PMID- 25329107
OWN - NLM
STAT- MEDLINE
DCOM- 20150825
LR  - 20171116
IS  - 2066-8279 (Electronic)
IS  - 1220-0522 (Linking)
VI  - 55
IP  - 3
DP  - 2014
TI  - The single versus combinatorial effects of MK-801, CNQX, Nifedipine and AP-3 on 
      primary cultures of cerebellar granule cells in an oxygen-glucose deprivation 
      model.
PG  - 811-6
AB  - The excitotoxicity cascade associated with energetic failure during and after 
      cerebral ischemia involves the overactivation of glutamate receptors and 
      intracellular calcium loading. We searched for synergistic neuroprotective 
      effects of various drugs designed to prevent intracellular calcium influx in a 
      model of oxygen-glucose deprivation (OGD) in cerebellar granule cells primary 
      cultures. 
      (5S,10R)-(-)-5-Methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine 
      hydrogen maleate (MK-801), D,L-2-Amino-3-phosphonopropionic acid (AP-3), 
      6-Cyano-7-nitroquinoxaline-2,3-dione disodium salt (CNQX) and Nifedipine were 
      tested alone or in combinations. Treatments were applied during a two-hour OGD 
      exposure and cellular outcome was assessed throughout 20-hour reoxygenation by 
      the measurement of Propidium Iodide (PI) fluorescence. All treatments were able 
      to prevent neuronal damage. OGD resulted in a mortality of 36.3+/-2.3% and 
      61.3+/-3.1% after 10 and 20 hours of reoxygenation, respectively. The most 
      effective single treatment was AP-3 (3.3+/-1.4%; 17.9+/-2.6% mortality after 10 and 
      20 hours), followed in order by Nifedipine (7.2+/-1.6%; 20.1+/-3.0%), CNQX (8.5+/-2.5%; 
      20.0+/-3.5%), and MK-801 (14.9+/-2.6%; 39.3+/-6.4%). The combination of AP-3 with 
      MK-801 showed a moderate synergistic effect (11.8+/-2.0% mortality at 20 hours), 
      while the combinations of CNQX with Nifedipine and CNQX with MK-801, as well as 
      the triple mix CNQX, Nifedipine and MK-801 failed to show a further improvement 
      in the reduction of cellular death. In conclusion, targeting two mechanisms of 
      cellular demise (ionotropic receptors and metabotropic glutamate receptors) 
      provided an advantage against several unimodal strategies (blocking calcium entry 
      through ionotropic glutamate receptors and L-type calcium channels). Our results 
      suggest that a multimodal combinatorial treatment strategy in cerebral ischemia 
      may increase neuroprotective efficacy and call for further research.
FAU - Zagrean, Ana Maria
AU  - Zagrean AM
AD  - Division of Physiology and Fundamental Neuroscience, "Carol Davila" University of 
      Medicine and Pharmacy, Bucharest, Romania; azagrean@umf.ro, azagrean@gmail.com.
FAU - Spataru, Ana
AU  - Spataru A
FAU - Ceanga, Mihai
AU  - Ceanga M
FAU - Zagrean, Leon
AU  - Zagrean L
LA  - eng
PT  - Comparative Study
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - Romania
TA  - Rom J Morphol Embryol
JT  - Romanian journal of morphology and embryology = Revue roumaine de morphologie et 
      embryologie
JID - 9112454
RN  - 0H89G8110O (2-amino-3-phosphonopropionic acid)
RN  - 36015-30-2 (Propidium)
RN  - 6LR8C1B66Q (Dizocilpine Maleate)
RN  - 6OTE87SCCW (6-Cyano-7-nitroquinoxaline-2,3-dione)
RN  - I9ZF7L6G2L (Nifedipine)
RN  - IY9XDZ35W2 (Glucose)
RN  - OF5P57N2ZX (Alanine)
RN  - S88TT14065 (Oxygen)
SB  - IM
MH  - 6-Cyano-7-nitroquinoxaline-2,3-dione/*pharmacology
MH  - Alanine/*analogs & derivatives/pharmacology
MH  - Animals
MH  - Cell Death/drug effects
MH  - Cells, Cultured
MH  - Cerebellum/*pathology
MH  - Dizocilpine Maleate/*pharmacology
MH  - Drug Therapy, Combination
MH  - Fluorescence
MH  - Glucose/*deficiency
MH  - Nifedipine/*pharmacology
MH  - Oxygen/*metabolism
MH  - Propidium/metabolism
MH  - Rats
EDAT- 2014/10/21 06:00
MHDA- 2015/08/26 06:00
CRDT- 2014/10/21 06:00
PHST- 2014/10/21 06:00 [entrez]
PHST- 2014/10/21 06:00 [pubmed]
PHST- 2015/08/26 06:00 [medline]
AID - 550314811816 [pii]
PST - ppublish
SO  - Rom J Morphol Embryol. 2014;55(3):811-6.