Reactive, degenerative, and proliferative Schwann cell responses in experimental galactose and human diabetic neuropathy

Abstract

Despite early descriptions of hypertrophic Schwann cells and onion-bulb formation in patients with diabetic neuropathy, clinical and experimental studies have emphasized axonal pathology. In recent years, the Schwann cell has been further implicated in diabetic neuropathy because it is the primary intrafascicular location for the first enzyme of the polyol pathway, aldose reductase, which appears to have a role in modulating a variety of complications of diabetes, including diabetic neuropathy. To further explore the role of polyol pathway flux in the pathogenesis of Schwann cell injury, ultrastructural abnormalities of Schwann cells in human diabetic neuropathy (HDN) were compared with those in experimental galactose neuropathy (EGN), a well-characterized model of hyperglycemia without hypoinsulinemia. Similar to previous studies of EGN, reactive, degenerative and proliferative changes of Schwann cells were observed after 2, 4 and 24 months of galactose intoxication. Reactive changes included accumulation of lipid droplets, pi granules of Reich and glycogen granules, increased numbers of subplasmalemmal vesicles, cytoplasmic expansion, and capping. Degenerative changes included enlargement of mitochondria and effacement of cristae, and disintegration of both abaxonal and adaxonal cytosol and organelles. Both demyelination and onion-bulb formation were seen at all time points, although supernumerary Schwann cells and axonal degeneration were most numerous after 24 months of galactose feeding. In sural nerve biopsy samples from patients with diabetes and progressive worsening of neuropathy, ultrastructural abnormalities in Schwann cells encompassed the full range of reactive, degenerative and proliferative changes described in galactose-fed rats. The concordance of fine-structural observations in nerves from galactose-fed rats and these adult-onset diabetic patients emphasizes the role of flux through aldose reductase in the complex pathology of diabetic neuropathy and points to the utility of galactose intoxication in helping to understand this metabolic disorder.

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…In addition, studies in cultured Schwann cells have suggested that increased flux through the polyol pathway drives Schwann cells towards an immature phenotype 51 . Furthermore, galactose intoxication, which increases polyol pathway activity 52 , can produce Schwann cell pathology that parallels the pathology seen in human diabetic neuropathy 29,53 , and can be prevented by inhibition of aldose reductase. This observation illustrates the cytotoxic capacity of increased flux through the aldose reductase component of the polyol pathway, and the fact that extreme stress is required to damage Schwann cells but does not necessarily evoke demyelination.…”

Evaluation of a sorbitol dehydrogenase inhibitor on diabetic peripheral nerve metabolism: a prevention study

“…Metabolic changes in nerve vasculature, with resulting decrease in nerve blood flow and endoneurial hypoxia, have a key role in nerve conduction slowing in short-term diabetes [4, 15±20]. Metabolic imbalances in the neural tissues, closely associated with impaired neurotrophism [13, 25±27, 33] and neurotransmission [34±36], contribute to Schwann cell injury [37,38] and axonopathy [39,40]. These abnormalities which develop gradually and become manifest in long-standing diabetes [38,39] exacerbate nerve functional deficits acquired in the initial phase of diabetic neuropathy.…”

“…Metabolic imbalances in the neural tissues, closely associated with impaired neurotrophism [13, 25±27, 33] and neurotransmission [34±36], contribute to Schwann cell injury [37,38] and axonopathy [39,40]. These abnormalities which develop gradually and become manifest in long-standing diabetes [38,39] exacerbate nerve functional deficits acquired in the initial phase of diabetic neuropathy. The importance of sorbitol pathway-linked metabolic imbalances in neural structures is illustrated by findings [41] of a large increase in neuroaxonal dystrophy with SDH inhibition by the dose of SDI not affecting nerve blood flow in the diabetic model of lesser duration [4].…”

An Update On Rodent Model Studies In Diabetic Neuropathy: A Brief Communication

“…Identification of supernumerary Schwann cell processes encircling thinly myelinated fibers reflects demyelination and subsequent remyelination. [34, 78,79] Similar profiles are seen in nerve from diabetic patients [34, 67,68] and can cause conduction slowing independent of axonopathy. [34,80] Although the proportion of thinly myelinated fibers was low, each cross section analyzed illustrates one of approximately 50 Schwann cells that myelinate an axon along its length, assuming a nerve of 5 cm length and an intermodal distance of 1 mm.…”