Dipyrone inhibits neuronal cell death and diminishes hypoxic/ischemic brain injury.

Abstract

BACKGROUND:

Dipyrone is an analgesic and antipyretic drug usually prescribed for patients with inflammatory conditions. We recently identified dipyrone as an antiapoptotic agent by screening a library of 1040 compounds for their ability to inhibit cytochrome c release from isolated mitochondria.

OBJECTIVE:

We investigated the potential neuroprotective properties of dipyrone in cerebral ischemia.

METHODS:

We evaluated the protective effects of dipyrone in experimental models of neuronal hypoxia/ischemia, including an oxygen/glucose deprivation model in primary cerebrocortical neurons and a focal cerebral ischemia model in mice.

RESULTS:

Dipyrone reduced hypoxia/ischemia injury in both cellular and animal models. Dipyrone inhibited the release of cytochrome c and other mitochondrial apoptogenic factors from mitochondria into the cytoplasm, and attenuated subsequent caspase-9 and caspase-3 activation both in vitro and in vivo. Moreover, dipyrone prevented ischemia-induced changes in Bcl-2 and tBid, and ameliorated oxygen/glucose deprivation-mediated loss of mitochondrial membrane potential. Dipyrone also inhibited ischemia-induced reactive microgliosis. In the cellular models evaluated, dipyrone did not inhibit oxygen/glucose deprivation-induced cyclooxygenase-2 activation.

CONCLUSION:

Dipyrone is remarkably neuroprotective in cerebral ischemia, and its cyclooxygenase-independent protective properties are, at least in part, due to the inhibition of mitochondrial cell death cascades.

• Authors: Yi Zhang, Xin Wang, Sergei V Baranov, Shan Zhu, Zhihong Huang, Wendy Fellows-Mayle, Jiying Jiang, Arthur L Day, Bruce S Kristal, Robert M Friedlander
• Journal: Neurosurgery (Neurosurgery) Vol. 69 Issue 4 Pg. 942-56 (Oct 2011) ISSN: 1524-4040 [Electronic] United States
• PMID: 21552169 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Inflammatory Agents, Non-Steroidal
• Neuroprotective Agents
• Dipyrone
• Cyclooxygenase 2

Topics

• Animals
• Anti-Inflammatory Agents, Non-Steroidal (pharmacology)
• Apoptosis (drug effects)
• Blotting, Western
• Cyclooxygenase 2 (metabolism)
• Dipyrone (pharmacology)
• Enzyme-Linked Immunosorbent Assay
• Hypoxia-Ischemia, Brain (drug therapy)
• Immunohistochemistry
• Male
• Membrane Potential, Mitochondrial (drug effects)
• Mice
• Mice, Inbred C57BL
• Neurons (drug effects, metabolism, pathology)
• Neuroprotective Agents (pharmacology)