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While enhanced nociceptor activity has been demonstrated in models of painful peripheral neuropathy, analyses of activity pattern, which could play a role in the symptoms experienced as well as help elucidate underlying mechanism, are still limited. We evaluated the pattern of C-fiber activity, in response to mechanical and chemical stimuli, in a rat model of diabetes induced by a pancreatic β-cell toxin, streptozotocin (STZ). In diabetic rats the number of action potentials produced by threshold and suprathreshold (10 g) sustained (60 s) mechanical stimuli was elevated in approximately half of C-fibers. These high-firing C-fibers demonstrated a disproportionate increase in interspike intervals (ISIs) between 100 and 199 ms, compared with low-firing diabetic and control C-fibers. The co-efficient of variability (CV2), a frequency independent measure of ISI variability, was also greater in high-firing fibers, compared with control fibers. Unexpectedly, instantaneous frequency of the initial burst of activity during the first second was lower in high-firing fibers, even though the average frequency over the last 59 s was significantly higher. The number of action potentials evoked by a noxious chemical stimulus, 300 and 600 mM KCl, injected adjacent to the mechanical receptive field was also significantly increased in C-fibers from diabetic rats and mechanically high-firing fibers had more action potentials in response to KCl than control fibers and a disproportionate increase in ISIs between 100 and 199 ms for responses to chemical stimuli appeared only in mechanically high-firing C-fibers, compared with the mechanically low-firing diabetic or control C-fibers. There was, however, no corresponding change in CV2 or instantaneous frequency plots for the response to chemical stimulation in mechanically high-firing fibers, as there was in the response to mechanical stimulation. Our data demonstrate specific changes in firing pattern of high-firing C-fibers in the rat model of painful neuropathy produced by STZ-diabetes that might contribute to the symptoms experienced by patients. [Copyright &y& Elsevier]

Sensory neurons mediate diabetic peripheral neuropathy. Using a mouse model of diabetic peripheral neuropathy (BKS.Cg-m+/+Lepr(db)/J (db/db) mice) and cultured dorsal root ganglion (DRG) neurons, the present study showed that hyperglycemia downregulated miR-146a expression and elevated interleukin-1 receptor-activated kinase (IRAK1) and tumor necrosis factor receptor-associated factor 6 (TRAF6) levels in DRG neurons. In vitro, elevation of miR-146a by miR-146a mimics in DRG neurons increased neuronal survival under high-glucose conditions. Downregulation and elevation of miR-146a in DRG neurons, respectively, were inversely related to IRAK1 and TRAF6 levels. Treatment of diabetic peripheral neuropathy with sildenafil, a phosphodiesterase type 5 inhibitor, augmented miR-146a expression and decreased levels of IRAK1 and TRAF6 in the DRG neurons. In vitro, blockage of miR-146a in DRG neurons abolished the effect of sildenafil on DRG neuron protection and downregulation of IRAK1 and TRAF6 proteins under hyperglycemia. Our data provide the first evidence showing that miR-146a plays an important role in mediating DRG neuron apoptosis under hyperglycemic conditions., (Published by Elsevier Ltd.)

Previous research has demonstrated that diabetes induces learning and memory deficits. However, the mechanism of memory impairment induced by diabetes is poorly understood. Dietary fatty acids, especially polyunsaturated fatty acids, have been shown to enhance learning and memory and prevent memory deficits in various experimental conditions. The present study investigated the effects of fish oil supplementation on the lipid peroxidation, inflammation and neuron apoptosis in the hippocampus of streptozotocin (STZ)-induced diabetes rats. The effects of diabetes and fish oil treatment on the spatial learning and memory were also evaluated using the Morris Water Maze. STZ-induced diabetes impaired spatial learning and memory of rats, which was associated with the inflammation, oxidative stress and apoptosis of hippocampal neurons. Fish oil administration ameliorated cognitive deficit, reduced oxidative stress and tumor necrosis factor α (TNF-α), protected the hippocampal neurons by increasing Protein Kinase B (AKT) phosphorylation and decreasing caspase-9 expression. These results suggested that the principle mechanisms involved in the antidiabetic and neuroprotective effect of fish oil were its antioxidant, anti-inflammatory and anti-apoptosis potential, supporting a potential role for fish oil as an adjuvant therapy for the prevention and treatment of diabetic complications., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Diabetes type 1 is a common autoimmune disease manifesting by insulin deficiency and hyperglycemia, which can lead to dementia-like brain dysfunctions. The factors triggering the pathological processes in hyperglycemic brain remain unknown. We reported in this study that brain areas with different susceptibility to diabetes (prefrontal cortex (PFC), hippocampus, striatum and cerebellum) revealed differential alterations in ceramide (Cer) and sphingomyelin (SM) profiles in rats with streptozotocin-induced hyperglycemia. Employing gas-liquid chromatography, we found that level of total Cer increased significantly only in the PFC of diabetic animals, which also exhibited a broad spectrum of sphingolipid (SLs) changes, such as elevations of Cer-C16:0, -C18:0, -C20:0, -C22:0, -C18:1, -C24:1 and SM-C16:0 and -C18:1. In opposite, only minor changes were noted in other examined structures. In addition, de novo synthesis pathway could play a role in generation of Cer containing monounsaturated fatty acids in PFC during hyperglycemia. In turn, simultaneous accumulation of Cers and their SM counterparts may suggest that overproduced Cers are converted to SMs to avoid excessive Cer-mediated cytotoxicity. We conclude that broad changes in SLs compositions in PFC induced by hyperglycemia may provoke membrane rearrangements in some cell populations, which can disturb cellular signaling and cause tissue damage., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Calcium/calmodulin-dependent protein kinase II (CaMKII) has been implicated in the transmission of nociceptive input in diabetic neuropathy. The aim of this study was to test whether intraganglionic (i.g.) injection of CaMKII inhibitors may alleviate pain-related behavior in diabetic rats. Diabetes was induced in Sprague-Dawley rats using 55 mg/kg streptozotocin intraperitoneally. Two weeks after diabetes induction, CaMKII inhibitors myristoil-AIP and KN93 were injected directly into the right L5 dorsal root ganglion (DRG). Behavioral testing with mechanical and thermal stimuli was performed before induction of diabetes, the day preceding the injection, as well as 2 and 24h after the i.g. injection. The expression of total CaMKII and its alpha isoform in DRG neurons was analyzed using immunohistochemistry. CaMKII inhibitors attenuated pain-related behavior in a modality-specific fashion. Attenuation of nociceptive behavior was accompanied with a corresponding decrease of CaMKII alpha expression in DRG neurons on the side of injection. A significant decrease of CaMKII alpha expression was seen in small- and medium-sized neurons. In conclusion, our study provides evidence that CaMKII inhibitors are potential pharmacological agents that should be further explored for treatment of diabetic neuropathy symptoms., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

Diabetes is associated with an increased risk for brain disorders, namely cognitive impairments associated with hippocampal dysfunction underlying diabetic encephalopathy. However, the impact of a prediabetic state on cognitive function is unknown. Therefore, we now investigated whether spatial learning and memory deficits and the underlying hippocampal dysfunction were already present in a prediabetic animal model. Adult Wistar rats drinking high-sucrose (HSu) diet (35% sucrose solution during 9 weeks) were compared to controls' drinking water. HSu rats exhibited fasting normoglycemia accompanied by hyperinsulinemia and hypertriglyceridemia in the fed state, and insulin resistance with impaired glucose tolerance confirming them as a prediabetic rodent model. HSu rats displayed a poorer performance in hippocampal-dependent short- and long-term spatial memory performance, assessed with the modified Y-maze and Morris water maze tasks, respectively; this was accompanied by a reduction of insulin receptor-β density with normal levels of insulin receptor substrate-1 pSer636/639, and decreased hippocampal glucocorticoid receptor levels without changes of the plasma corticosterone levels. Importantly, HSu animals exhibited increased hippocampal levels of AMPA and NMDA receptor subunits GluA1 and GLUN1, respectively, whereas the levels of protein markers related to nerve terminals (synaptophysin) and oxidative stress/inflammation (HNE, RAGE, TNF-α) remained unaltered. These findings indicate that 9 weeks of sucrose consumption resulted in a metabolic condition suggestive of a prediabetic state, which translated into short- and long-term spatial memory deficits accompanied by alterations in hippocampal glutamatergic neurotransmission and abnormal glucocorticoid signaling., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)

The role of spinal cannabinoid systems in neuropathic pain of streptozotocin (STZ)-induced diabetic mice was studied. In normal mice, injection of the cannabinoid receptor agonist WIN-55,212-2 (1 and 3μg, i.t.) dose-dependently prolonged the tail-flick latency, whereas there were no changes with the injection of either cannabinoid CB1 (AM 251, 1 μg, i.t.) or CB2 (AM 630, 4 μg, i.t.) receptor antagonists. AM 251 (1 μg, i.t.), but not AM 630 (4 μg, i.t.), significantly inhibited the prolongation of the tail-flick latency induced by WIN-55,212-2 (3 μg, i.t.). In STZ-induced diabetic mice, the tail-flick latency was significantly shorter than that in normal mice. A low dose of WIN-55,212-2 (1 μg, i.t.) significantly recovered the tail-flick latency in STZ-induced diabetic mice. The effect of WIN-55,212-2 (1 μg, i.t.) in STZ-induced diabetic mice was significantly inhibited by AM 630 (4 μg, i.t.), but not AM 251 (1 μg). The selective cannabinoid CB2 receptor agonist L-759,656 (19 and 38 μg, i.t.) also dose-dependently recovered the tail-flick latency in STZ-induced diabetic mice, and this recovery was inhibited by AM 630 (4 μg, i.t.). The protein levels of cannabinoid CB1 receptors, CB2 receptors and diacylglycerol lipase α (DGL-α), the enzyme that synthesizes endocannabinoid 2-arachidonoylglycerol, in the spinal cord were examined using Western blotting. The protein levels of both cannabinoid CB1 and CB2 receptors were increased in STZ-induced diabetic mice, whereas the protein level of DGL-α was significantly decreased. These results indicate that spinal cannabinoid systems are changed in diabetic mice and suggest that cannabinoid CB2 receptor agonists might have an ability to recover diabetic neuropathic pain., (Copyright © 2013 IBRO. Published by Elsevier Ltd. All rights reserved.)