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• W971405982 abstract "Optic neuritis is one of the most common clinical manifestations of multiple sclerosis (MS), a chronic inflammatory disease of the central nervous system (CNS). After an episode of optic neuritis, 30 50 % of patients develop persistent impairment of vision caused by degeneration of optic nerve (ON) axon fibers. Our group has previously shown that in Brown Norway (BN) rats, myelin oligodendrocyte glycoprotein (MOG) induced experimental autoimmune encephalomyelitis (EAE) affects the optic nerve in more than 90% of immunized animals, leading to inflammation, demyelination, and degeneration of axons. The precise pathological mechanisms of axonal degeneration are not fully understood, but are likely to involve excess accumulation of calcium ions (Ca2+) into axons. One of the possible routes of entry of Ca2+ under pathological conditions is via different types of voltage-dependent calcium channels (VDCCs). Since manganese ions (Mn2+) also enter neurons via VDCCs and cause signal enhancement in T1-weighted magnetic resonance images (MRI), we have used Mn2+- enhanced MRI to evaluate the effects of type specific VDCC blockers. We found that application of ω conotoxin GVIA, a specific blocker of N-type VDCCs, caused a significant decrease of Mn2+- induced enhancement in T1-weighted MR images. In order to further investigate N-type VDCC expression in the ON, we have performed immunohistochemistry for α1B, the pore-forming subunit of N-type VDCCs, which revealed a significant difference in both the degree and the pattern of N-type VDCC expression between healthy and inflamed ONs. In healthy, myelinated ONs, a modest degree of α1B immunoreactivity was detected. However, a highly significant up-regulation of expression was seen in MOG-immunized ONs. Furthermore, a highly significant positive correlation between the number of α1B-positive sites per ON and the percentage of demyelination was detected by myelin-specific histopathological staining. A highly significant negative correlation was observed between the number of α1B-positive sites per ON and the percentage of axonal survival. Additionally, we have tested the N-type VDCC blocker, ω conotoxin GVIA, during an in vivo calcium imaging study. After ω-conotoxin GVIA was topically applied to the inflamed ONs, depolarization-induced influx of Ca2+ was significantly inhibited in comparison to the control group of MOG-immunized ONs. Treatment of healthy rats with the N-type VDCC blocker decreased the Ca2+ signal to a smaller extent which was not significantly different to healthy ONs after topical application of normal saline. These results confirm the previously obtained data about up-regulated expression of N-type VDCCs in MOG-immunized ONs and indicate further that the newly expressed N-type VDCCs are functional. Taken together, our data indicate N-type VDCCs to have the most prominent effect on Ca2+ influx in MOG-induced optic neuritis. Further corroboration was acquired by showing therapeutically significant effects of a specific N-type VDCC blocker, ω-conotoxin GVIA, after intracerebroventricular continuous infusion. We detected significantly decreased demyelination and a significant increase of axonal survival in the ONs of ω-conotoxin GVIA-treated animals. Thus, our data show an ectopic expression of N-type VDCCs in MOG-induced optic neuritis in BN rats, which mainly contribute to an increased Ca2+ influx under autoimmune inflammatory conditions. Furthermore, we introduce ω-conotoxin GVIA as a neuroprotective agent in the treatment of autoimmune optic neuritis." @default.
• W971405982 created "2016-06-24" @default.
• W971405982 creator A5044189348 @default.
• W971405982 date "2022-02-16" @default.
• W971405982 modified "2023-10-14" @default.
• W971405982 title "Involvement of N-type voltage dependent calcium channels in axon degeneration during experimental autoimmune optic neuritis" @default.
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