Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor

Middlemas, Alicia; Agthong, Sithiporn; Tomlinson, David R.

doi:10.1007/s00125-005-0133-z

Cited by 12 publications

(6 citation statements)

References 25 publications

(31 reference statements)

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“…This is an important observation considering that SAPK/JNK activation has also been identified in sural nerve of human subjects with diabetes mellitus [40]. In the present study, increased phosphorylation of p38 MAPK, ERK, and SAPK/JNK was detected in peripheral nerve, spinal cord, and DRG of diabetic mice, consistent with the data for DRG reported for diabetic rats by others [14, 40, 68]. The mechanisms underlying MAPK activation in tissue-sites for DPN remain unknown, although oxidative stress was implicated in p38 MAPK and ERK, but not SAPK/JNK, activation in DRG neurons [14, 40].…”

Section: Discussionsupporting

confidence: 92%

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Stavniichuk

Shevalye

Hirooka³

et al. 2012

Biochemical Pharmacology

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The interactions among multiple pathogenetic mechanisms of diabetic peripheral neuropathy largely remain unexplored. Increased activity of aldose reductase, the first enzyme of the sorbitol pathway, leads to accumulation of cytosolic Ca++, essentially required for 12/15-lipoxygenase activation. The latter, in turn, causes oxidative-nitrosative stress, an important trigger of MAPK phosphorylation. This study therefore evaluated the interplay of aldose reductase, 12/15-lipoxygenase, and MAPKs in diabetic peripheral neuropathy. In experiment 1, male control and streptozotocin-diabetic mice were maintained with or without the aldose reductase inhibitor fidarestat, 16 mg kg−1 d−1, for 12 weeks. In experiment 2, male control and streptozotocin-diabetic wild-type (C57Bl6/J) and 12/15-lipoxygenase-deficient mice were used. Fidarestat treatment did not affect diabetes-induced increase in glucose concentrations, but normalized sorbitol and fructose concentrations (enzymatic spectrofluorometric assays) as well as 12(S) hydroxyeicosatetraenoic concentration (ELISA), a measure of 12/15-lipoxygenase activity, in the sciatic nerve and spinal cord. 12/15-lipoxygenase expression in these two tissues (Western blot analysis) as well as dorsal root ganglia (immunohistochemistry) was similarly elevated in untreated and fidarestat-treated diabetic mice. 12/15-lipoxygenase gene deficiency prevented diabetesassociated p38 MAPK and ERK, but not SAPK/JNK, activation in the sciatic nerve (Western blot analysis) and all three MAPK activation in the dorsal root ganglia (immunohistochemistry). In contrast, spinal cord p38 MAPK, ERK, and SAPK/JNK were similarly activated in diabetic wild-type and 12/15-lipoxygenase−/− mice. These findings identify the nature and tissue specificity of interactions among three major mechanisms of diabetic peripheral neuropathy, and suggest that combination treatments, rather than monotherapies, can sometimes be an optimal choice for its management.

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Section: Discussionsupporting

confidence: 92%

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Stavniichuk

Shevalye

Hirooka³

et al. 2012

Biochemical Pharmacology

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“…To evaluate if the inhibition of MAPK activated by inflammatory pain is also involved in the effects produced by SFN, we investigated the expression of phosphorylated JNK, ERK1/2, and p38 in the spinal cord and paw tissues from mice treated with SFN. It is well known that the activation of JNK executes an important role in the development and maintenance of chronic pain (Middlemas et al, 2006;Gao and Ji, 2008). Our findings confirmed these results with the increased levels of phosphorylated JNK in the spinal cord as well as in the paw from mice with chronic inflammatory pain, and furthermore revealed that treatment with SFN completely reduced the JNK activation in both tissues.…”

Section: Discussionsupporting

confidence: 90%

Treatment with Sulforaphane Produces Antinociception and Improves Morphine Effects during Inflammatory Pain in Mice

Redondo

Ferreira-Chamorro

Riego

et al. 2017

J Pharmacol Exp Ther

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The activation of nuclear factor erythroid 2-related factor 2 (Nrf2) exerts potent antioxidative and anti-inflammatory effects; however, its participation in the modulation of chronic inflammatory pain and on the antinociceptive effects of -opioid receptor (MOR) agonists has not been evaluated. We investigated whether the induction of Nrf2 could alleviate chronic inflammatory pain and augment the analgesic effects of morphine and mechanisms implicated. In male C57BL/6 mice with inflammatory pain induced by complete Freund's adjuvant (CFA) subplantarly administered, we assessed: 1) antinociceptive actions of the administration of 5 and 10 mg/kg of a Nrf2 activator, sulforaphane (SFN); and 2) effects of SFN on the antinociceptive actions of morphine and on protein levels of Nrf2, heme oxygenase 1 (HO-1), and NAD(P)H: quinone oxidoreductase 1 (NQO1) enzymes, microglial activation and inducible nitric oxide synthase (NOS2) overexpression, as well as on mitogen-activated protein kinase (MAPK) and MOR expression in the spinal cord and paw of animals with inflammatory pain. Results showed that treatment with SFN inhibited allodynia and hyperalgesia induced by CFA and increased the local antinociceptive actions of morphine. This treatment also augmented the expression of Nrf2, HO-1, NQO1, and MOR, and inhibited NOS2 and CD11b/c overexpression and MAPK phosphorylation induced by inflammation. Thus, this study shows that the induction of Nrf2 might inhibit inflammatory pain and enhance the analgesic effects of morphine by inhibiting oxidative stress and inflammatory responses induced by peripheral inflammation. This study suggests the administration of SFN alone and in combination with morphine are potential new ways of treating chronic inflammatory pain.

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“…The increased activation of JNK/SAPK present in diabetic AR +/+ mice was absent in diabetic AR −/− mice, thus suggesting a detrimental role for JNK/SAPK. In agreement with the results obtained by Ho et al (2006) , Middlemas et al (2006) have shown in STZ‐induced diabetic rats an increase in activated JNK/SAPK and c‐Jun (transcriptional substrates both of p38 and of JNK/SAPK), primarily associated with nociceptors and sensitive to fidarestat (a specific ARI) administration. These results support the hypothesis that JNK/SAPK may be the glucose transducer via the polyol pathway and that its phosphorylation could impair nerve conduction and induce neuropathic pain.…”

Section: Diabetic Neuropathysupporting

confidence: 91%

Emerging role of mitogen‐activated protein kinases in peripheral neuropathies

Cavaletti

Miloso

Nicolini

et al. 2007

J Peripheral Nervous Sys

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Among the different families of intracellular molecules that can be modulated during cell damage and repair, mitogen-activated protein kinases (MAPKs) are particularly interesting because they are involved in several intracellular pathways activated by injury and regeneration signals. Despite most of the studies have been performed in non-neurological models, recently a causal role for MAPKs has been postulated in central nervous system disorders. However, also in some peripheral neuropathies, MAPK changes can occur and these modifications might be relevant in the pathogenesis of the damage as well as during regeneration and repair. In this review, the current knowledge on the role of MAPKs in peripheral neuropathies will be discussed.

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Phosphorylation of c-Jun N-terminal kinase (JNK) in sensory neurones of diabetic rats, with possible effects on nerve conduction and neuropathic pain: prevention with an aldose reductase inhibitor

Cited by 12 publications

References 25 publications

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Interplay of sorbitol pathway of glucose metabolism, 12/15-lipoxygenase, and mitogen-activated protein kinases in the pathogenesis of diabetic peripheral neuropathy

Treatment with Sulforaphane Produces Antinociception and Improves Morphine Effects during Inflammatory Pain in Mice

Emerging role of mitogen‐activated protein kinases in peripheral neuropathies

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