Propofol anesthesia induces proapoptotic tumor necrosis factor-α and pro-nerve growth factor signaling and prosurvival Akt and XIAP expression in neonatal rat brain.
Previously we observed that prolonged exposure to propofol anesthesia causes caspase-3- and calpain-mediated neuronal death in the developing brain. The present study examines the effects of propofol anesthesia on the expression of tumor necrosis factor-α (TNFα), pro-nerve growth factor (NGF), and their receptors in the cortex and the thalamus. We also investigated how propofol influences the expression of Akt and X-linked inhibitor of apoptosis (XIAP) expression, proteins that promote prosurvival pathways. Seven-day-old rats (P7) were exposed to propofol anesthesia lasting 2, 4, or 6 hr and killed 0, 4, 16, or 24 hr after anesthesia termination. The relative levels of mRNA and protein expression were estimated by RT-PCR and Western blot analysis, respectively. The treatments caused marked activation of TNFα and its receptor TNFR-1 and pro-NGF and p75(NTR) receptor expression. In parallel with the induction of these prodeath signals, we established that propofol anesthesia promotes increased expression of the prosurvival molecules pAkt and XIAP during the 24-hr postanesthesia period. These results show that different brain structures respond to propofol anesthesia with a time- and duration of exposure-dependent increase in proapoptotic signaling and with concomitant increases in activities of prosurvival proteins. We hypothesized that the fine balance between these opposing processes sustains homeostasis in the immature rat brain and prevents unnecessary damage after exposure to an injurious stimulus. The existence of this highly regulated process provides a time frame for potential therapeutic intervention directed toward suppressing the deleterious component of propofol anesthesia.
Department of Neurobiology, Institute for Biological Research, University of Belgrade, Belgrade, Republic of Serbia.
Desanka
D
Milanović
Vesna
V
Pešić
Jelena
J
Popić
Nikola
N
Tanić
Selma
S
Kanazir
Vesna
V
Jevtović-Todorović
Sabera
S
Ruždijić
D000704:Analysis of Variance; D018686:Anesthetics, Intravenous / Q000494:pharmacology*; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000254:growth & development; D005786:Gene Expression Regulation / Q000187:drug effects; D008297:Male; D020932:Nerve Growth Factor / Q000378:metabolism*; D009419:Nerve Tissue Proteins; D051058:Oncogene Protein v-akt / Q000378:metabolism*; D015742:Propofol / Q000494:pharmacology*; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000378:metabolism*
D018686:Anesthetics, Intravenous; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger; D017978:Receptors, Growth Factor; D017475:Receptors, Nerve Growth Factor; D014409:Tumor Necrosis Factor-alpha; D051636:X-Linked Inhibitor of Apoptosis Protein; C068313:Ngfr protein, rat; D020932:Nerve Growth Factor; D051058:Oncogene Protein v-akt; D015742:Propofol
neonatal rat; neurotoxicity; propofol anesthesia; prosurvival proteins