Effects of Chronic Sodium Azide on Brain and Muscle Cytochrome Oxidase Activity: A Potential Model to Investigate Environmental Contributions to Neurodegenerative Diseases

Abstract

Deficits in oxidative phosphorylation have been implicated in many neurodegenerative diseases. In this study, cytochrome oxidase activity was inhibited following a 28-d systemic administration of nonlethal sodium azide via subcutaneous osmotic pumps. Quantitative enzyme histochemistry was performed on tissue sections from brain, skeletal muscle, and heart to localize cytochrome oxidase activity both globally and in regions within each tissue. Significant decreases of cytochrome oxidase activity were found in the brain and skeletal muscle but not heart. In addition, regions within each tissue were also analyzed, such as cortex and striatum in the brain and red and white fibers in skeletal muscle. The tissue specific inhibition of cytochrome oxidase by sodium azide could serve as a positive control for studies of other mitochondrial toxins in aerobically compromised cells. Therefore, chronic nonlethal sodium azide administration may provide a potential rat model for the study of mitochondrial dysfunction and the role of environmental pollutants in brain and muscle tissues affected in certain neurodegenerative diseases.

Extinction Memory Improvement by the Metabolic Enhancer Methylene Blue

“…For example, it has been shown that sodium azide decreases cytochrome oxidase activity when chronically administered to rats (Cada et al 1995;Berndt et al 2001) and causes spatial memory deficits in rats tested in the Morris water maze (Bennett et al 1996) and the holeboard maze (Callaway et al 2002). Remarkably, when MB is administered to rats with reduced brain cytochrome oxidase activity, their memory retention scores are raised to the same level as that of control animals (Callaway et al 2002).…”

Accumulation of Amyloid Precursor Protein in the Mitochondrial Import Channels of Human Alzheimer’s Disease Brain Is Associated with Mitochondrial Dysfunction

“…Altered mitochondrial fluidity and the activity of mitochondrial cytochrome c oxidase, which is the terminal oxidase in the respiratory chain, have been reported to be low in the AD brains (Parker, 1991;Sims, 1996;Maurer et al, 2000). Furthermore, a correlation was reported between decreased cytochrome c oxidase activity and deficits in cognitive abilities (Cada et al, 1995;Agin et al, 2001;Berndt et al, 2001). Nevertheless, the mechanisms related to the impairment of mitochondrial functions specific to AD remain unclear.…”

Chronic Treatment with Azide in Situ Leads to an Irreversible Loss of Cytochrome c Oxidase Activity via Holoenzyme Dissociation

“…MnSOD activity was measured from mitochondrial extracts in the presence of 5 mM KCN to inhibit any contaminating CuZn SOD. Protocols for measuring cellular protein content, lactate concentration in the culture media, and whole cell respiration were as previously described (16).…”

“…The mechanism(s) by which azide mediates these effects is unknown. Moreover, its potential relevance to COX deficiency observed in a more physiologically relevant context has not been evaluated despite previous reports of selective COX losses leading to Alzheimer's diseaselike symptoms in rats that had been chronically infused with sodium azide (15,16).…”