Exposure of Rat Optic Nerves to Nitric Oxide Causes Protein S-Nitrosation and Myelin Decompaction

Abstract

This study investigates the effect of nitric oxide (NO) on both the chemical modifications of CNS proteins and the architecture of the myelinated internode. Incubation of rat optic nerves for 2 h with 1 mM concentration of the NO-donors S-nitroso-N-acetyl-penicillamine (SNAP), ethyl-2-[hydroxyimino]-5-nitro-3-hexeneamide (NOR-3), and 4-phenyl-3-furoxan carbonitrile (PFC) led to decompaction of myelin at the level of the intraperiod line (IPL). In contrast, incubation with 1 mM sodium nitroprusside, which slowly releases NO, sodium nitrite, and N-nitrosopyrrolidine failed to cause myelin disassembly. This suggests that free NO and/or some of its direct oxidation products (e.g., N2O3) are the active molecular species. NO-induced alterations in myelin architecture could not be assigned to protein or lipid degradation, lipid peroxidation, ATP depletion, calcium uptake, protein nitration, protein carbonylation, and nerve depolarization. NO-treatment, however, resulted in the S-nitrosation of a number of proteins. In myelin, one of the major S-nitrosated substrates was identified as proteolipid protein (PLP), an abundant cysteine-rich protein that is responsible for IPL stabilization. Peripheral nervous system myelin, whose stability depends on proteins other than PLP, was not decompacted upon incubation of sciatic nerves with SNAP. It is proposed that NO-mediated nitrosation of sulfhydryl groups is likely to interfere with the normal function of PLP and other important CNS myelin proteins leading to the structural demise of this membrane. These findings are relevant to multiple sclerosis and other inflammatory demyelinating disorders where both excessive NO production and myelin instability are known to occur.

Effects of temperature on vibration‐induced damage in nerves and arteries

“…In addition, nitrosylation and nitration of myelin integral membrane proteins, which cross-link the membranes, may disrupt cross-linking and allow decompaction of myelin. 4 The effects of vibration on nerve blood flow are unknown, but vibration appears to activate vasoconstriction in arteries via the somatosympathetic pathway. 26 Blood flow in the vasa nervorum is likely to decline in response to vibration as occurs in digital arteries.…”

“…14 In vitro nitration of isolated optic nerves produces dramatic decompaction of myelin similar to that observed in the tail nerves. 4 The nitration is thought to disrupt cross-linking of the proteolipid proteins, leading to myelin decompaction. 4 Nerve tissues were consumed in analysis before the nitrotyrosine staining method was operational in our laboratory.…”

“…4 The nitration is thought to disrupt cross-linking of the proteolipid proteins, leading to myelin decompaction. 4 Nerve tissues were consumed in analysis before the nitrotyrosine staining method was operational in our laboratory. Whether nitrotyrosine formation is occurring in vibrated tail nerves remains to be examined.…”

Comparison of continuous and intermittent vibration effects on rat‐tail artery and nerve

“…9 S-nitrosylation of the proteolipid protein in the presence of toxic doses of nitric oxide has been proposed to cause decompaction of myelin. 1 A similar modification of myelin structural proteins in the peripheral nerve may cause unraveling of the myelin sheath in vibration injury. Alternatively, the repeated mechanical displacement of nerves imparted by vibration may be the cause of myelin disruption.…”

Evidence of Nitrosative Damage in the Brain White Matter of Patients with Multiple Sclerosis

“…myelin proteins from MS and control patients was therefore investigated. In addition, we analyzed the chemical modifications of myelin PLP, since the chemical structure of this molecule is affected upon incubation of CNS tissue with several NO-donors (41).…”