minocycline and Optic-Neuritis

Optic neuritis (ON) is a common manifestation of aquaporin-4 (AQP4) antibody seropositive neuromyelitis optica (NMO). The extent of tissue damage is frequently severe, often leading to loss of visual function, and there is no curative treatment for this condition. To develop a novel therapeutic strategy, elucidating the underlying pathological mechanism using a clinically relevant experimental ON model is necessary. However, previous ON animal models have only resulted in mild lesions with limited functional impairment. In the present study, we attempted to establish a feasible ON model with severe pathological and functional manifestations using a high-affinity anti-AQP4 antibody. Subsequently, we aimed to address whether our model is suitable for potential drug evaluation by testing the effect of minocycline, a well-known microglia/macrophage inhibitor.. AQP4-immunoglobulin G (IgG)-related ON in rats was induced by direct injection of a high-affinity anti-AQP4 monoclonal antibody, E5415A. Thereafter, the pathological and functional characterizations were performed, and the therapeutic potential of minocycline was investigated.. We established an experimental ON model that reproduces the histological characteristics of ON in seropositive NMO, such as loss of AQP4/glial fibrillary acidic protein immunoreactivity, immune cell infiltration, and extensive axonal damage. We also observed that our rat model exhibited severe visual dysfunction. The histological analysis showed prominent accumulation of macrophages/activated microglia in the lesion site in the acute phase. Thus, we investigated the possible effect of the pharmacological inhibition of macrophages/microglia activation by minocycline and revealed that it effectively ameliorated axonal damage and functional outcome.. We established an AQP4-IgG-induced ON rat model with severe functional impairments that reproduce the histological characteristics of patients with NMO. Using this model, we revealed that minocycline treatment ameliorates functional and pathological outcomes, highlighting the usefulness of our model for evaluating potential therapeutic drugs for ON in NMO.

Topics: Animals; Aquaporin 4; Autoantibodies; Immunoglobulin G; Minocycline; Neuromyelitis Optica; Optic Neuritis; Rats

Optic nerve (ON) damage following nonarteritic anterior ischemic optic neuropathy (NAION) and its models is associated with neurodegenerative inflammation. Minocycline is a tetracycline derivative antibiotic believed to exert a neuroprotective effect by selective alteration and activation of the neuroinflammatory response. We evaluated minocycline's post-induction ability to modify early and late post-ischemic inflammatory responses and its retinal ganglion cell (RGC)-neuroprotective ability.. We used the rodent NAION (rNAION) model in male Sprague-Dawley rats. Animals received either vehicle or minocycline (33 mg/kg) daily intraperitoneally for 28 days. Early (3 days) ON-cytokine responses were evaluated, and oligodendrocyte death was temporally evaluated using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) analysis. Cellular inflammation was evaluated with immunohistochemistry, and RGC preservation was compared with stereology of Brn3a-positive cells in flat mounted retinas.. Post-rNAION, oligodendrocytes exhibit a delayed pattern of apoptosis extending over a month, with extrinsic monocyte infiltration occurring only in the primary rNAION lesion and progressive distal microglial activation. Post-induction minocycline failed to improve retinal ganglion cell survival compared with the vehicle treated (893.14 vs. 920.72; p>0.9). Cytokine analysis of the rNAION lesion 3 days post-induction revealed that minocycline exert general inflammatory suppression without selective upregulation of cytokines associated with the proposed alternative or neuroprotective M2 inflammatory pathway.. The pattern of cytokine release, extended temporal window of oligodendrocyte death, and progressive microglial activation suggests that selective neuroimmunomodulation, rather than general inflammatory suppression, may be required for effective repair strategies in ischemic optic neuropathies.

Topics: Animals; Anti-Bacterial Agents; Apoptosis; Arteritis; Cytokines; Disease Models, Animal; In Situ Nick-End Labeling; Inflammation; Injections, Intraperitoneal; Male; Minocycline; NADPH Oxidase 2; Oligodendroglia; Optic Neuritis; Optic Neuropathy, Ischemic; Rats; Rats, Sprague-Dawley; Retinal Ganglion Cells; Transcription Factor Brn-3A

Axonal destruction and neuronal loss occur early during multiple sclerosis, an autoimmune inflammatory CNS disease that frequently manifests with acute optic neuritis. Available therapies mainly target the inflammatory component of the disease but fail to prevent neurodegeneration. To investigate the effect of minocycline on the survival of retinal ganglion cells (RGCs), the neurons that form the axons of the optic nerve, we used a rat model of myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis. Optic neuritis in this model was diagnosed by recording visual evoked potentials and RGC function was monitored by measuring electroretinograms. Functional and histopathological data of RGCs and optic nerves revealed neuronal and axonal protection when minocycline treatment was started on the day of immunization. Furthermore, we demonstrate that minocycline-induced neuroprotection is related to a direct antagonism of multiple mechanisms leading to neuronal cell death such as the induction of anti-apoptotic intracellular signalling pathways and a decrease in glutamate excitotoxicity. From these observations, we conclude that minocycline exerts neuroprotective effects independent of its anti-inflammatory properties. This hypothesis was confirmed in a non-inflammatory disease model leading to degeneration of RGCs, the surgical transection of the optic nerve.

Topics: Acute Disease; Animals; Anti-Bacterial Agents; Apoptosis; Cell Survival; Encephalomyelitis, Autoimmune, Experimental; Evoked Potentials, Visual; Excitatory Amino Acid Transporter 1; Excitatory Amino Acid Transporter 2; Excitatory Amino Acid Transporter 3; Female; Glutamic Acid; Minocycline; Myelin Proteins; Myelin-Associated Glycoprotein; Myelin-Oligodendrocyte Glycoprotein; Neuroprotective Agents; Optic Nerve; Optic Neuritis; Rats; Rats, Inbred BN; Retinal Ganglion Cells; Severity of Illness Index