Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice
| العنوان: | Inhibiting heat-shock protein 90 reverses sensory hypoalgesia in diabetic mice |
|---|---|
| المؤلفون: | Roger A. Rajewski, Rick T. Dobrowsky, Michael Joseph Urban, Brian S. J. Blagg, Michelle P. McIntosh, Cuijuan Yu, Joanna Krise, Yuanming Lu, Chengyuan Li |
| المصدر: | ASN NEURO ASN Neuro, Vol 2 (2010) |
| سنة النشر: | 2010 |
| مصطلحات موضوعية: | medicine.medical_treatment, Mice, 0302 clinical medicine, Diabetic Neuropathies, heat-shock protein 70 (HSP70), Ganglia, Spinal, Cells, Cultured, Pain Measurement, Mice, Knockout, 0303 health sciences, Mice, Inbred BALB C, diabetes, General Neuroscience, Axotomy, Anatomy, diabetic neuropathy, 3. Good health, medicine.anatomical_structure, Neuregulin, Novobiocin, medicine.drug, medicine.medical_specialty, Sensory Receptor Cells, Schwann cell, S7, Biology, S3, lcsh:RC321-571, Diabetes Mellitus, Experimental, 03 medical and health sciences, Internal medicine, medicine, heat-shock protein (HSP), Animals, Humans, HSP90 Heat-Shock Proteins, MNCV, motor nerve conduction velocity, lcsh:Neurosciences. Biological psychiatry. Neuropsychiatry, 030304 developmental biology, Hypoalgesia, Insulin, HSP, heat-shock protein, IENF, intra-epidermal nerve fibres, Streptozotocin, medicine.disease, Sensory neuron, Coculture Techniques, Rats, Mice, Inbred C57BL, Peripheral neuropathy, Endocrinology, Commentary, Neurology (clinical), 030217 neurology & neurosurgery |
| الوصف: | Increasing the expression of Hsp70 (heat-shock protein 70) can inhibit sensory neuron degeneration after axotomy. Since the onset of DPN (diabetic peripheral neuropathy) is associated with the gradual decline of sensory neuron function, we evaluated whether increasing Hsp70 was sufficient to improve several indices of neuronal function. Hsp90 is the master regulator of the heat-shock response and its inhibition can up-regulate Hsp70. KU-32 (N-{7-[(2 R, 3 R, 4S, 5 R)-3, 4-dihydroxy-5-methoxy-6, 6-dimethyl-tetrahydro-2H-pyran-2-yloxy]-8-methyl-2-oxo-2H-chromen-3-yl}acetamide) was developed as a novel, novobiocin-based, C-terminal inhibitor of Hsp90 whose ability to increase Hsp70 expression is linked to the presence of an acetamide substitution of the prenylated benzamide moiety of novobiocin. KU-32 protected against glucose-induced death of embryonic DRG (dorsal root ganglia) neurons cultured for 3 days in vitro. Similarly, KU-32 significantly decreased neuregulin 1-induced degeneration of myelinated Schwann cell DRG neuron co-cultures prepared from WT (wild-type) mice. This protection was lost if the co-cultures were prepared from Hsp70.1 and Hsp70.3 KO (knockout) mice. KU-32 is readily bioavailable and was administered once a week for 6 weeks at a dose of 20 mg/kg to WT and Hsp70 KO mice that had been rendered diabetic with streptozotocin for 12 weeks. After 12 weeks of diabetes, both WT and Hsp70 KO mice developed deficits in NCV (nerve conduction velocity) and a sensory hypoalgesia. Although KU-32 did not improve glucose levels, HbA1c (glycated haemoglobin) or insulin levels, it reversed the NCV and sensory deficits in WT but not Hsp70 KO mice. These studies provide the first evidence that targeting molecular chaperones reverses the sensory hypoalgesia associated with DPN. |
| تدمد: | 1759-0914 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::cc8d0090fcc341f67aa1d1f75a3dea41Test https://pubmed.ncbi.nlm.nih.gov/20842208Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....cc8d0090fcc341f67aa1d1f75a3dea41 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 17590914 |
|---|