Semi-quantitative analysis of the effects of cyclosporine on remyelination following gliotoxic injection in the brainstem

Abstract

The use of cyclosporine (CsA) has shown to induce an increase in the density of oligodendrocytes near remyelinating areas following the injection of ethidium bromide (EB), a demyelinating agent, in the rat brainstem. This study was designed in order to evaluate if CsA has the capacity of increasing remyelination. In this context, a comparison between the final balance of myelin repair in CsA treated and non-treated rats was assessed using a semi-quantitative method developed for documenting the extent and nature of remyelination in gliotoxic lesions. Wistar rats were submitted to intracisternal injection of 10 microliters of 0.1% EB. Some were treated during 31 days with CsA (group III -10 mg/kg/day by 7 days and, thereafter, 3 times a week, with a minimal interval of 48 hours) by intraperitonial route. Others were not treated with CsA (group I). A control group was planned receiving into the cisterna pontis 10 microliters of 0.9% saline solution and following after that the same CsA administration protocol (group II). Results clearly demonstrate that in vivo administration of CsA after EB-demyelinating lesions stimulated oligodendrocyte remyelination (mean remyelination scores of 3.72±0.25 for oligodendrocytes and 1.04±0.39 for Schwann cells) compared to non-treated animals (3.13±0.71 and 1.31±0.62, respectively), although the mechanisms by which this positive CsA effect occurs are unclear.

Effects of propentofylline on CNS remyelination in the rat brainstem

“…In our study, there was no apparent difference regarding astrocyte, lymphocyte, or macrophage presence in the EB‐induced lesions between both groups (treated or not with PPF). Lesions were similar to those found in this toxic model (Blakemore, ; Bondan et al, ; Graça and Blakemore, ; Pereira et al, ; Yajima and Suzuki, ); however rats treated with PPF presented lesions that resembled those observed with CsA treatment (Bondan et al, ; Bondan and Martins, ), with a higher density of oligodendrocytes over the edges of the lesions and increased remyelination. The precise mechanisms by which these beneficial PPF effects occur remain obscure.…”

“…As previously observed, the inhibition of IL‐2 secretion induced by cyclosporine (CsA) stimulated oligodendrocyte remyelination in rats (Bondan et al, ), even in diabetic rats (Bondan and Martins, ). On the other hand, Saneto et al () noticed that IL‐2 presence was capable of inhibiting the proliferation of oligodendrocyte progenitor cells (OPCs) in vitro even though stimulating their maturation in adult oligodendrocytes.…”

“…On the other hand, Saneto et al () noticed that IL‐2 presence was capable of inhibiting the proliferation of oligodendrocyte progenitor cells (OPCs) in vitro even though stimulating their maturation in adult oligodendrocytes. Thus, the lack of IL‐2 in the CNS inflammatory environment could allow the migration and division of OPCs, explaining the increased remyelination with CsA (Bondan et al, ).…”

“…In such context, the aim of this study was to evaluate whether PPF had also the capacity of affecting glial cell behavior during the process of demyelination and remyelination following gliotoxic injury induced by ethidium bromide (EB). It is known that focal EB injection into the central nervous system (CNS) is a well‐established experimental demyelinating model inducing local oligodendroglial and astrocytic death and resulting in primary demyelination, blood–brain barrier and glia limitans disruption, as well as Schwann cell invasion from peripheral nerves (Blakemore, ; Bondan et al, ; Bondan and Martins, ; Graça and Blakemore, ; Pereira et al, ; Yajima and Suzuki, ).…”

Cyclosporine improves remyelination in diabetic rats submitted to a gliotoxic demyelinating model in the brainstem

“…Using a semi‐quantitative method developed by Gilson and Blakemore () for documenting the extent and nature of remyelination in gliotoxic lesions, it was clearly demonstrated that in vivo administration of CsA after EB‐demyelinating process stimulated oligodendrocyte remyelination, although the mechanisms by which that positive effect occurred remained unclear (Bondan et al, ). It was suggested that CsA could produce a direct or indirect effect on persisting niches of OPCs in the mature CNS environment, thus affecting the final balance between proliferative/antiproliferative factors related to oligodendroglial populations in the lesion site, maybe facilitating the former and resulting in greater numbers of oligodendrocytes.…”