Contributions
Abstract: 110
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 22 OCT
Background: In Multiple sclerosis (MS), longterm clinical disability is mainly due to neuro-axonal damage, which is at least in part linked to oxidative stress. Optic neuritis occurs in up to 20% of MS patients leading to degeneration of retinal layers which can be investigated in vivo using optical coherence tomography (OCT). Αlpha-lipoic acid (LA) is a naturally occurring sulfhydryl compound with strong anti-oxidative and potential anti-inflammatory properties and might therefore be a suitable treatment to counteract oxidative stress during MS.
Objectives: We aimed to identify the LA isoform with the best neuroprotective properties. Subsequently, we intended to characterize the mode of action in the experimental autoimmune encephalomyelitis-optic neuritis (EAE/ON) model by OCT and optokinetic response (OKR) as longitudinal in vivo measurements of degeneration and function as well as by histological stainings for endpoint measurements. Our goal was to use a preclinical experimental design that would be directly applicable to a phase II optic neuritis clinical trial.
Methods: In vitro cell culture models of oxidative stress were used to determine whether the reduced form dihydrolipoic acid (DHLA) or one of the enantiomers of LA is more neuroprotective than others.
The MOG35-55 peptide induced EAE in C57BL/6J mice and was used as animal model for MS and ON. Spectral domain OCT was used for the analysis of retinal degeneration. Visual function was assessed by optokinetic response (OKR) measurement. In addition, histological stainings of retinal ganglion cells (RGCs) and optic nerves were used to evaluate the mode of action.
Results: In vitro, the reduced form DHLA acts fasted than LA but after 24 hours of preincubation all forms had similar protective efficacy. In EAE/ON, LA attenuated the clinical score and reduced the degeneration of the inner retinal layers. The visual function was superior in mice treated with LA. Histological examination of RGCs confirmed a robust protective effect of LA, while LA had no effect on infiltration of inflammatory cells, microglial activation or demyelination.
Conclusions: The neuroprotective effect of LA in EAE/ON appears to be attributable to direct, antioxidative effects rather than to anti-inflammatory properties. Moreover, we demonstrate that OCT and OKR are ideally suited for the screening of substances in an EAE/ON-animal model as a basis for future clinical studies.
Disclosure:
Michael Dietrich reports nothing to disclose.
Niklas Helling reports nothing to disclose.
Alexander Hilla reports nothing to disclose.
Annemarie Heskamp reports nothing to disclose.
Andrea Issberner reports nothing to disclose.
Thomas Hildebrandt reports nothing to disclose.
Zippora Kohne reports nothing to disclose.
Carsten Berndt reports nothing to disclose.
Orhan Aktas reports grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF/KKNMS PI for NationNMO); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono and Roche outside of the submitted work.
Dietmar Fischer reports nothing to disclose.
Hans-Peter Hartung has received fees for serving on steering committees from Biogen Idec, GeNeuro, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, MedImmune, Bayer HealthCare, Forward Pharma, and Roche, fees for serving on advisory boards from Biogen Idec, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, and Roche, and lecture fees from Biogen Idec, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, MedImmune, and Roche.
Philipp Albrecht has received speaker honoraria, consulting fees or travel support by Allergan, Biogen, Esai, GSK, IPSEN, Merz, Novartis, TEVA and research grants by Biogen, Ipsen, Merz, Novartis and Roche.
Abstract: 110
Type: Oral
Abstract Category: Pathology and pathogenesis of MS - 22 OCT
Background: In Multiple sclerosis (MS), longterm clinical disability is mainly due to neuro-axonal damage, which is at least in part linked to oxidative stress. Optic neuritis occurs in up to 20% of MS patients leading to degeneration of retinal layers which can be investigated in vivo using optical coherence tomography (OCT). Αlpha-lipoic acid (LA) is a naturally occurring sulfhydryl compound with strong anti-oxidative and potential anti-inflammatory properties and might therefore be a suitable treatment to counteract oxidative stress during MS.
Objectives: We aimed to identify the LA isoform with the best neuroprotective properties. Subsequently, we intended to characterize the mode of action in the experimental autoimmune encephalomyelitis-optic neuritis (EAE/ON) model by OCT and optokinetic response (OKR) as longitudinal in vivo measurements of degeneration and function as well as by histological stainings for endpoint measurements. Our goal was to use a preclinical experimental design that would be directly applicable to a phase II optic neuritis clinical trial.
Methods: In vitro cell culture models of oxidative stress were used to determine whether the reduced form dihydrolipoic acid (DHLA) or one of the enantiomers of LA is more neuroprotective than others.
The MOG35-55 peptide induced EAE in C57BL/6J mice and was used as animal model for MS and ON. Spectral domain OCT was used for the analysis of retinal degeneration. Visual function was assessed by optokinetic response (OKR) measurement. In addition, histological stainings of retinal ganglion cells (RGCs) and optic nerves were used to evaluate the mode of action.
Results: In vitro, the reduced form DHLA acts fasted than LA but after 24 hours of preincubation all forms had similar protective efficacy. In EAE/ON, LA attenuated the clinical score and reduced the degeneration of the inner retinal layers. The visual function was superior in mice treated with LA. Histological examination of RGCs confirmed a robust protective effect of LA, while LA had no effect on infiltration of inflammatory cells, microglial activation or demyelination.
Conclusions: The neuroprotective effect of LA in EAE/ON appears to be attributable to direct, antioxidative effects rather than to anti-inflammatory properties. Moreover, we demonstrate that OCT and OKR are ideally suited for the screening of substances in an EAE/ON-animal model as a basis for future clinical studies.
Disclosure:
Michael Dietrich reports nothing to disclose.
Niklas Helling reports nothing to disclose.
Alexander Hilla reports nothing to disclose.
Annemarie Heskamp reports nothing to disclose.
Andrea Issberner reports nothing to disclose.
Thomas Hildebrandt reports nothing to disclose.
Zippora Kohne reports nothing to disclose.
Carsten Berndt reports nothing to disclose.
Orhan Aktas reports grants from the German Research Foundation (DFG) and the German Ministry of Education and Research (BMBF/KKNMS PI for NationNMO); grants and personal fees from Bayer HealthCare, Biogen, Genzyme, Novartis, and Teva; and personal fees from Almirall, MedImmune, Merck Serono and Roche outside of the submitted work.
Dietmar Fischer reports nothing to disclose.
Hans-Peter Hartung has received fees for serving on steering committees from Biogen Idec, GeNeuro, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, MedImmune, Bayer HealthCare, Forward Pharma, and Roche, fees for serving on advisory boards from Biogen Idec, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, and Roche, and lecture fees from Biogen Idec, Sanofi Genzyme, Merck, Novartis Pharmaceuticals, Octapharma, Opexa Therapeutics, Teva Pharmaceuticals, MedImmune, and Roche.
Philipp Albrecht has received speaker honoraria, consulting fees or travel support by Allergan, Biogen, Esai, GSK, IPSEN, Merz, Novartis, TEVA and research grants by Biogen, Ipsen, Merz, Novartis and Roche.