General anesthesia activates BDNF-dependent neuroapoptosis in the developing rat brain.
Brain-derived neurotrophic factor (BDNF) is important in supporting neuronal development. BDNF imbalance due to excessive neuronal inhibition can result in the apoptotic degeneration of developing neurons. Since general anesthetics cause profound depression of neuronal activity and are known to induce widespread degeneration in the developing brain, we studied their potential to activate BDNF-mediated developmental neuroapoptosis. When P7 rats (at the peak of brain development) were exposed to a commonly-used and highly pro-apoptotic anesthesia protocol (midazolam, isoflurane, nitrous oxide) for a period of 2, 4 or 6 h, we found that anesthesia modulates the key steps in BDNF-activated apoptotic cascade in two of the most vulnerable brain regions--cerebral cortex and thalamus in time-dependent fashion by activating both Trk-dependent (in thalamus) and Trk-independent p75NTR dependent (in cerebral cortex) neurotrophic pathways. beta-estradiol, a sex hormone that upregulates the protein levels of the activated Akt, protects against anesthesia-induced neuroapoptosis.
Lu
Lucy X
LX
Department of Anasthesiology, University of Virginia Health System, P.O. Box 800710, Charlottesville, 22908, USA.
Yon
Jun-Heum
JH
Carter
Lisa B
LB
Jevtovic-Todorovic
Vesna
V
D000768:Anesthesia, General / Q000009:adverse effects*; D000777:Anesthetics / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D001921:Brain / Q000187:drug effects / Q000254:growth & development*; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism / Q000502:physiology*; D002540:Cerebral Cortex / Q000187:drug effects / Q000254:growth & development; D015536:Down-Regulation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D008954:Models, Biological; D009410:Nerve Degeneration / Q000139:chemically induced; D009474:Neurons / Q000187:drug effects*; D051058:Oncogene Protein v-akt / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012131:Respiratory Insufficiency / Q000139:chemically induced; D015398:Signal Transduction / Q000187:drug effects; D013788:Thalamus / Q000187:drug effects / Q000254:growth & development
D000777:Anesthetics; D019208:Brain-Derived Neurotrophic Factor; D015513:Oncogene Proteins; C065400:oncogene protein trk; D004958:Estradiol; D051058:Oncogene Protein v-akt