Melatonin reduces the severity of anesthesia-induced apoptotic neurodegeneration in the developing rat brain

Jun Heum Yon, Lisa B. Carter, Russel J. Reiter, Vesna Jevtovic-Todorovic

Research output: Contribution to journalArticlepeer-review

177 Scopus citations


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-XL, 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.

Original languageEnglish (US)
Pages (from-to)522-530
Number of pages9
JournalNeurobiology of Disease
Issue number3
StatePublished - Mar 2006


  • Apoptosis
  • Caspase
  • Cytochrome c
  • Mitochondria
  • Synaptogenesis
  • bcl-2

ASJC Scopus subject areas

  • Neurology


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