Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain.
General anesthetics cause widespread apoptotic neurodegeneration in many regions of the developing rat brain. The activation of mitochondria-dependent apoptotic pathway is important in the early stages of anesthesia-induced developmental neuroapoptosis. To investigate potential means of protecting against this type of damage, we studied melatonin, a sleep-promoting agent and antioxidant known to inhibit apoptotic-type neuronal damage by improving mitochondrial homeostasis and stabilizing the inner mitochondrial membrane. When 7-day-old rats (the peak of synaptogenesis) were exposed to a commonly used and highly pro-apoptotic anesthesia cocktail (midazolam, isoflurane, nitrous oxide) in combination with the escalating doses of melatonin (from 1 to 20 mg/kg, s.c.), the severity of anesthesia-induced damage was reduced in a dose-dependent manner in two most vulnerable brain regions--the cerebral cortex and anterior thalamus. Melatonin-induced neuroprotection was mediated, at least in part, via the inhibition of mitochondria-dependent apoptotic pathway since melatonin caused an up-regulation of the anti-apoptotic protein, bcl-X(L), reduction in anesthesia-induced cytochrome c release into the cytoplasm and a decrease in anesthesia-induced activation of caspase-3, an important step in the activation of DNAses and the formation of the apoptotic bodies.
Yon
Jun-Heum
JH
Department of Anesthesiology, University of Virginia Health System, PO Box 800710, Charlottesville, VA 22908, USA.
Carter
Lisa B
LB
Reiter
Russel J
RJ
Jevtovic-Todorovic
Vesna
V
D018681:Anesthetics, General / Q000009:adverse effects*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001921:Brain / Q000187:drug effects* / Q000254:growth & development / Q000473:pathology; D053148:Caspase 3; D020169:Caspases / Q000187:drug effects; D045304:Cytochromes c / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D008550:Melatonin / Q000627:therapeutic use*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D009410:Nerve Degeneration / Q000139:chemically induced / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D051020:bcl-X Protein / Q000187:drug effects
D018681:Anesthetics, General; D018696:Neuroprotective Agents; D051020:bcl-X Protein; D045304:Cytochromes c; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D008550:Melatonin