Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

Kim, Hyoh; Sasaki, Teiji; Maeda, Kengo; Koya, Daisuke; Kashiwagi, Atsunori; Yasuda, Hitoshi

doi:10.2337/diabetes.52.8.2102

Cited by 58 publications

(34 citation statements)

References 53 publications

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“…In this study, the immunohistochemical results clearly demonstrated the in situ translocation of PKC-␣ isoform from the membrane to the cytoplasm, which accords with the results of our Western blot analysis. Contrariwise, PKC-␤II isoform in diabetic transgenic mice was slightly elevated, consistent with the data obtained from the STZ rat model (35,36). Interestingly, ARI treatment corrected the alterations of both PKC-␣ and -␤II isoforms.…”

Section: Discussionsupporting

confidence: 78%

“…Our study revealed that the pain sensation in diabetic animals was initially hyperalgesic followed by late hypoesthesia in the presence of a progressive delay of both MNCV and SNCV. This result argues against the results obtained from the STZ-induced diabetic rat (36) and the diabetic mice with short duration (40). We only conducted the paw withdrawal test under mechanical pressure for the pain sensation and therefore need further evaluation using different methods such as a test for thermal sensitivities.…”

Section: Discussioncontrasting

confidence: 46%

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Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

et al. 2004

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We explored the specific impact of polyol pathway hyperactivity on dorsal root ganglia (DRG) using transgenic mice that overexpress human aldose reductase because DRG changes are crucial for the development of diabetic sensory neuropathy. Littermate mice served as controls. Half of the animals were made diabetic by streptozotocin injection and followed for 12 weeks. After diabetes onset, diabetic transgenic mice showed a significant elevation of pain sensation threshold after transient decrease and marked slowing of motor and sensory nerve conduction at the end of the study, while these changes were modest in diabetic littermate mice. Protein kinase C (PKC) activities were markedly reduced in diabetic transgenic mice, and the changes were associated with reduced expression of membrane PKC-␣ isoform that was translocated to cytosol. Membrane PKC-␤II isoform expression was contrariwise increased. Calcitonin gene-related peptide-and substance P-positive neurons were reduced in diabetic transgenic mice and less severely so in diabetic littermate mice. Morphometric analysis disclosed neuronal atrophy only in diabetic transgenic mice. Treatment with an aldose reductase inhibitor (fidarestat 4 mg ⅐ kg -1 ⅐ day -1, orally) corrected all of the changes detected in diabetic transgenic mice. These findings underscore the pathogenic role of aldose reductase in diabetic sensory neuropathy through the altered cellular signaling and peptide expressions in DRG neurons. Diabetes 53:3239 -3247, 2004 P olyol pathway hyperactivity has been extensively studied for the mechanisms of diabetic neuropathy, where aldose reductase is a key regulating enzyme (1,2). In animal models, diabetes-induced peripheral nerve conduction deficits, neurometabolic imbalances, altered nerve blood flow, and morphologic abnormalities are prevented by structurally diverse aldose reductase inhibitors (ARIs) (3-5). Past clinical trials of ARIs were not, however, convincingly successful (6,7), and specific effects of polyol pathway hyperactivity on the clinical and structural aspects of diabetic sensory neuropathy is yet to be clear (8,9). The development of a transgenic animal model provides an ideal tool to identify the specific role of single molecules in disease mechanisms. We have established a strain of transgenic mice that overexpress human aldose reductase (10 -12). In this model, we confirmed that polyol pathway hyperactivity was indeed related to the severity of motor nerve conduction delay and nerve fiber atrophy. More recently, a new transgenic model that overexpresses aldose reductase, specifically in Schwann cells by use of myelin protein Po promoter, has enabled researchers to address more precise mechanisms of polyol pathway in the development of neuropathy in diabetes (13). Nevertheless, from these studies, it was not shown which measures were comparable with those found in human diabetic neuropathy, and it still remains obscure what could be the most appropriate target for the intervention with a potent and specific inhibitor for human aldos...

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Section: Discussionsupporting

confidence: 78%

Section: Discussioncontrasting

confidence: 46%

Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

et al. 2004

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“…In rats with streptozotocin-induced diabetes, decreases in the number of NOS-expressing neurons, in nNOS expression and cGMP content were revealed in DRGs together with mechanical hyperalgesia that all were completely prevented by insulin treatment (360,628). In subsequent studies, however, no significant change in nNOS mRNA levels was observed in DRG neurons; moreover, increased NOS activity was revealed as late as 12 mo after diabetes induction (446,806).…”

Section: Experimental Paradigms Yielding Inconsistent Results Regardimentioning

confidence: 94%

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Pethő

Reeh

2012

Physiological Reviews

244

200

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Peripheral mediators can contribute to the development and maintenance of inflammatory and neuropathic pain and its concomitants (hyperalgesia and allodynia) via two mechanisms. Activation or excitation by these substances of nociceptive nerve endings or fibers implicates generation of action potentials which then travel to the central nervous system and may induce pain sensation. Sensitization of nociceptors refers to their increased responsiveness to either thermal, mechanical, or chemical stimuli that may be translated to corresponding hyperalgesias. This review aims to give an account of the excitatory and sensitizing actions of inflammatory mediators including bradykinin, prostaglandins, thromboxanes, leukotrienes, platelet-activating factor, and nitric oxide on nociceptive primary afferent neurons. Manifestations, receptor molecules, and intracellular signaling mechanisms of the effects of these mediators are discussed in detail. With regard to signaling, most data reported have been obtained from transfected nonneuronal cells and somata of cultured sensory neurons as these structures are more accessible to direct study of sensory and signal transduction. The peripheral processes of sensory neurons, where painful stimuli actually affect the nociceptors in vivo, show marked differences with respect to biophysics, ultrastructure, and equipment with receptors and ion channels compared with cellular models. Therefore, an effort was made to highlight signaling mechanisms for which supporting data from molecular, cellular, and behavioral models are consistent with findings that reflect properties of peripheral nociceptive nerve endings. Identified molecular elements of these signaling pathways may serve as validated targets for development of novel types of analgesic drugs.

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“…Traditional approaches to PKC inhibition have been marred by toxicity and lack of specificity. However, more recently, a range of less toxic and more specific approaches to PKC inhibition (21), including specific ␤-isoform inhibitors such as ruboxistaurin (LY 333531), that have been used in preclinical and clinical studies of diabetic retinopathy (22), neuropathy (23), and vascular dysfunction (24) have been developed. In diabetic nephropathy, ruboxistaurin is currently undergoing clinical eval- (17,26).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cβ Inhibition Attenuates Osteopontin Expression, Macrophage Recruitment, and Tubulointerstitial Injury in Advanced Experimental Diabetic Nephropathy

Kelly

Chanty

Gow

et al. 2005

Journal of the American Society of Nephrology

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Tubulointerstitial macrophage accumulation is an important marker of prognosis that correlates closely with declining renal function in a range of human and experimental diseases, including diabetic nephropathy. These inflammatory cells are rich in the profibrotic growth factor TGF-␤ such that their presence in areas of injury is frequently associated with tissue fibrosis. The migration of macrophages occurs in response to the site-specific production of chemokines, with osteopontin closely associated with their trafficking into the tubulointerstitium of the kidney. Although cell culture studies indicate that protein kinase C (PKC) mediates the expression of osteopontin, its role in the in vivo setting is unknown. Accordingly, Ren-2 control and diabetic rats that were treated with or without the specific PKC-␤ isoform inhibitor ruboxistaurin (10 mg/kg per d) were examined. After 12 wk, diabetic rats showed increases in osteopontin expression in tubular epithelial cells of the cortex in association with macrophage infiltration, interstitial fibrosis, and activity of TGF-␤ as indicated by the expression of its receptor activated protein phospho-Smad2 (P < 0.05 for all parameters). Ruboxistaurin treatment significantly attenuated these parameters (P < 0.05) in diabetic rats without affecting either BP or glycemic control. These findings suggest that osteopontin and macrophage accumulation may play a role in the tubulointerstitial injury in diabetic nephropathy and that inhibition of osteopontin expression may be one of the mechanisms by which inhibition of the ␤-isoform of PKC confers a renoprotective effect.

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Protein Kinase Cβ Selective Inhibitor LY333531 Attenuates Diabetic Hyperalgesia Through Ameliorating cGMP Level of Dorsal Root Ganglion Neurons

Cited by 58 publications

References 53 publications

Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

Effects of Polyol Pathway Hyperactivity on Protein Kinase C Activity, Nociceptive Peptide Expression, and Neuronal Structure in Dorsal Root Ganglia in Diabetic Mice

Sensory and Signaling Mechanisms of Bradykinin, Eicosanoids, Platelet-Activating Factor, and Nitric Oxide in Peripheral Nociceptors

Protein Kinase Cβ Inhibition Attenuates Osteopontin Expression, Macrophage Recruitment, and Tubulointerstitial Injury in Advanced Experimental Diabetic Nephropathy

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