidal Cells/drug effects/ultrastructure
MH  - Rats, Long-Evans
MH  - Synaptic Transmission/*drug effects
MH  - Synaptic Vesicles/*drug effects/ultrastructure
PMC - PMC5837521
OTO - NOTNLM
OT  - 7,8-dihydroxyflavone (7,8-DHF)
OT  - brain derived neurotrophic factor (BDNF)
OT  - lead (Pb2+) neurotoxicity
OT  - vesicular release
EDAT- 2017/10/14 06:00
MHDA- 2019/01/29 06:00
PMCR- 2019/01/01
CRDT- 2017/10/14 06:00
PHST- 2017/10/14 06:00 [pubmed]
PHST- 2019/01/29 06:00 [medline]
PHST- 2017/10/14 06:00 [entrez]
PHST- 2019/01/01 00:00 [pmc-release]
AID - 4344844 [pii]
AID - kfx210 [pii]
AID - 10.1093/toxsci/kfx210 [doi]
PST - ppublish
SO  - Toxicol Sci. 2018 Jan 1;161(1):186-195. doi: 10.1093/toxsci/kfx210.