Delayed Schwann cell and oligodendrocyte remyelination after ethidium bromide injection in the brainstem of Wistar rats submitted to streptozotocin diabetogenic treatment

Abstract

Schwann cell disturbance followed by segmental demyelination in the peripheral nervous system occurs in diabetic patients. Since Schwann cell and oligodendrocyte remyelination in the central nervous system is a well-known event in the ethidium bromide (EB) demyelinating model, the aim of this investigation was to determine the behavior of both cell types after local EB injection into the brainstem of streptozotocin diabetic rats. Adult male Wistar rats received a single intravenous injection of streptozotocin (50 mg/kg) and were submitted 10 days later to a single injection of 10 µL 0.1% (w/v) EB or 0.9% saline solution into the cisterna pontis. Ten microliters of 0.1% EB was also injected into non-diabetic rats. The animals were anesthetized and perfused through the heart 7 to 31 days after EB or saline injection and brainstem sections were collected and processed for light and transmission electron microscopy. The final balance of myelin repair in diabetic and non-diabetic rats at 31 days was compared using a semiquantitative method. Diabetic rats presented delayed macrophage activity and lesser remyelination compared to non-diabetic rats. Although oligodendrocytes were the major remyelinating cells in the brainstem, Schwann cells invaded EB-induced lesions, first appearing at 11 days in non-diabetic rats and by 15 days in diabetic rats. Results indicate that short-term streptozotocin-induced diabetes hindered both oligodendrocyte and Schwann cell remyelination (mean remyelination scores of 2.57 ± 0.77 for oligodendrocytes and 0.67 ± 0.5 for Schwann cells) compared to non-diabetic rats (3.27 ± 0.85 and 1.38 ± 0.81, respectively).

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

“…The finding of huge amounts of myelin-derived membranes in the PNS demyelinating lesions of diabetic rats resembled the one observed in the brainstem of rats immunosuppressed with cyclophosphamide 3 or dexamethasone 4 as well as in streptozotocin-diabetic rats 5 in which was observed a delay in the scavenging activi-ty of macrophages and in the subsequent CNS remyelinating process. Short-term diabetes mimics lesions of slow development induced by EB in the rat CNS and delays all the subsequent repair events 5 . Furthermore abnormal macrophage function has been described in diabetes mellitus 9,11 and may explain why clearance of cellular debris tends to be a longer-term process in the diabetic group.…”

“…By contrast there was an apparent delay in the whole remyelinating process as well as in the phagocytic activity in the lesions of diabetic rats, similar to that found in the brainstem of diabetic animals 5 , indicating that their outstanding potential to remyelinate after EB gliotoxic damage is somehow compromised by the diabetic state.…”

“…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 .…”

“…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 .…”

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

“…This gliotoxic agent is known to induce early astrocyte disappearance and oligodendroglial loss when injected in the central nervous system (CNS) leading to, respectively, blood-brain barrier disruption and primary demyelination. Subsequent remyelination occurs performed by surviving oligodendrocytes and by invasive Schwann cells [1][2][3][4][5][6] .…”