Abstract
The diabetic state induced by streptozotocin injection is known to impair oligodendroglial remyelination in the rat brainstem following intracisternal injection with the gliotoxic agent ethidium bromide (EB). In such experimental model, propentofylline (PPF) recently showed to improve myelin repair, probably due to its neuroprotective, antiinflammatory and antioxidant effects. The aim of this study was to evaluate the effect of PPF administration in diabetic rats submitted to the EB-demyelinating model. Adult male rats, diabetic or not, received a single injection of 10 microlitres of 0.1% EB solution into the cisterna pontis. For induction of diabetes mellitus the streptozotocin-diabetogenic model was used (50 mg/kg, intraperitoneal route - IP). Some diabetic rats were treated with PPF (12.5 mg/kg/day, IP route) during the experimental period. The animals were anesthetized and perfused from 7 to 31 days after EB injection and brainstem sections were collected for analysis of the lesions by light and transmission electron microscopy. Diabetic rats injected with EB showed larger amounts of myelin-derived membranes in the central areas of the lesions and considerable delay in the remyelinating process played by surviving oligodendrocytes and invading Schwann cells after the 15th day. On the other hand, diabetic rats that received PPF presented lesions similar to those of non-diabetic animals, with rapid remyelination at the edges of the lesion site and fast clearance of myelin debris from the central area. The administration of PPF apparently reversed the impairment in remyelination induced by the diabetic state.
Highlights
I t is widely described that focal injection of the gliotoxic agent ethidium bromide (EB) in the white matter of the central nervous system (CNS) causes local oligodendroglial and astrocytic death, with consequent primary demyelination, blood-brain barrier disruption and Schwann cell invasion due to the glia limitans breakdown [1,2,3,4,5,6]
Diabetic rats were distributed into two groups – untreated rats and rats treated with 12.5 mg/kg/day of PPF (Agener União Química, São Paulo, SP, 20 mg/mL solution) by IP route during the experimental period
Differences in remyelination between diabetic rats from group I and diabetic rats treated with PPF or non-diabetic rats from group III clearly appeared from day 15 p.i. as the last two groups presented a greater proportion of oligodendrocyte remyelinated axons when compared to the diabetic ones without PPF
Summary
I t is widely described that focal injection of the gliotoxic agent ethidium bromide (EB) in the white matter of the central nervous system (CNS) causes local oligodendroglial and astrocytic death, with consequent primary demyelination, blood-brain barrier disruption and Schwann cell invasion due to the glia limitans breakdown [1,2,3,4,5,6]. Glial modifications were clearly pointed in some studies using streptozotocin-diabetic rats after the injection of EB [13,14,15], with marked delay on macrophagic scavenging activity of myelin debris, on oligodendrocyte and Schwann cell remyelination [13], on blood-brain barrier repair [14] as well as on glial fibrillary acidic protein (GFAP) expression in reactive astrocytes at the periphery of the injury site [15].
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