NMDAR blockade-induced neonatal brain injury: Reversal by the calcium channel agonist BayK 8644.
We have previously shown that P7 rat pups injected with the N-methyl-d-aspartate receptor (NMDAR) blocker MK801 displayed robust apoptotic injury within hours after injection. Further studies from our lab suggest that loss of calcium cannot be compensated for when vulnerable neurons lack calcium buffering capabilities. Thus, to elevate calcium in these neurons prior to MK801 exposure, we injected P7 rats with the calcium channel agonist BayK 8644. Whereas BayK 8644 did not induce apoptosis by itself, it was found to block MK801-induced injury in a dose-dependent manner. Reversal of MK801 toxicity was complete in the caudate-putamen, partial in the somatosensory cortex but was not observed in the retrosplenial cortex. These results suggest that postnatal brain injury resulting from agents that block the NMDAR, which include commonly used anesthetics as well as drugs of abuse, may be prevented in vulnerable neurons by compensatory increases in calcium prior to exposure to these antagonists.
Turner
Christopher P
CP
Neurobiology and Anatomy, Wake Forest University School of Medicine, USA. cpturner@wfubmc.edu
Debenedetto
Danielle
D
Liu
Chun
C
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D001925:Brain Damage, Chronic / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology; D002120:Calcium Channel Agonists / Q000494:pharmacology*; D015220:Calcium Channels / Q000187:drug effects / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D016291:Dizocilpine Maleate / Q000633:toxicity; D018691:Excitatory Amino Acid Antagonists / Q000633:toxicity*; D017072:Neostriatum / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013003:Somatosensory Cortex / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D016291:Dizocilpine Maleate; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester