Dynamics of intracellular calcium and free radical production during ischemia in pyramidal neurons.

Abstract

Biochemical cascades initiated by oxidative stress and excitotoxic intracellular calcium rises are thought to converge on mitochondrial dysfunction. We investigated the contribution of mitochondrial dysfunction to free radical (FR) overproduction in rat CA1 pyramidal neurons of organotypic slices subjected to a hypoxic-hypoglycemic insult. Ischemia-induced FR generation was decreased by the mitochondrial complex I blocker, rotenone, indicating that mitochondria are the principal source of ischemic FR production. Measurements of mitochondrial calcium with the mitochondrial calcium probe dihydroRhod-2, revealed that FR production during and after the anoxic episode correlates with the accumulation of mitochondrial calcium. However, the mitochondrial calcium uptake inhibitor Ru360 did not prevent FR generation during ischemia and attenuated it to some degree during reoxygenation. On the other hand, the mitochondrial permeability transition blocker cyclosporinA (CsA) completely arrested both ischemic FR generation and mitochondrial calcium overload, and prevented deterioration of neuronal intrinsic membrane properties. CsA had no effect on the accumulation of intracellular calcium during ischemia-reperfusion. Nicotinamide, a blocker of NAD+ hydrolysis, reproduced the CsA effects on FR generation, mitochondrial calcium accumulation and cytoplasmic calcium increases. These observations suggest that a major determinant of ischemic FR generation in pyramidal neurons is the uncoupling of the mitochondrial respiratory chain, which may be associated with the mitochondrial permeability transition.

• Authors: M V Frantseva, P L Carlen, J L Perez Velazquez
• Journal: Free radical biology & medicine (Free Radic Biol Med) Vol. 31 Issue 10 Pg. 1216-27 (Nov 15 2001) ISSN: 0891-5849 [Print] United States
• PMID: 11705700 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Aniline Compounds
• Calcium Channels
• Calcium-Binding Proteins
• Fluorescent Dyes
• Free Radicals
• Heterocyclic Compounds, 3-Ring
• Rhodamines
• Ru 360
• Ruthenium Compounds
• Xanthenes
• mitochondrial calcium uniporter
• Rotenone
• dihydrorhodamine 123
• rhod-2
• Fluo-3
• Niacinamide
• Cyclosporine
• NADH, NADPH Oxidoreductases
• Electron Transport Complex I
• Calcium

Topics

• Aniline Compounds (chemistry)
• Animals
• Brain Ischemia (metabolism)
• Calcium (analysis, antagonists & inhibitors, metabolism)
• Calcium Channels
• Calcium-Binding Proteins (antagonists & inhibitors, metabolism)
• Culture Techniques
• Cyclosporine (pharmacology)
• Electron Transport Complex I
• Fluorescent Dyes (chemistry)
• Free Radicals (analysis, antagonists & inhibitors, metabolism)
• Heterocyclic Compounds, 3-Ring
• Hippocampus (cytology, drug effects)
• Intracellular Fluid (metabolism)
• Mitochondria (drug effects, metabolism)
• NADH, NADPH Oxidoreductases (antagonists & inhibitors, metabolism)
• Niacinamide (pharmacology)
• Pyramidal Cells (drug effects, metabolism)
• Rats
• Rats, Wistar
• Reperfusion Injury (metabolism)
• Rhodamines (chemistry)
• Rotenone (pharmacology)
• Ruthenium Compounds (pharmacology)
• Xanthenes (chemistry)