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Methazolamide and melatonin inhibit mitochondrial cytochrome C release and are neuroprotective in experimental models of ischemic injury.

AbstractBACKGROUND AND PURPOSE:
The identification of a neuroprotective drug for stroke remains elusive. Given that mitochondria play a key role both in maintaining cellular energetic homeostasis and in triggering the activation of cell death pathways, we evaluated the efficacy of newly identified inhibitors of cytochrome c release in hypoxia/ischemia induced cell death. We demonstrate that methazolamide and melatonin are protective in cellular and in vivo models of neuronal hypoxia.
METHODS:
The effects of methazolamide and melatonin were tested in oxygen/glucose deprivation-induced death of primary cerebrocortical neurons. Mitochondrial membrane potential, release of apoptogenic mitochondrial factors, pro-IL-1beta processing, and activation of caspase -1 and -3 were evaluated. Methazolamide and melatonin were also studied in a middle cerebral artery occlusion mouse model. Infarct volume, neurological function, and biochemical events were examined in the absence or presence of the 2 drugs.
RESULTS:
Methazolamide and melatonin inhibit oxygen/glucose deprivation-induced cell death, loss of mitochondrial membrane potential, release of mitochondrial factors, pro-IL-1beta processing, and activation of caspase-1 and -3 in primary cerebrocortical neurons. Furthermore, they decrease infarct size and improve neurological scores after middle cerebral artery occlusion in mice.
CONCLUSIONS:
We demonstrate that methazolamide and melatonin are neuroprotective against cerebral ischemia and provide evidence of the effectiveness of a mitochondrial-based drug screen in identifying neuroprotective drugs. Given the proven human safety of melatonin and methazolamide, and their ability to cross the blood-brain-barrier, these drugs are attractive as potential novel therapies for ischemic injury.
AuthorsXin Wang, Bryan E Figueroa, Irina G Stavrovskaya, Yi Zhang, Ana C Sirianni, Shan Zhu, Arthur L Day, Bruce S Kristal, Robert M Friedlander
JournalStroke (Stroke) Vol. 40 Issue 5 Pg. 1877-85 (May 2009) ISSN: 1524-4628 [Electronic] United States
PMID19299628 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
Chemical References
  • Antioxidants
  • Carbonic Anhydrase Inhibitors
  • Interleukin-1beta
  • Neuroprotective Agents
  • Cytochromes c
  • L-Lactate Dehydrogenase
  • Caspase 3
  • Caspase 1
  • Melatonin
  • Methazolamide
Topics
  • Animals
  • Antioxidants (pharmacology)
  • Blotting, Western
  • Brain Ischemia (pathology, prevention & control)
  • Carbonic Anhydrase Inhibitors (pharmacology)
  • Caspase 1 (metabolism)
  • Caspase 3 (metabolism)
  • Cell Death (drug effects)
  • Cytochromes c (metabolism)
  • Enzyme Activation (drug effects)
  • In Situ Nick-End Labeling
  • Interleukin-1beta (metabolism)
  • L-Lactate Dehydrogenase (metabolism)
  • Melatonin (pharmacology)
  • Membrane Potentials (drug effects)
  • Methazolamide (pharmacology)
  • Mice
  • Mice, Inbred C57BL
  • Mitochondria (drug effects, enzymology)
  • Mitochondrial Membranes (drug effects)
  • Neurodegenerative Diseases (pathology)
  • Neurons (pathology)
  • Neuroprotective Agents

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