PMID- 9751147
OWN - NLM
STAT- MEDLINE
DCOM- 19981022
LR  - 20190815
IS  - 0953-816X (Print)
IS  - 0953-816X (Linking)
VI  - 10
IP  - 5
DP  - 1998 May
TI  - Induction of neurosteroid synthesis by NMDA receptors in isolated rat retina: a 
      potential early event in excitotoxicity.
PG  - 1752-63
AB  - Here we investigated the possible regulation of neurosteroidogenesis by 
      N-methyl-D-aspartic acid (NMDA) receptor activation and addressed the hypothesis 
      that neurosteroid synthesis may be involved in acute excitotoxicity. In the 
      isolated retina, exposure to NMDA modified pregnenolone and pregnenolone sulphate 
      formation. This effect was dose and time dependent, the synthesis being increased 
      by relatively moderate NMDA doses (1-100 microM) within 30 min exposure and 
      reduced to its control value by 60 min or by raising drug concentrations. 
      NMDA-stimulated neurosteroid synthesis was blocked by 
      (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclo-hepten-5,10-imine hydrogen 
      maleate (MK-801) and 3(2-carboxypiperazine-4-yl)propyl-1-phosphonic acid (CPP), 
      depended on extracellular calcium and reproduced by glutamate. Lactate 
      dehydrogenase (LDH) release and morphological analysis revealed that retinal cell 
      viability was not significantly affected after 30 min exposure to 50 microM NMDA, 
      but severe cell damage occurred by 60 min. When the GABAA (gamma-aminobutyric 
      acid) receptor agonist muscimol (1-1000 microM), known to activate retinal 
      neurosteroidogenesis, was added together with NMDA, no additional increase in 
      neurosteroid synthesis was observed, and NMDA-induced LDH release remained 
      unchanged. However, exposure to a high concentration of muscimol alone (500 
      microM) provoked a similar degree of toxicity to NMDA. By contrast, bicuculline 
      abolished the increase in neurosteroidogenesis and LDH release. Similarly, 
      pretreatment with R (+)-p-aminoglutethimide (AMG), an inhibitor of cholesterol 
      side-chain cleavage cytochrome P450, attenuated acute retinal cell damage. The 
      inhibitory nature of AMG on NMDA-stimulated neurosteroidogenesis was confirmed in 
      the observation that drug treatment reduced pregnenolone content and did not 
      affect the bindings of [3H] MK-801 and [3H] muscimol. The results demonstrate 
      that NMDA receptors regulate neurosteroidogenesis through a transneuronal 
      mechanism, which implies GABAA receptor activation. The early NMDA-mediated 
      stimulation of neurosteroid synthesis seems to play a critical role in acute 
      excitotoxicity; consequently, its inhibition is likely to delay neuronal cell 
      death.
FAU - Guarneri, P
AU  - Guarneri P
AD  - Istituto di Biologia dello Sviluppo, C.N.R., Palermo, Italy. 
      pguarneri@ibs.pa.cnr.it
FAU - Russo, D
AU  - Russo D
FAU - Cascio, C
AU  - Cascio C
FAU - De Leo, G
AU  - De Leo G
FAU - Piccoli, F
AU  - Piccoli F
FAU - Guarneri, R
AU  - Guarneri R
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - France
TA  - Eur J Neurosci
JT  - The European journal of neuroscience
JID - 8918110
RN  - 0 (Excitatory Amino Acid Antagonists)
RN  - 0 (Receptors, GABA-A)
RN  - 0 (Receptors, N-Methyl-D-Aspartate)
RN  - 04Y4D91RG0 (pregnenolone sulfate)
RN  - 40709-69-1 (bicuculline methiodide)
RN  - 73R90F7MQ8 (Pregnenolone)
RN  - Y37615DVKC (Bicuculline)
SB  - IM
MH  - Animals
MH  - Bicuculline/analogs & derivatives/pharmacology
MH  - Cell Death/drug effects
MH  - Excitatory Amino Acid Antagonists/pharmacology
MH  - In Vitro Techniques
MH  - Male
MH  - Pregnenolone/*biosynthesis
MH  - Rats
MH  - Rats, Wistar
MH  - Receptors, GABA-A/physiology
MH  - Receptors, N-Methyl-D-Aspartate/drug effects/*physiology
MH  - Retina/*drug effects/metabolism/pathology
MH  - Time Factors
EDAT- 1998/09/29 00:00
MHDA- 1998/09/29 00:01
CRDT- 1998/09/29 00:00
PHST- 1998/09/29 00:00 [pubmed]
PHST- 1998/09/29 00:01 [medline]
PHST- 1998/09/29 00:00 [entrez]
AID - 10.1046/j.1460-9568.1998.00191.x [doi]
PST - ppublish
SO  - Eur J Neurosci. 1998 May;10(5):1752-63. doi: 10.1046/j.1460-9568.1998.00191.x.