Laquinimod protects the optic nerve and retina in an experimental autoimmune encephalomyelitis model

Abstract

BackgroundThe oral immunomodulatory agent laquinimod is currently evaluated for multiple sclerosis (MS) treatment. Phase II and III studies demonstrated a reduction of degenerative processes. In addition to anti-inflammatory effects, laquinimod might have neuroprotective properties, but its impact on the visual system, which is often affected by MS, is unknown. The aim of our study was to investigate potential protective effects of laquinimod on the optic nerve and retina in an experimental autoimmune encephalomyelitis (EAE) model.MethodsWe induced EAE in C57/BL6 mice via MOG35–55 immunization. Animals were divided into an untreated EAE group, three EAE groups receiving laquinimod (1, 5, or 25 mg/kg daily), starting the day post-immunization, and a non-immunized control group. Thirty days post-immunization, scotopic electroretinograms were carried out, and mice were sacrificed for histopathology (HE, LFB), immunohistochemistry (MBP, Iba1, Tmem119, F4/80, GFAP, vimentin, Brn-3a, cleaved caspase 3) of the optic nerve and retina, and retinal qRT-PCR analyses (Brn-3a, Iba1, Tmem119, AMWAP, CD68, GFAP). To evaluate the effect of a therapeutic approach, EAE animals were treated with 25 mg/kg laquinimod from day 16 when 60% of the animals had developed clinical signs of EAE.ResultsLaquinimod reduced neurological EAE symptoms and improved the neuronal electrical output of the inner nuclear layer compared to untreated EAE mice. Furthermore, cellular infiltration, especially recruited phagocytes, and demyelination in the optic nerve were reduced. Microglia were diminished in optic nerve and retina. Retinal macroglial signal was reduced under treatment, whereas in the optic nerve macroglia were not affected. Additionally, laquinimod preserved retinal ganglion cells and reduced apoptosis. A later treatment with laquinimod in a therapeutic approach led to a reduction of clinical signs and to an improved b-wave amplitude. However, no changes in cellular infiltration and demyelination of the optic nerves were observed. Also, the number of retinal ganglion cells remained unaltered.ConclusionFrom our study, we deduce neuroprotective and anti-inflammatory effects of laquinimod on the optic nerve and retina in EAE mice, when animals were treated before any clinical signs were noted. Given the fact that the visual system is frequently affected by MS, the agent might be an interesting subject of further neuro-ophthalmic investigations.Electronic supplementary materialThe online version of this article (10.1186/s12974-018-1208-3) contains supplementary material, which is available to authorized users.

Systemic Mesenchymal Stem Cell Treatment Mitigates Structural and Functional Retinal Ganglion Cell Degeneration in a Mouse Model of Multiple Sclerosis

“…This outcome might also be due to the nature of the MOG 35-55 EAE model, in which several studies aimed at RGC neuroprotection have indicated a huge variability in RGC survival from no to almost complete preservation. [40][41][42] An important factor on RGC survival in EAE models may be the timing of intervention and response of dosages, as nicely demonstrated by Wilmes et al 41 The group of Shindler et al reported a strong correlation on the magnitude RGC survival and the timepoint of corticosteroid intervention in the PLP-induced EAE model. 43 We used a single injection of MSC seven days after EAE induction and taking the half-life of MSC into consideration, a single MSC injection rather than multiple administrations might limit longer lasting neuroprotection as indicated by Payne et al 44 On the other hand, we see a robust rescue effect of the PERG amplitude, preservation of the RNFL, and notable mitigation of RGC loss, which is indicative of a sustained effect on the visual system.…”

Progressive optic atrophy in a retinal ganglion cell-specific mouse model of complex I deficiency

“…However, while a subset of cone photoreceptors exhibited Cre-dependent tdTomato expression, no rod photoreceptors or bipolar cells expressed Cre in Vglut2-Cre;ndufs4 loxP/loxP mice and would therefore be expected to be physiologically normal. It is conceivable that a mild reduction in b-wave amplitudes could be an indirect effect of RGC pathology and/or inner retinal inflammation, as animal models of traumatic or inflammatory optic neuropathy have exhibited variable effects on outer retinal signaling properties 34,35 . The reduction in oscillatory potentials observed in ERG recordings of the conditional knockout mice is consistent with abnormal RGC function, as seen previously in mouse glaucoma models 33,36 .…”

Molecular Effects of FDA-Approved Multiple Sclerosis Drugs on Glial Cells and Neurons of the Central Nervous System

“…Importantly, in AhR-knockout mice, no effect of LQ on the number of IBA1-positive cells was found [262], indicating that AhR is the main target of LQ. LQ also decreased the number of MAC-3-and CD45-positive microglia cells in cuprizone mice, EAE mice and mouse TLR4-knockout and myeloid differentiation primary response 88 (MyD88)-knockout demyelination models [261,[265][266][267][268][269]. Moreover, LQ increased the protein level of the pro-inflammatory microglia marker translocator protein (TSPO) [267] in the CNS of cuprizone-exposed mice [265].…”

“…LQ is an orally administered, synthetic derivative of linomide, that targets peripheral immune cells, such as activated IL-21-producing CD4 + CD44 + T-cells, C11c + CD4 + dendritic cells dendritic cells and B-cells [260], but it also displays neuroprotective effects in the mouse EAE model [30,31]. In addition, the linomide derivative might work via the AhR because LQ-treated mice showed major transcriptional changes of genes downstream of this receptor [261], such as the AhR hydroxylase Cytochrome P450 (CYP1A1). Here, we deal with the specific molecular effects of LQ on CNS cell types (for details, see Supplementary Table S6; for article search terms, see Supplementary Information).…”