Journal
NEUROBIOLOGY OF DISEASE
Volume 21, Issue 3, Pages 522-530Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.nbd.2005.08.011
Keywords
synaptogenesis; apoptosis; caspase; bcl-2; cytochrome c; mitochondria
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Funding
- NIA NIH HHS [AG 11355] Funding Source: Medline
- NICHD NIH HHS [HD 44517] Funding Source: Medline
- NIDA NIH HHS [K08-DA00406] Funding Source: Medline
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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, bel-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. (C) 2005 Elsevier Inc. All rights reserved.
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