Early alpha-lipoic acid therapy protects from degeneration of the inner retinal layers and vision loss in an experimental autoimmune encephalomyelitis-optic neuritis model

Abstract

BackgroundIn multiple sclerosis (MS), neurodegeneration is the main reason for chronic disability. Alpha-lipoic acid (LA) is a naturally occurring antioxidant which has recently been demonstrated to reduce the rate of brain atrophy in progressive MS. However, it remains uncertain if it is also beneficial in the early, more inflammatory-driven phases. As clinical studies are costly and time consuming, optic neuritis (ON) is often used for investigating neuroprotective or regenerative therapeutics. We aimed to investigate the prospect for success of a clinical ON trial using an experimental autoimmune encephalomyelitis-optic neuritis (EAE-ON) model with visual system readouts adaptable to a clinical ON trial.MethodsUsing an in vitro cell culture model for endogenous oxidative stress, we compared the neuroprotective capacity of racemic LA with the R/S-enantiomers and its reduced form. In vivo, we analyzed retinal neurodegeneration using optical coherence tomography (OCT) and the visual function by optokinetic response (OKR) in MOG35–55-induced EAE-ON in C57BL/6J mice. Ganglion cell counts, inflammation, and demyelination were assessed by immunohistological staining of retinae and optic nerves.ResultsAll forms of LA provided equal neuroprotective capacities in vitro. In EAE-ON, prophylactic LA therapy attenuated the clinical EAE score and prevented the thinning of the inner retinal layer while therapeutic treatment was not protective on visual outcomes.ConclusionsA prophylactic LA treatment is necessary to protect from visual loss and retinal thinning in EAE-ON, suggesting that a clinical ON trial starting therapy after the onset of symptoms may not be successful.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1111-y) contains supplementary material, which is available to authorized users.

Optical Coherence Tomography in Multiple Sclerosis

“…45 In animal model studies, use of a putative neuroprotective agent, α-lipoic acid, reduced the loss of INL thickness over time. 54 Unfortunately, this apparent protection was not associated with better visual outcomes.…”

Using Optical Coherence Tomography and Optokinetic Response As Structural and Functional Visual System Readouts in Mice and Rats

“…OKR monitoring provides a functional readout of the neurodegeneration seen by OCT. In these experiments, visual function assessed as spatial frequency by OKR, and neuroaxonal damage assessed as IRL thinning by OCT, were in close correlation 17 . Various protocols can be employed to examine the visual acuity by changing the spatial or temporal frequency, contrast sensitivity, orientation or speed of the moving grid.…”

“…The examination of the visual pathway, as a part of the central nervous system, has been proven to be an effective starting point in addressing not only ophthalmologic 1,2,3,4,5 , but also neurologic 6,7,8,9,10,11,12,13,14,15,16 questions. In recent years, OCT and OKR have been identified as useful analytic, non-invasive tools to evaluate a large variety of retinopathies and retinal manifestations in various rodent models 17,18,19,20,21,22,23,24,25 . OCT allows for fast and high resolution in vivo visualization of the retinal morphology and structure in mice and rats, with results in good accordance with histological sections of the animals retinae 26 .…”

Antioxidant lipoic acid ligand-shell gold nanoconjugates against oxidative stress caused by α-synuclein aggregates

“…The neuroprotective capacity of LA in the neurodegeneration has been reported recently, which demonstrated that therapeutic treatment with LA preserved the survival of the retinal ganglion cells 71 . Moreover, Melli et al 72 showed that LA exerts neuroprotective effects by preventing the mitochondrial dysfunction via the expression of the mitochondrial iron chaperone or iron storage protein, frataxin.…”