Inducing neuronal oxidative stress could create a mouse model with similar characteristics to multiple sclerosis (MS), according to a study recently published in Redox Biology.
“In summary, our data show that a reduction of [Mn superoxide dismutase (MnSOD)] in spinal cord neurons promotes a phenotype of demyelination, inflammation, and progressive paralysis that mimics phenotypes associated with multiple sclerosis but does not induce muscle atrophy and weakness,” the authors wrote.
This experimental study included mice that underwent MnSOD knockout by Sod2 gene deletion. The researchers achieved this variation by using a neuron-specific Cre recombinase in Sod2-floxed mice. The direct effect of this genotype is an increase in oxidative stress on neurons, a pathological state known to play a role in aging and neurodegenerative disorders.
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The deletion of the Sod2 gene in the spinal cord neurons translated into mitochondrial impairment and subsequent peroxide generation. The phenotypic characteristics of these mice, referred to as i-mm Sod2 KO, included hindlimb paralysis, tail atony, gait abnormalities, diminished visual acuity, and clasping behavior.
The researchers identified the pathological patterns in mice with such signs: extensive demyelination, which led to decreased neuronal conduction velocity; axonal degeneration; and higher blood-brain barrier permeability. Marked changes also occurred regarding the immune system, such as microglial activation, higher levels of inflammatory cytokines, neutrophil infiltration of the spinal cord, and necroptosis.
“Axonal degeneration is a major cause of permanent neurological damage during multiple sclerosis and recent studies identified necroptosis as a key mechanism for axonal degeneration,” the authors explained.
Regardless of these similarities with MS, the number of neurons in the spinal cord, overall muscle mass, contractile capacity, and neuromuscular junction innervation were not altered. Moreover, clinical signs began to manifest about 2 months after gene deletion, reaching complete hindlimb paralysis 3 months later.
Bhaskaran S, Kumar G, Thadathil N, et al. Neuronal deletion of MnSOD in mice leads to demyelination, inflammation and progressive paralysis that mimics phenotypes associated with progressive multiple sclerosis. Redox Biol. Published online November 26, 2022. doi:10.1016/j.redox.2022.102550