Ultrastructural study of the effects of cyclosporine in the brainstem of Wistar rats submitted to the ethidium bromide demyelinating model

Martins

Branco

et al. 2011

Arq. Neuro-Psiquiatr.

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.

mentioning

confidence: 99%

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

Martins

Branco

et al. 2011

Arq. Neuro-Psiquiatr.

“…Several studies reported the invasive capacity of Schwann cells into the CNS from spinal or cranial nerves due to the glia limitans disruption following injection of the gliotoxin [1][2][3][4][5] . This invasion however appeared to be diminished in the diabetic state induced by streptozotocin treatment 6 .…”

Section: Discussionmentioning

confidence: 90%

“…Schwann cell disturbance followed by segmental demyelination in the PNS is a prominent finding in diabetes mellitus of humans 9 and cats 10 , but this is not so commonly observed in spontaneous or experimental diabetes in rats 6 .…”

Section: Discussionmentioning

confidence: 99%

“…The gliotoxic agent ethidium bromide (EB) induces early astrocyte disappearance and oligodendroglial loss when injected in the central nervous system (CNS) leading to blood-brain barrier disruption and primary demyelination respectively. Subsequent remyelination occurs performed by surviving oligodendrocytes and by invasive Schwann cells [1][2][3][4][5][6] . After local EB injection in the peripheral nervous system (PNS) no destruction of myelinating cells but rather intoxication of Schwann cells is observed 7 .…”

mentioning

confidence: 99%

“…Diabetes mellitus is also known to disturb the functioning and integrity of Schwann cells as they are a pri-mary target of polyol pathway abnormalities linked to related hyperglycemia 6 .…”

mentioning

confidence: 99%

See 2 more Smart Citations

Ethidium bromide-induced demyelination in the sciatic nerve of diabetic rats

Custódio

Lallo

et al. 2009

Arq. Neuro-Psiquiatr.

Self Cite

-This study aims to observe the process of myelin loss and repair following the injection of the gliotoxic agent ethidium bromide (EB) in the sciatic nerve of rats previously induced to diabetes mellitus by streptozotocin. Injection of EB was also done in non-diabetic rats. The animals were euthanatized from 3 to 31 days after intraneural injection and nerve sections were collected for ultrastructural study. In nondiabetic rats, Schwann cells (CS) showed signs of intoxication 3 days after, with cytoplasmic vacuolization and rejection of their myelin sheaths. Myelin debris were removed by macrophages in the endoneurium and mast cells were abundant in the lesions. From 14 days following EB injection, supernumerary CS were seen in the expanded endoneurium as well as thin myelin sheaths indicating remyelination. Diabetic rats presented a more extensive myelin vesiculation and segmentar demyelination, with delayed activities from both macrophages and remyelinating SC. No mast cells were noted.KEY WORDS: demyelination, diabetes mellitus, ethidium bromide, peripheral nervous system, remyelination, Schwann cells.desmielinização induzida pelo brometo de etídio no nervo ciático de ratos diabéticos resumo -O estudo visa à observação do processo de perda e reparo mielínico pós-injeção do gliotóxico brometo de etídio (BE) no nervo ciático de ratos previamente induzidos a diabetes mellitus pela estreptozotocina. Injeção de BE foi igualmente realizada em ratos não-diabéticos. Os animais foram eutanasiados dos 3 aos 31 dias pós-injeção intraneural, com colheita de amostras neurais para estudo ultraestrutural. Nos animais não-diabéticos, as células de Schwann (CS) mostraram sinais de intoxicação a partir dos 3 dias pós-gliotóxico, com vacuolização citoplasmática e rejeição de suas bainhas de mielina. Restos mielínicos eram removidos por macrófagos no interior do endoneuro e mastócitos eram abundantes nas lesões. A partir dos 14 dias, CS supranumerárias foram encontradas no endoneuro expandido, além de finas bainhas de mielina indicativas de remielinização. Os ratos diabéticos apresentaram vesiculação mielínica e desmielinização segmentar mais extensas, bem como ausência de mastócitos e atraso na atividade macrofágica e na função remielinizante das CS. PALAVRAS-CHAVE: brometo de estídio, células de Schwann, desmielinização, diabetes mellitus, remielinização, sistema nervoso periférico.

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

Martins

2013

Microsc. Res. Tech.

Self Cite

The use of cyclosporine (CsA) has shown to induce an increase in density of oligodendrocytes near remyelinating areas following the injection of ethidium bromide (EB), a demyelinating agent, in the rat brainstem. It is also known that diabetes mellitus was capable of delaying remyelination by both oligodendrocytes and Schwann cells in this gliotoxic model. This study was designed to assess whether CsA had the capacity to improve remyelination in streptozotocin-induced (50 mg/kg, intraperitoneal route) diabetic rats. Diabetic Wistar rats were divided in different groups receiving 10 microlitres of 0.1% EB or 0.9% saline solution into the cisterna pontis and were treated or not with CsA. During 7 days and, thereafter, three times a week, 10 mg/kg/day of CsA were given by intraperitoneal route. The rats were euthanized from 7 to 31 days after EB or saline injection and brainstem sections were collected and processed for light and transmission electron microscopy studies. Results from different groups were compared by using a semi-quantitative method developed for documenting the extent and nature of remyelination in semithin sections following gliotoxic lesions. Results showed that CsA administration to diabetic rats after EB injection stimulate both oligodendroglial and Schwann cell remyelination (mean remyelination scores of 3.15 ± 0.5 for oligodendrocytes and 1.36 ± 0.58 for Schwann cells) compared to untreated animals (2.52 ± 0.71 for oligodendrocytes and 0.73 ± 0.47 for Schwann cells, respectively). CsA given to diabetic rats was capable of reversing some of the deleterial effects of diabetes on remyelination.