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There is an increasing awareness that diabetes has an impact on the CNS and that diabetes is a risk factor for Alzheimer's disease (AD). Links between AD and diabetes point to impaired insulin signaling as a common mechanism leading to defects in the brain. However, diabetes is predominantly characterized by peripheral, rather than central, neuropathy, and despite the common central mechanisms linking AD and diabetes, little is known about the effect of AD on the peripheral nervous system (PNS). In this study, we compared indexes of peripheral neuropathy and investigated insulin signaling in the sciatic nerve of insulin-deficient mice and amyloid precursor protein (APP) overexpressing transgenic mice. Insulin-deficient and APP transgenic mice displayed similar patterns of peripheral neuropathy with decreased motor nerve conduction velocity, thermal hypoalgesia, and loss of tactile sensitivity. Phosphorylation of the insulin receptor and glycogen synthase kinase 3β (GSK3β) was similarly affected in insulin-deficient and APP transgenic mice despite significantly different blood glucose and plasma insulin levels, and nerve of both models showed accumulation of Aβ-immunoreactive protein. Although diabetes and AD have different primary etiologies, both diseases share many abnormalities in both the brain and the PNS. Our data point to common deficits in the insulin-signaling pathway in both neurodegenerative diseases and support the idea that AD may cause disorders outside the higher CNS., (Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.)

There are sporadic reports that assorted combinations of B vitamins can alleviate pain in diabetic patients, but there is neither agreement on the relative efficacy of individual B vitamins nor understanding of the mechanisms involved. We therefore investigated the efficacy of a cocktail of the vitamins B1, B6 and B12 in alleviating behavioral indices of sensory dysfunction such as allodynia and hyperalgesia in diabetic rats and also the relative contribution of individual components of the cocktail. Repeated daily treatment with the cocktail of B vitamins for 7-9 days ameliorated tactile allodynia and formalin-evoked hyperalgesia in a dose-dependent manner and also improved sensory nerve conduction velocity in diabetic rats. Investigation of the contribution of individual B vitamins suggested that all three participated with variable efficacy in the alleviation of allodynia after protracted, but not single dose treatment. Only vitamin B6 improved sensory nerve conduction velocity slowing in diabetic rats when given alone. To address potential mechanisms of action, we measured markers of oxidative stress (lipid and protein oxidation) and inflammation (cyclooxygenase-2 (COX-2) and TNFalpha protein) in the nerve but treatment with the vitamin B cocktail did not significantly affect any of these parameters. The positive effects of B vitamins on functional and behavioral disorders of diabetic rats suggest a potential for use in treating painful diabetic neuropathy.

We investigated the ability of Neotrofin, an agent that enhances endogenous nerve growth factor (NGF) levels, to prevent phenotypic, functional and structural changes that occur in the peripheral nerve of streptozotocin-diabetic rats. Eight weeks of Neotrofin treatment prevented depletion of NGF protein in plantar foot skin and sciatic nerve of diabetic rats and increased NGF protein in associated skeletal muscles. These effects were accompanied by maintenance of normal nerve levels of the neuropeptides substance P and calcitonin gene related peptide. Thermal hypoalgesia and conduction slowing of large sensory fibres in diabetic rats were ameliorated by Neotrofin treatment, whereas there was no effect on conduction slowing in large motor fibres or on reduced myelinated fibre axonal calibre. Enhancing endogenous production of neurotrophic factors using small molecules may be an alternative to either exogenous treatment with neurotrophic factors or gene therapy as a therapeutic approach to treating diabetic neuropathy.

Paclitaxel (Taxol), a chemotherapeutic agent used to treat breast and ovarian tumors, has been reported to induce a predominantly sensory neuropathy. Co-treatment with neurotrophic factors and paclitaxel has been proposed for preventing or reversing paclitaxel-induced peripheral neuropathy. Prosaposin, the precursor of saposins A, B, C and D was recently identified as a neurotrophic factor and was reported to facilitate nerve regeneration in vivo. Peptides (prosaptides) encompassing the neurotrophic sequence located in the saposin C domain, have neurotrophic activity similar to the holoprotein (O'Brien et al. 1995). In the present study, we investigated the effect of a 14-mer prosaptide, TX14(A), or a 22-mer prosaptide, 769P, on paclitaxel-induced neutrotoxicity in vitro and in vivo. Paclitaxel treatment (1 microM) decreased cell viability of both PC12 and Schwann cells. TX14(A) (10 nM) prevented paclitaxel-induced loss of cell viability in PC12 cells but not in Schwann cells. Systemic injections (i.p.) of paclitaxel (1.2 mg/kg/day) given five times per week for three weeks (cumulative dose 18 mg/kg) or given every third day (25, 12.5 and 12.5 mg/kg) for 10 ten days (cumulative dose 50 mg/kg) in adult rats induced thermal hypoalgesia that was not accompanied by morphological changes in the sciatic nerve or changes of nerve conduction velocity. Co-administration of paclitaxel with prosaptides (cumulative dose 3 or 10 mg/kg) prevented paclitaxel-induced thermal hypoalgesia. In the short-term high dose study, paclitaxel treated rats lost 10% of their body weight, had reduced erythrocyte counts, hematocrit and hemoglobin concentrations which were not prevented by treatment with prosaptide. TX14(A) did not diminish paclitaxel cytotoxicity of breast cancer cells in vitro. These findings suggest that prosaptide prevents the neurotoxic effects of paclitaxel while not interfering with its anti-tumor activity.

This study examined the effect of two structurally dissimilar aldose reductase inhibitors, N-[[5-(trifluoromethyl)-6-methoxy-1- napthalenyl]thioxomethyl]-N-methlyglycine (tolrestat) and 4-amino-2,6-dimethylphenyl-sulphonyl nitromethane (ICI 222155), on formalin-evoked behavioural responses in control and diabetic rats and on capsaicin-evoked release of prostaglandin E from spinal cord slices in vitro. Both compounds, given orally for 4 weeks, prevented hyperalgesia in diabetic rats 5-20 min after hindpaw formalin injection. ICI 222155 also prevented hyperalgesia in diabetic rats 21-60 min after formalin, whereas tolrestat suppressed activity in diabetic rats below controls and also suppressed activity in controls when given orally or intrathecally. Capsaicin-evoked release of prostaglandin E from spinal cord slices of control rats was significantly reduced by tolrestat, but not ICI 222155. These data suggest that hyperalgesia in diabetic rats is related to glucose metabolism by aldose reductase, whereas tolrestat has specific effects on formalin-evoked nociception associated with an ability to reduce spinal prostaglandin release.

Two chemically distinct aldose reductase inhibitors, ponalrestat and tolrestat, were tested against laser Doppler blood flow and conduction deficits in the sciatic nerve of diabetic rats. The effects of two months of streptozotocin-induced diabetes and aldose reductase inhibition on body weight, plasma glucose, and nerve sugars and polyols were comparable to those reported previously. Nerve blood flow, reflected by laser Doppler flow measurements, and motor nerve conduction velocity were both significantly less in diabetic than in control animals. Both of these reductions were prevented by ponalrestat, but not tolrestat. Thus, either deficits in laser Doppler blood flow and conduction are not aldose reductase inhibitor-dependent or tolrestat has some other property which offsets the beneficial effects of aldose reductase inhibition. In either case, these data are consistent with the hypothesis that reduced nerve blood flow contributes to conduction deficits in diabetes.

Nerve conduction abnormalities in peripheral nerves from diabetic patients may be early indicators for the future development of symptomatic neuropathy. In this study, three weeks of experimental diabetes in the rat caused a significant decrease in motor nerve conduction velocity measured in vivo (45.3 +/- 3.6 m/s; mean +/- S.D.) compared to controls (57.7 +/- 4.5 m/s). myo-Inositol administration to diabetic rats (500 mg/rat per day) for the duration of the study, partially prevented this decrease (50 +/- 4.4 m/s). An analogue of myo-inositol, PP56 (D-myo-inositol-1,2,6-trisphosphate), at a dose of 24 mg/rat per day completely prevented this reduction in diabetic rats (53.4 +/- 5.8 m/s). Resistance to hypoxic conduction block was determined in vitro in endoneurial preparations and was assessed as the decline in compound action potential amplitude over a 40 min period of hypoxia. Compound action potential amplitude (as % of initial value +/- S.D.) was significantly greater in diabetic preparations compared with controls at 40 min of hypoxia (76.1 +/- 9.1 vs. 54.8 +/- 14.7 respectively). Treatment to diabetic rats with myo-inositol did not significantly affect this value (79.9 +/- 16.6) but PP56 treatment partially prevented the increased resistance to hypoxic conduction block (69.4 +/- 16.0). This study demonstrates that these acute abnormalities of nerve function in early experimental diabetes may be attenuated by the administration of PP56, possibly acting via a vascular mechanism.