PMID- 22442695
OWN - NLM
STAT- MEDLINE
DCOM- 20120723
LR  - 20220309
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 7
IP  - 3
DP  - 2012
TI  - Brain-derived neurotrophic factor ameliorates brain stem cardiovascular 
      dysregulation during experimental temporal lobe status epilepticus.
PG  - e33527
LID - 10.1371/journal.pone.0033527 [doi]
LID - e33527
AB  - BACKGROUND: Status epilepticus (SE) is an acute, prolonged epileptic crisis with 
      a mortality rate of 20-30%; the underlying mechanism is not completely 
      understood. We assessed the hypothesis that brain stem cardiovascular 
      dysregulation occurs during SE because of oxidative stress in rostral 
      ventrolateral medulla (RVLM), a key nucleus of the baroreflex loop; to be 
      ameliorated by brain-derived neurotrophic factor (BDNF) via an antioxidant 
      action. METHODOLOGY/PRINCIPAL FINDINGS: In a clinically relevant experimental 
      model of temporal lobe SE (TLSE) using Sprague-Dawley rats, sustained hippocampal 
      seizure activity was accompanied by progressive hypotension that was preceded by 
      a reduction in baroreflex-mediated sympathetic vasomotor tone; heart rate and 
      baroreflex-mediated cardiac responses remained unaltered. Biochemical experiments 
      further showed concurrent augmentation of superoxide anion, phosphorylated 
      p47(phox) subunit of NADPH oxidase and mRNA or protein levels of BDNF, 
      tropomyosin receptor kinase B (TrkB), angiotensin AT1 receptor subtype (AT1R), 
      nitric oxide synthase II (NOS II) or peroxynitrite in RVLM. Whereas pretreatment 
      by microinjection bilaterally into RVLM of a superoxide dismutase mimetic 
      (tempol), a specific antagonist of NADPH oxidase (apocynin) or an AT1R antagonist 
      (losartan) blunted significantly the augmented superoxide anion or phosphorylated 
      p47(phox) subunit in RVLM, hypotension and the reduced baroreflex-mediated 
      sympathetic vasomotor tone during experimental TLSE, pretreatment with a 
      recombinant human TrkB-Fc fusion protein or an antisense bdnf oligonucleotide 
      significantly potentiated all those events, alongside peroxynitrite. However, 
      none of the pretreatments affected the insignificant changes in heart rate and 
      baroreflex-mediated cardiac responses. CONCLUSIONS/SIGNIFICANCE: We conclude that 
      formation of peroxynitrite by a reaction between superoxide anion generated by 
      NADPH oxidase in RVLM on activation by AT1R and NOS II-derived NO leads to a 
      reduction in baroreflex-mediated sympathetic vasomotor tone during experimental 
      TLSE; to be ameliorated by the upregulated BDNF/TrkB signaling via inhibition of 
      p47(phox) phosphorylation. This information offers a new vista in devising 
      therapeutic strategy towards minimizing mortality associated with TLSE.
FAU - Tsai, Ching-Yi
AU  - Tsai CY
AD  - Center for Translational Research in Biomedical Sciences, Kaohsiung Chang Gung 
      Memorial Hospital, Kaohsiung, Taiwan, Republic of China.
FAU - Chan, Julie Y H
AU  - Chan JY
FAU - Hsu, Kuei-sen
AU  - Hsu KS
FAU - Chang, Alice Y W
AU  - Chang AY
FAU - Chan, Samuel H H
AU  - Chan SH
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20120319
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (Acetophenones)
RN  - 0 (Antioxidants)
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Cyclic N-Oxides)
RN  - 0 (Enzyme Inhibitors)
RN  - 0 (RNA, Messenger)
RN  - 0 (Receptor, Angiotensin, Type 1)
RN  - 0 (Spin Labels)
RN  - 11062-77-4 (Superoxides)
RN  - 14691-52-2 (Peroxynitrous Acid)
RN  - B6J7B9UDTR (acetovanillone)
RN  - EC 1.14.13.39 (Nitric Oxide Synthase Type II)
RN  - EC 1.14.13.39 (Nos2 protein, rat)
RN  - EC 1.6.3.- (NADPH Oxidases)
RN  - EC 1.6.3.1 (neutrophil cytosolic factor 1)
RN  - EC 2.7.10.1 (Receptor, trkB)
RN  - JMS50MPO89 (Losartan)
RN  - U78ZX2F65X (tempol)
SB  - IM
MH  - Acetophenones/pharmacology
MH  - Animals
MH  - Antioxidants/*metabolism
MH  - Brain Stem
MH  - Brain-Derived Neurotrophic Factor
MH  - Cardiovascular System/*metabolism/physiopathology
MH  - Cyclic N-Oxides/pharmacology
MH  - Enzyme Inhibitors/pharmacology
MH  - Epilepsy, Temporal Lobe/*metabolism/pathology/physiopathology/therapy
MH  - Humans
MH  - Losartan/pharmacology
MH  - NADPH Oxidases/antagonists & inhibitors/metabolism
MH  - Nitric Oxide Synthase Type II/metabolism
MH  - Oxidative Stress/drug effects
MH  - Peroxynitrous Acid/metabolism
MH  - Phosphorylation/drug effects
MH  - RNA, Messenger/metabolism
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptor, Angiotensin, Type 1/metabolism
MH  - Receptor, trkB/antagonists & inhibitors/metabolism
MH  - Spin Labels
MH  - Status Epilepticus/*metabolism/pathology/physiopathology/therapy
MH  - Superoxides/metabolism
PMC - PMC3307740
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2012/03/24 06:00
MHDA- 2012/07/24 06:00
PMCR- 2012/03/19
CRDT- 2012/03/24 06:00
PHST- 2011/11/22 00:00 [received]
PHST- 2012/02/14 00:00 [accepted]
PHST- 2012/03/24 06:00 [entrez]
PHST- 2012/03/24 06:00 [pubmed]
PHST- 2012/07/24 06:00 [medline]
PHST- 2012/03/19 00:00 [pmc-release]
AID - PONE-D-11-23227 [pii]
AID - 10.1371/journal.pone.0033527 [doi]
PST - ppublish
SO  - PLoS One. 2012;7(3):e33527. doi: 10.1371/journal.pone.0033527. Epub 2012 Mar 19.