PMID- 19371576
OWN - NLM
STAT- MEDLINE
DCOM- 20090702
LR  - 20211020
IS  - 1873-7064 (Electronic)
IS  - 0028-3908 (Print)
IS  - 0028-3908 (Linking)
VI  - 56
IP  - 5
DP  - 2009 Apr
TI  - BDNF mediates the neuroprotective effects of positive AMPA receptor modulators 
      against MPP+-induced toxicity in cultured hippocampal and mesencephalic slices.
PG  - 876-85
LID - 10.1016/j.neuropharm.2009.01.015 [doi]
AB  - Neurotoxicity is involved in various neurodegenerative diseases including 
      Parkinson's disease (PD), which affects mesencephalic dopaminergic neurons of the 
      substantia nigra (SN). Positive 
      alpha-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor 
      modulators (PARMs, a.k.a. Ampakines, such as CX614) increase brain-derived 
      neurotrophic factor (BDNF) protein levels in vivo and in cultured hippocampal 
      slices. BDNF is a survival factor for various neuronal cell types including 
      mesencephalic dopaminergic neurons. Using cultured mesencephalic and hippocampal 
      slices, we investigated whether preincubation with CX614 could provide 
      neuroprotection against MPP(+) toxicity and whether such neuroprotection was 
      mediated by BDNF. Various treatment protocols were tested to demonstrate 
      CX614-induced neuroprotection against MPP(+). Pretreatment with CX614 
      significantly reduced MPP(+)-induced toxicity and increased BDNF levels in both 
      hippocampal and mesencephalic cultured slices; CX614 pretreatment for 6 h in 
      hippocampal slices and 24 h in mesencephalic slices was sufficient to produce 
      significant neuroprotection as assessed with lactate dehydrogenase release in 
      slice medium and propidium iodide uptake in slices. Both a BDNF scavenger and an 
      inhibitor of the BDNF receptor TrkB, abrogated CX614-mediated reduction of 
      MPP(+)-induced toxicity. Inhibition of Ca(2+)-activated proteases, calpains, was 
      also protective against MPP(+)-induced toxicity. However, co-application of 
      calpain inhibitor with CX614 abolished CX614-mediated protection, suggesting a 
      dual action of calpains in this model. We conclude that CX614 is neuroprotective 
      against MPP(+)-induced toxicity, an effect mediated by increased BDNF expression 
      and activation of BDNF-dependent signaling pathways. Our results provide support 
      for using PARMs as a new therapy for neurodegenerative disorders, including PD.
FAU - Jourdi, H
AU  - Jourdi H
AD  - Neurobiology, University of Southern California, 3641 Watt way, Los Angeles, CA 
      90089-2520, USA.
FAU - Hamo, L
AU  - Hamo L
FAU - Oka, T
AU  - Oka T
FAU - Seegan, A
AU  - Seegan A
FAU - Baudry, M
AU  - Baudry M
LA  - eng
GR  - P01 NS045260/NS/NINDS NIH HHS/United States
GR  - R01 NS048521/NS/NINDS NIH HHS/United States
GR  - NS048521-02/NS/NINDS NIH HHS/United States
GR  - P01NS045260-01/NS/NINDS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
DEP - 20090121
PL  - England
TA  - Neuropharmacology
JT  - Neuropharmacology
JID - 0236217
RN  - 0 (Brain-Derived Neurotrophic Factor)
RN  - 0 (Neuroprotective Agents)
RN  - 0 (Oxazines)
RN  - 0 (Receptors, AMPA)
RN  - 87V631480W (2H,3H,6aH-pyrrolidino(2'',1''-3',2')1,3-oxazino(6',5'-5,4)benzo(e)1, 
      4-dioxan-10-one)
RN  - EC 1.1.1.27 (L-Lactate Dehydrogenase)
RN  - EC 2.7.10.1 (Protein-Tyrosine Kinases)
RN  - EC 3.4.22.- (Calpain)
RN  - R865A5OY8J (1-Methyl-4-phenylpyridinium)
SB  - IM
MH  - 1-Methyl-4-phenylpyridinium/*toxicity
MH  - Allosteric Regulation
MH  - Animals
MH  - Animals, Newborn
MH  - Brain-Derived Neurotrophic Factor/biosynthesis/*physiology
MH  - Calpain/antagonists & inhibitors
MH  - Hippocampus/*drug effects/metabolism/pathology
MH  - L-Lactate Dehydrogenase/metabolism
MH  - Mesencephalon/*drug effects/metabolism/pathology
MH  - Neuroprotective Agents/*pharmacology
MH  - Oxazines/*pharmacology
MH  - Protein-Tyrosine Kinases/antagonists & inhibitors
MH  - Rats
MH  - Rats, Sprague-Dawley
MH  - Receptors, AMPA/*physiology
MH  - Tissue Culture Techniques
PMC - PMC3659791
MID - NIHMS469083
EDAT- 2009/04/18 09:00
MHDA- 2009/07/03 09:00
PMCR- 2013/05/21
CRDT- 2009/04/18 09:00
PHST- 2008/08/01 00:00 [received]
PHST- 2008/12/24 00:00 [revised]
PHST- 2009/01/13 00:00 [accepted]
PHST- 2009/04/18 09:00 [entrez]
PHST- 2009/04/18 09:00 [pubmed]
PHST- 2009/07/03 09:00 [medline]
PHST- 2013/05/21 00:00 [pmc-release]
AID - S0028-3908(09)00028-8 [pii]
AID - 10.1016/j.neuropharm.2009.01.015 [doi]
PST - ppublish
SO  - Neuropharmacology. 2009 Apr;56(5):876-85. doi: 10.1016/j.neuropharm.2009.01.015. 
      Epub 2009 Jan 21.