Mechanisms of 1S,3R-ACPD-induced neuroprotection in rat hippocampal slices subjected to oxygen and glucose deprivation.
The efficacy and mechanisms of 1-amino-cyclopentyl-1S,3R-dicarboxylate (1S,3R-ACPD)-induced neuroprotection were investigated in rat hippocampal slices subjected to 10 min of oxygen and glucose deprivation. Neuronal viability was assessed by measuring both the amplitude of evoked population spike in the CA1 pyramidale and by imaging CA1 neurons using a live/dead fluorescence assay with confocal microscopy. CA1 pyramidal neurons in oxygen-glucose deprived slices remained viable for up to 120 min following the insult but were dead by 240 min. Pretreatment with 1S,3R-ACPD significantly protected the oxygen-glucose deprived slices in a concentration-dependent fashion. Oxygen-glucose deprived slices pretreated for the same period with the protein kinase C (PKC) activation phorbol 12-myristate 13-acetate (PMA; 1 microM) were significantly protected whereas oxygen-glucose deprived slices treated with the adenylyl cyclase activator, forskolin (30 microM) were not. Oxygen-glucose deprivation induced a rapid and persistent decrease (approximately 50%) in PKC activity and a > 6 fold increase in cyclic adenosine monophosphate (cAMP) levels in whole hippocampal slices. While 1S,3R-ACPD did not stimulate PKC activity and had no effect on basal cAMP in whole slices, it significantly enhanced the rate of return of cAMP to basal levels following reperfusion. Consistent with this observation, the 1S,3R-ACPD-induced neuroprotection was inhibited by forskolin (30 microM). These results suggest that in vitro neuroprotection of CA1 neurons by 1S,3R-ACPD involves metabotropic glutamate receptors negatively linked to cAMP and possibly those which increase PKC activity.
Small
D L
DL
Institute for Biological Sciences, National Research Council of Canada, Ottawa, Canada. small@biologym54.lan.nrc.ca
Monette
R
R
Chakravarthy
B
B
Durkin
J
J
Barbe
G
G
Mealing
G
G
Morley
P
P
Buchan
A M
AM
D000818:Animals; D000242:Cyclic AMP / Q000037:antagonists & inhibitors / Q000378:metabolism; D003515:Cycloleucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D005947:Glucose / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology; D002534:Hypoxia, Brain / Q000201:enzymology / Q000473:pathology*; D066298:In Vitro Techniques; D008297:Male; D018613:Microscopy, Confocal; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology; D015398:Signal Transduction / Q000187:drug effects
D018696:Neuroprotective Agents; D003515:Cycloleucine; C036361:1-amino-1,3-dicarboxycyclopentane; D000242:Cyclic AMP; D011493:Protein Kinase C; D005947:Glucose