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MATRIX METALLOPROTEINASES AND EXPERIMENTAL DIABETIC NEUROPATHY

Brooke, Heather

[Thesis]. Manchester, UK: The University of Manchester; 2011.

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Abstract

Diabetic symmetrical polyneuropathy is the most common secondary complication of diabetes, with no effective treatment, apart from maintaining tight glycemic control. It is therefore essential to understand the mechanisms underlying the pathogenesis of the disease in order to develop new therapeutic strategies. Biochemical and structural changes are observed in the extracellular matrix (ECM) of the peripheral nerve in diabetes: including increased endoneurial collagen; reduplication of basement membranes around endoneurial capillaries; a thickening of basal lamina; and accumulation of advanced glycation end-products (AGEs). In normal nerves, ischaemic or other damage to distal axons provokes a regenerative response; in diabetes this is abortive and failure of axonal regeneration is a hallmark of clinical and experimental diabetic neuropathy. Matrix metalloproteinases (MMPs) are a large family of zinc-dependent proteolytic enzymes that cleave the protein components of the ECM. MMP-2 and MMP-9 play a central role in Wallerian degeneration and regeneration following nerve injury. This thesis investigates whether MMP-2 and -9 expression and/or activity were altered in the peripheral nerve in diabetes, and could contribute to regenerative failure in diabetic neuropathy. Using an experimental model of diabetes, we have demonstrated that MMP-2, but not MMP-9, is upregulated at gene, protein and activity levels in the rat sciatic nerve 8 weeks post-streptozotocin (STZ). This upregulation was not maintained at later time-points of diabetes. In vitro sciatic nerve cryoculture studies showed that peripheral nerve from STZ-diabetic rats was less supportive for neurite outgrowth from dissociated adult rat sensory neurons than nerve obtained from age-matched control rats. Cyrocultures were pre-treated with either MMP-2 or chondroitinase ABC, remodelling the peripheral nerve ECM, via the removal of inhibitory chondroitin sulfate proteoglycans from the sciatic nerve, and significantly enhanced its ability to support axonal regeneration, and partially restored the diabetes-associated regenerative deficit. However, exogenous MMP-2 or MMP-9 did not directly affect neurite outgrowth of dissociated adult rat sensory neurons. Finally, we assessed the neuroprotective effects of the AGE inhibitors LR90 and pyridoxamine in experimental diabetes, using a number of electrophysiological, behavioural and biochemical endpoints. These inhibitors were effective at preventing the development of some of the functional deficits observed in STZ-diabetes. Sensory nerve conduction velocity deficits and lipid peroxidation in the sciatic nerve were prevented by both LR90 and pyridoxamine. These agents have potential for the treatment of diabetic neuropathy.