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Protective effects of melatonin against mitochondrial injury in a mouse model of multiple sclerosis
Iraj Ragerdi Kashani1, Zahra Rajabi, Mohammad Akbari
1Department of Anatomical Sciences, School of Medicine, Tehran University of Medical Sciences, 16 Azar Street, Poursina Street, Tehran, Iran, ragerdi@sina.tums.ac.ir.
Abstract:
Multiple sclerosis (MS) is the most prevalent inflammatory demyelinating disease of the central nervous system. Besides other pathophysiological mechanisms, mitochondrial injury is crucially involved in the development and progression of this disease. Mitochondria have been identified as targets for the peptide hormone melatonin. In the present study, we sought to evaluate the impact of oxidative stress on mitochondrial density and enzyme transcription during experimentally induced demyelination and the protective influence of melatonin. Adult male mice were fed with cuprizone for 5 weeks which caused severe demyelination of the corpus callosum (CC). Animals were simultaneously treated with melatonin by daily intra-peritoneal injections. Melatonin exposure reversed cuprizone-induced demyelination and axon protection. Transmission electron microscopy demonstrated significantly increased mitochondrial numbers and slightly increased mitochondrial size within CC axons after cuprizone exposure. Melatonin antagonized these effects and, in addition, induced the expression of subunits of the respiratory chain complex over normal control values reflecting a mechanism to compensate cuprizone-mediated down-regulation of these genes. Similarly, melatonin modulated gene expression of mitochondrial fusion and fission proteins. Biochemical analysis showed that oxidative stress induced by cuprizone was regulated by melatonin. The data implicate that melatonin abolishes destructive cuprizone effects in the CC by decreasing oxidative stress, restoring mitochondrial respiratory enzyme activity and fusion and fission processes as well as decreasing intra-axonal mitochondria accumulation.
Insights
Melatonin protects against demyelination in the central nervous system by reducing oxidative stress and restoring mitochondrial function. This peptide hormone offers a potential therapeutic strategy for multiple sclerosis (MS).
Area of Science:
- Neuroscience
- Cell Biology
- Biochemistry
Background:
- Multiple sclerosis (MS) is a leading cause of inflammatory demyelination in the central nervous system.
- Mitochondrial dysfunction is a key factor in MS pathogenesis.
- Melatonin, a peptide hormone, targets mitochondria and may offer neuroprotection.
Purpose of the Study:
- To investigate the impact of oxidative stress on mitochondrial density and enzyme transcription during experimental demyelination.
- To evaluate the protective effects of melatonin against cuprizone-induced demyelination and mitochondrial alterations.
Main Methods:
- Experimental autoimmune encephalomyelitis (EAE) was induced in mice using cuprizone.
- Mice were co-treated with melatonin via daily intra-peritoneal injections.
- Mitochondrial density, size, and gene expression of respiratory chain and fusion/fission proteins were analyzed using transmission electron microscopy and biochemical assays.
Main Results:
- Cuprizone induced severe demyelination and axonal damage in the corpus callosum (CC).
- Melatonin treatment reversed cuprizone-induced demyelination and protected axons.
- Melatonin normalized increased mitochondrial numbers and size, upregulated respiratory chain enzyme subunits, and modulated mitochondrial dynamics, while reducing oxidative stress.
Conclusions:
- Melatonin effectively counteracts cuprizone-induced demyelination and axonal injury in the CC.
- Melatonin mitigates oxidative stress, restores mitochondrial respiratory enzyme activity, and normalizes mitochondrial fusion/fission processes.
- Melatonin's protective effects suggest its therapeutic potential for MS by targeting mitochondrial dysfunction.
