Dissection of Metabolic, Vascular, and Nerve Conduction Interrelationships in Experimental Diabetic Neuropathy by Cyclooxygenase Inhibition and Acetyl-<scp>l</scp>-Carnitine Administration

Pop‐Busui, Rodica; Marinescu, Victor; Huysen, Carol Van; Li, Fēi; Sullivan, Kelli A.; Greene, Douglas A.; Larkin, Dennis; Stevens, Martin J.

doi:10.2337/diabetes.51.8.2619

Cited by 93 publications

(77 citation statements)

References 85 publications

(103 reference statements)

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“…We postulated that upregulation of COX-2, by inflammatory stimuli (12,13), protein kinase C activation (14), and/or oxidative stress (15), contributes to an altered prostaglandin (PG) profile in diabetes that favors vasoconstriction and additional ROS generation, further exacerbating oxidative stress (16). We have also shown that short-term selective chemical COX-2 inhibition in rats and COX-2 gene inactivation in mice prevented diabetes-induced functional and biochemical peripheral nerve deficits (11,16).…”

mentioning

confidence: 81%

“…Male Wistar rats (200 -250 g) were purchased from Charles River (Wilmington, MA). After fasting overnight, rats were rendered diabetic by STZ as previously described (11). Experimental groups comprised of nondiabetic and diabetic rats (eight or more per group) were randomly assigned to either no treatment or treatment with the selective COX-2 inhibitor (IC50 4.8 nmol/l) celecoxib (50 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 in drinking water) and maintained for up to 6 months.…”

Section: Methodsmentioning

confidence: 99%

“…Western blot analysis. Nerve tissue from treated and untreated nondiabetic and diabetic rats were analyzed as previously described (11). Rabbit anti-COX-1 and -COX-2 antibodies (1:100) (Santa Cruz, CA) or mouse antiglyceraldehyde 3-phosphate dehydrogenase (1:5,000) (Chemicon, Temecula, CA) were used to visualize the selected proteins.…”

Section: Methodsmentioning

confidence: 99%

“…We have previously demonstrated a link between hyperglycemia and cyclooxygenase (COX)-2 activation in the pathogenesis of experimental DPN (11). We postulated that upregulation of COX-2, by inflammatory stimuli (12,13), protein kinase C activation (14), and/or oxidative stress (15), contributes to an altered prostaglandin (PG) profile in diabetes that favors vasoconstriction and additional ROS generation, further exacerbating oxidative stress (16).…”

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confidence: 99%

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Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes

et al. 2007

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OBJECTIVE—Activation of the cyclooxygenase (COX) pathway with secondary neurovascular deficits are implicated in the pathogenesis of experimental diabetic peripheral neuropathy (DPN). The aim of this study was to explore the interrelationships between hyperglycemia, activation of the COX-2 pathway, and oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long-term experimental diabetes. RESEARCH DESIGN AND METHODS—Motor and sensory digital nerve conduction velocities, sciatic nerve indexes of oxidative stress, prostaglandin content, markers of inflammation, and intraepidermal nerve fiber (IENF) density were measured after 6 months in control and diabetic COX-2–deficient (COX-2−/−) and littermate wild-type (COX-2+/+) mice. The effects of a selective COX-2 inhibitor, celecoxib, on these markers were also investigated in diabetic rats. RESULTS—Under normal conditions, there were no differences in blood glucose, peripheral nerve electrophysiology, markers of oxidative stress, inflammation, and IENF density between COX-2+/+ and COX-2−/− mice. After 6 months, diabetic COX-2+/+ mice experienced significant deterioration in nerve conduction velocities and IENF density and developed important signs of increased oxidative stress and inflammation compared with nondiabetic mice. Diabetic COX-2−/− mice were protected against functional and biochemical deficits of experimental DPN and against nerve fiber loss. In diabetic rats, selective COX-2 inhibition replicated this protection. CONCLUSIONS—These data suggest that selective COX-2 inhibition may be useful for preventing or delaying DPN.

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confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes

et al. 2007

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“…nuclear factor-kappa B, activator protein-1, signal transducer and activator of transcription-1, octamer-1 and p53 protein via direct binding, poly(ADPribosyl)ation or both [8,9]. This, in turn, up-regulates numerous genes [9,10], including those implicated in the pathogenesis of peripheral diabetic neuropathy (PDN), such as endothelin-1 [11], cyclooxygenase-2 [12,13] and inflammatory genes [14]. Thus, PARP activation can be a trigger of multiple mechanisms implicated in diabetes-associated neuropathic changes.…”

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confidence: 99%

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

Szabó

Pacher

et al. 2004

Diabetologia

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Aims/hypothesis. Poly(ADP-ribose) polymerase activation depletes NAD + and high-energy phosphates, activates protein kinase C, and affects gene expression in various tissues. This study was designed to characterise the effects of the potent, orally active poly(ADP-ribose) polymerase inhibitor PJ34 in the Wistar rat model of early diabetic neuropathy. Methods. Control and streptozotocin-diabetic rats were maintained with or without PJ34 treatment (30 mg·kg −1 ·day −1 ) for two weeks, after two weeks without treatment. Endoneurial blood flow was assessed by hydrogen clearance; metabolites and highenergy phosphates were assayed by enzymatic spectrofluorometric methods; and poly(ADP-ribose) was detected by immunohistochemistry.Results. Blood glucose concentrations were increased to a similar extent in untreated and PJ34-treated diabetic rats compared with controls. Intense poly(ADPribose) immunostaining was observed in the sciatic nerve of diabetic rats, but not in other groups. Final sciatic motor nerve conduction velocity and digital sensory nerve conduction velocity were reduced by 24% and 22% respectively in diabetic rats compared with controls (p<0.01 for both), and both were 98% corrected by PJ34 (p<0.01 vs diabetic group for both).In contrast, with PJ34 treatment, nerve blood flow showed a modest (17%) increase, and vascular conductance showed a tendency to increase. Free mitochondrial and cytosolic NAD + :NADH ratios, assessed from the glutamate and lactate dehydrogenase systems, phosphocreatine concentrations, and phosphocreatine:creatine ratios were decreased in diabetic rats and essentially normalised by PJ34. In both untreated and PJ34-treated diabetic rats, nerve glucose, sorbitol and fructose were increased to a similar extent. PJ34 did not affect any variables in control rats. Conclusions/interpretation. Short-term poly(ADP-ribose) polymerase inhibitor treatment reverses functional and metabolic abnormalities of early diabetic neuropathy. Complete normalisation of nerve blood flow is not required for correction of motor or sensory nerve conduction velocities, provided that a therapeutic agent can restore nerve energy state via direct action on Schwann cells.Keywords Energy state · Motor and sensory nerve conduction · Nerve blood flow · Oxidative and nitrosative stress · Peripheral diabetic neuropathy · PJ34 · Poly(ADP-ribose) polymerase · Rat · Sorbitol pathway of glucose metabolism · Streptozotocindiabetes

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Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy

et al. 2017

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Morin, a bioflavonoid with diverse pharmacological effects against various diseases; in most cases morin protective effects were attributed to its detoxifying effect against reactive oxygen species (ROS). Diabetic neuropathy (DN) is a chronic, debilitating neuronal pain associated with intense generation of free radicals and proinflammatory cytokine accumulation in peripheral neurons. We investigated the pharmacological effect of morin against metabolic excess mediated mitochondrial ROS generation and corresponding effect on Nrf2, NF-κB pathways in Streptozotocin (STZ)-induced diabetic rats and in high glucose insulted Mouse neuroblastoma cell line, Neuro 2A (N2A). Animals were evaluated for nerve function parameters, motor and sensory nerve conduction velocities (MNCV and SNCV) and nerve blood flow (NBF) followed by TUNEL and immunoblot analysis. Mitochondrial function was evaluated by performing JC-1 and MitoSOX assays in high glucose (30 mM) incubated N2A cells. Diabetic animals showed significant impairment in MNCV, SNCV, and NBF as well as increased pain hypersensitivity. However, oral administration of morin at 50 and 100 mg/kg improved SNCV, MNCV, and NBF and reduced sensorimotor alterations (hyperalgesia and allodynia) in diabetic animals. Studies in N2A cells have revealed that morin ameliorated the high glucose-induced mitochondrial superoxide production, membrane depolarization, and total ROS generation. Morin effectively counteracted NF-κB-mediated neuroinflammation by reducing ROS mediated IKK activation and increased Nrf2-mediated antioxidant defenses in high glucose-induced N2A cells. The results of our study suggest that morin has exquisite role in offering neuroprotection in experimental DN and further clinical investigation may reward in finding better alternative for the management of DN. © 2017 BioFactors, 44(2):109-122, 2018.

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Dissection of Metabolic, Vascular, and Nerve Conduction Interrelationships in Experimental Diabetic Neuropathy by Cyclooxygenase Inhibition and Acetyl-l-Carnitine Administration

Abstract: Alterations in cyclooxygenase (COX) pathway activity have been implicated in the pathogenesis of experimental diabetic neuropathy (EDN).

Cited by 93 publications

References 85 publications

Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes

Protective Effects of Cyclooxygenase-2 Gene Inactivation Against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fiber Loss in Experimental Diabetes

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

Morin exerts neuroprotection via attenuation of ROS induced oxidative damage and neuroinflammation in experimental diabetic neuropathy

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