Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

OBJECTIVE-Peripheral neuropathy associated with type 2 diabetes (DPN) is not widely modeled. We describe unique features of DPN in type 2 diabetic Zucker diabetic fatty (ZDF) rats.RESEARCH DESIGN AND METHODS-We evaluated the structural, electrophysiological, behavioral, and molecular features of DPN in ZDF rats and littermates over 4 months of hyperglycemia. The status of insulin signaling transduction molecules that might be interrupted in type 2 diabetes and selected survival-, stress-, and pain-related molecules was emphasized in dorsal root ganglia (DRG) sensory neurons.RESULTS-ZDF rats developed slowing of motor sciatic-tibial and sensory sciatic digital conduction velocity and selective mechanical allodynia with preserved thermal algesia. Diabetic sural axons, preserved in number, developed atrophy, but there was loss of large-calibre dermal and small-calibre epidermal axons. In diabetic rats, insulin signal transduction pathways in lumbar DRGs were preserved or had trends toward upregulation: mRNA levels of insulin receptor ␤-subunit (IR␤), insulin receptor substrate (IRS)-1, and IRS-2. The numbers of neurons expressing IR␤ protein were also preserved. There were trends toward early rises of mRNA levels of heat shock protein 27 (HSP27), the ␣2␦1 calcium channel subunit, and phosphatidylinositol 3-kinase in diabetes. Others were unchanged, including nuclear factor-B (NF-B; p50/p105) and receptor for advanced glycosylation endproducts (RAGE) as was the proportion of neurons expressing HSP27, NF-B, and RAGE protein.CONCLUSIONS-ZDF type 2 diabetic rats develop a distal degenerative sensory neuropathy accompanied by a selective long-term pain syndrome. Neuronal insulin signal transduction molecules are preserved.

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“…It does this by inhibiting cytochrome c-mediated apoptosis (47), stabilizing mRNA, and stabilizing the neuron cytoskeleton (48,49).…”

Section: Discussionmentioning

confidence: 99%

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

et al. 2008

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“…In addition, this chaperone is known to contribute to preconditioning induced by a range of stimuli including opioids, isoproterinol, and ischemia (28)(29)(30). The protective effect of Hsp27 may include an anti-apoptotic role, which has been implicated in studies reporting an interaction of Hsp27 with cytochrome c and inhibition of apoptosome function (31).…”

Section: Discussionmentioning

confidence: 99%

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Moench

Prentice

Rickaway³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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We have recently shown that sulindac, an anti-inflammatory drug, enhances the killing of cancer cells, but not normal cells, under conditions of oxidative stress, by mechanisms unrelated to its cyclooxygenase (COX) inhibition. To further study the protective effect of sulindac on cells exposed to oxidative stress, we have investigated the effect of sulindac on rat cardiac myocytes subjected to hypoxia/reoxygenation, as well as in a Langendorff model of myocardial ischemia. Low levels of sulindac could protect cardiac myocytes against cell death due to hypoxia/reoxygenation. In the Langendorff model sulindac provided significant protection against cell death, when the drug was fed to the animals before the removal of the heart for the Langendorff procedure. The results indicate that the primary protective effect of sulindac in these experiments does not involve its role as a COX inhibitor. Numerous signaling pathways have been implicated in myocardial protective mechanisms, many of which involve fluctuations in reactive oxygen species (ROS) levels. The results suggest that low levels of sulindac can induce a preconditioning response, triggered by ROS, to protect cardiac tissues against oxidative damage. Blocking of preconditioning pathways by administration of the PKC blocker chelerythrine abrogated the ischemic protection afforded by sulindac. Secondly, after feeding of sulindac, two end-effectors of preconditioning, inducible nitric oxide synthase and heat shock protein 27, were found to be markedly induced in the heart, dependent on PKC. These results suggest that sulindac may have therapeutic potential as a preconditioning agent.cardioprotection ͉ myocardial ischemia

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“…Immunostaining of free-floating thoracic and lumbar spinal cord sections (30 µm) was performed as previously described (46,47) using the Elite ABC Kit (Vector Laboratories, Burlingame, CA, USA). Sections were first washed for 10 min in PBS with 0.3% Triton X-100 (PBST) and then incubated for 30 min in ice-cold methanol containing 1% H 2 O 2 to abolish endogenous peroxidase activity.…”

Section: Immunohistochemistrymentioning

confidence: 99%

Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice

Hendricks

Pak

Owensby

et al. 2006

Mol Med

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Embryonic stem (ES) cells have been investigated in repair of the CNS following neuronal injury and disease; however, the efficacy of these cells in treatment of postinjury pain is far from clear. In this study, we evaluated the therapeutic potential of predifferentiated mouse ES cells to restore sensory deficits following spinal cord injury (SCI) in mice. The pain model used unilateral intraspinal injection of quisqualic acid (QUIS) into the dorsal horn between vertebral levels T13 and L1. Seven days later, 60,000 predifferentiated ES cells or media were transplanted into the site of the lesion. Histological analysis at 7, 14, and 60 days posttransplantation revealed that animals receiving ES cell transplants suffered significantly less tissue damage than animals receiving media alone. Transplanted cells provided immediate effects on both spontaneous and evoked pain behaviors. Treatment with ES cells resulted in 0% (n = 28) excessive grooming behavior versus 60% (18 of 30) in media-treated animals. In the acetone test (to assess thermal allodynia), mice recovered to preinjury levels by 12 days after ES cell transplant, whereas control animals injected with media after SCI did not show any improvement up to 60 days. Similarly, the von Frey test (to assess mechanical allodynia) and the formalin test (to assess nociceptive hyperalgesia) showed that transplantation of predifferentiated ES cells significantly reduced these pain behaviors following injury. Here we show that predifferentiated ES cells act in a neuroprotective manner and provide antinociceptive and therapeutic effects following excitotoxic SCI.

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Crosstalk between p38, Hsp25 and Akt in spinal motor neurons after sciatic nerve injury

Cited by 92 publications

References 29 publications

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

Distal Degenerative Sensory Neuropathy in a Long-Term Type 2 Diabetes Rat Model

Sulindac confers high level ischemic protection to the heart through late preconditioning mechanisms

Predifferentiated Embryonic Stem Cells Prevent Chronic Pain Behaviors and Restore Sensory Function Following Spinal Cord Injury in Mice

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