We sought to determine if oral vitamin D supplementation provided a neuroprotective benefit in a novel, mouse model of the cerebral demyelinating phenotype of X-linked adrenoleukodystrophy (ALD).

ALD is caused by mutations in a peroxisomal gene (ABCD1) and affects 1 in 15,000 live births. Most males with ALD develop a progressive inflammatory demyelinating phenotype, known as cerebral ALD, which is often fatal. No preventive therapies currently exist. Recent data suggests that early-life exposure to vitamin D, a steroid hormone with anti-inflammatory and antioxidant properties, may reduce the risk of developing cerebral ALD.

We assigned newly-weaned, male Abcd1-null and wild-type mice to one of three diets that differed only in their vitamin D content (100 vs. 1500 vs. 5000 IU/kg; n=7-10 mice/arm). After four weeks on diet, we used a two-hit combination of cuprizone intoxication and MOG-peptide injections to induce inflammatory cerebral demyelination. We compared clinical, radiologic, and histologic markers across the three treatment arms.

We found that higher vitamin D dietary exposure reduced the clinical disability score and gadolinium enhancement on brain MRI. Similarly, on histologic analysis, we found that higher vitamin D exposure reduced microglial activation, blood brain barrier disruption, immune cell infiltration, oxidative stress markers, and cerebral demyelination. We also observed a decrease in IL-18 immunoreactivity in brain microglia and macrophages, consistent with reduced activation of NLRP3 inflammasome, a potential driver of neuroinflammation in ALD.

Our findings offer preclinical evidence that early-life vitamin D supplementation offers neuroprotective benefits against cerebral ALD. Further studies are required to understand vitamin D's underlying mechanisms in ALD mice and whether a similar benefit can be translated to clinical trials for boys with ALD.