Regulatory effect of triiodothyronine on brain myelination and astrogliosis after cuprizone-induced demyelination in mice

Abstract

Chronic demyelination and plaque formation in multiple sclerosis is accompanied by persisting astrogliosis, negatively influencing central nervous system recovery and remyelination. Triiodothyronin (T3) is thought to enhance remyelination in the adult brain by the induction of oligodendrocyte maturation. We investigated additional astrocyte-mediated mechanisms by which T3 might promote remyelination in chronically demyelinated lesions using the cuprizone mouse model. C57BL/6 mice were fed cuprizone for 12 weeks to induce lesions with an impaired remyelination capacity. While the expression of oligodenrocyte progenitor markers, i.e., platelet derived growth factor-α receptor was not affected by T3 administration, myelination status, myelin protein expression as well as total and adult oligodendrocyte numbers were markedly increased compared to cuprizone treated controls. In addition to these effects on oligodendrocyte numbers and function, astrogliosis but not microgliosis was ameliorated by T3 administration. Intermediate filament proteins vimentin and nestin as well as the extracellular matrix component tenascin C were significantly reduced after T3 exposure, indicating additional effects of T3 on astrocytes and astrogliosis. Our data clearly indicate that T3 promotes remyelination in chronic lesions by both enhancing oligodendrocyte maturation and attenuating astrogliosis.

Acid sphingomyelinase deficiency enhances myelin repair after acute and chronic demyelination

“…Results are expressed as relative GFAP orIba-1covered area of the CCm (percentage of the stained area in relation to the non-stained area) as previously described. [17]…”

Remodeling of the interstitial extracellular matrix in white matter multiple sclerosis lesions: Implications for remyelination (failure)

“…Upon ethidium bromide‐induced demyelination, both tenascin‐C and tenascin‐R are upregulated and produced by reactive astrocytes and recruited OPCs, respectively (Zhao et al, ). While tenascin‐C and tenascin‐R are enhanced at the gene expression level upon cuprizone‐induced demyelination in one study (Zendedel et al, ), another study shows that tenascin‐C mRNA is not strongly upregulated (Hibbits et al, ). In active MS lesions, both tenascin‐C and tenascin‐R are significantly downregulated, extending even beyond the edge of the lesion, that is at NAWM areas where the presence of macrophages is abundant (Gutowski et al, ).…”

Protective effects of cannabidiol on cuprizone-induced demyelination in C57BL/6 mice

“…Animal handling and treatment protocols have been previously described in detail. 4 For IHC and biochemical studies, the numbers of animals in the experimental groups were as follows: control (n = 4), CPZ (n = 5), CPZ plus CBD (n = 6).…”

“…3 MS has long been considered as T-cell-mediated autoimmune disease of the CNS characterized by microglia activation, recruitment of systemic immune-competent cells and production of cytotoxic mediators and pro-inflammatory cytokines, which lead to neuronal tissue damage (inflammatory cascade). 4 Although controlled clinical studies published evidence for the effectiveness of immune-modulatory, antiinflammatory or immunosuppressive therapies, however this effect is mainly seen in patients at early stages of the disease, and the effects are limited, especially in improvement of the accumulation of constant clinical deficits. 5,6 Therefore, there is a high need for new effective drugs that limit demyelination and axonal degeneration, thus complementing the currently available therapies.…”

“…7 A number of studies suggest the importance of primary neurodegenerative mechanisms that are evident in chronically demyelinating plaques and are believed to be the result of oxidative stress. 4,8 Oxidative stress basically reflects a condition in which the pro-oxidant-anti-oxidant balance in a cell is disturbed; cellular biomolecules undergo severe oxidative damage, ultimately impairing cell viability. 9 The CNS is particularly sensitive to oxidative stress because of high oxygen consumption, relatively small amounts of conventional anti-oxidants and anti-oxidative enzymes, and large amounts of polyunsaturated lipids which are highly susceptible to oxidation.…”