RESUMO
Introduction: Five to eight percent of the world population currently suffers from at least one autoimmune disorder. Despite multiple immune modulatory therapies for autoimmune demyelinating diseases of the central nervous system, these treatments can be limiting for subsets of patients due to adverse effects and expense. To circumvent these barriers, we investigated a nutritional intervention in mice undergoing experimental autoimmune encephalomyelitis (EAE), a model of autoimmune-mediated demyelination that induces visual and motor pathologies similar to those experienced by people with multiple sclerosis (MS). Methods: EAE was induced in female and male mice and the impact of limiting dietary carbohydrates by feeding a ketogenic diet (KD) enriched in medium chain triglycerides (MCTs), alpha-linolenic acid (an omega-3 fatty acid), and fiber was evaluated in both a preventive regimen (prior to immunization with MOG antigen) and an interventional regimen (following the onset of symptoms). Motor scores were assigned daily and visual acuity was measured using optokinetic tracking. Immunohistochemical analyses of optic nerves were done to assess inflammatory infiltrates and myelination status. Fatty acid and cytokine profiling from blood were performed to evaluate systemic inflammatory status. Results: The KD was efficacious when fed as a preventive regimen as well as when initiated as an interventional regimen following symptom onset. The KD minimally impacted body weight during the experimental time course, increased circulating ketones, prevented motor and ocular deficits, preserved myelination of the optic nerve, and reduced infiltration of immune cells to optic nerves. The KD also increased anti-inflammatory-associated omega-3 fatty acids in the plasma and reduced select cytokines in the circulation associated with EAE-mediated pathological inflammation. Discussion: In light of ongoing clinical trials using dietary strategies to treat people with MS, these findings support that a KD enriched in MCTs, omega-3 fatty acids, and fiber promotes a systemic anti-inflammatory milieu and ameliorates autoimmune-induced demyelinating visual and motor deficits.
RESUMO
Purpose: Sulforaphane (SFN) is an isothiocyanate derived from cruciferous vegetables that has therapeutic efficacy in numerous animal models of human disease, including mouse models of retinal degeneration. However, despite dozens of clinical trials, the compound remains to be tested as a clinical treatment for ocular disease. Numerous cellular activities of SFN have been identified, including the activation of Nrf2, a transcription factor that induces a battery of target gene products to neutralize oxidative and xenobiotic stresses. As Nrf2 expression and function reportedly decrease with aging, we tested whether the loss of the transcription factor limits the therapeutic efficacy of SFN against retinal degeneration. Methods: Six- to 8-month-old wild-type and Nrf2 knockout mice were treated with SFN beginning 1 month after ribozyme-mediated knockdown of superoxide dismutase 2 (SOD2) mRNA in the RPE. The impacts of MnSOD (the protein product of SOD2) knockdown and the efficacy of SFN were evaluated using a combination of electroretinography (ERG), spectral domain optical coherence tomography (SD-OCT), and postmortem histology. Results: SFN restored the ERG photopic b-wave suppressed by MnSOD loss in wild-type mice, but not in the Nrf2 knockout mice. In contrast, ERG scotopic a- and b-wave loss was not restored for either genotype. SFN significantly improved retinal thickness in the Nrf2 knockout mice with MnSOD knockdown, but this was not observed in the wild-type mice. In both genotypes, SFN treatment reduced morphological markers of RPE atrophy and degeneration, although these improvements did not correlate proportionally with functional recovery. Conclusions: These findings highlight the capacity of SFN to preserve cone function, as well as the potential challenges of using the compound as a standalone treatment for age-related retinal degeneration under conditions associated with reduced Nrf2 function.
