Key Laboratory of Anesthesiology of Jiangsu Province

Tongshan, China

Key Laboratory of Anesthesiology of Jiangsu Province

Tongshan, China
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Wang F.,Key Laboratory of Anesthesiology of Jiangsu Province | Wang F.,Xuzhou Medical College | Liu Q.-Z.,Nanjing General Hospital of Nanjing Military Command | Liu J.,Nanjing General Hospital of Nanjing Military Command | And 4 more authors.
Chinese Pharmacological Bulletin | Year: 2015

Aim To explore the effect of knockdown spinal cord LCN2 by RNAi on the development of morphine tolerance in normal rats. Methods After successful intrathecal implantation, fourty-eight male Sprague-Dawley rats weighing 180-220 grams were randomly divided into 4 groups (n=12): group I: control group, group II: morphine tolerance group, group IH: mismatch siRNA group, group IV: LCN2 siRNA group. The sixth day after intrathecal implantation, rats were tested to ensure the position of catheters, and it was recorded as d 0. On d 2-8, rats were subcutaneously (s. c) injected of normal saline (NS) (group I) or morphine (group II, III, IV) 10 μg g-1 twice a day at 8:00 and 16:00. Before everyday s. c injection, rats were intrathecally injected of 10 μL DEPC solution (group I, JJ), 10 μL DEPC solution containing 4 μg mismatch siRNA (group III) and 4 μg LCN2 siRNA solution (group IV). Paw withdrawal latencies to thermal stimuli (PWTL) were tested before morphine injection and 45 minutes after morphine injection on d 1 and d 9. The percentage of maximal possible effect (% MPE) was calculated later. Animals were sacrificed on d 9 after the behavioral test and the lumbar enlargement segments of the spinal cord were removed for detecting the expression of phosphorylated-p38 mitogen-activated protein kinase (p-p38 MAPK) and LCN2 by Western blot and microglia marker Ibal by immunofluorecence. Results On d 1, there was no significant difference in % MPE among four groups. On d 9, compared to group I, % MPE was significantly reduced (P<0.05) while p-p38MAPK, LCN2 and Ibal were markedly up-regulated in group II and HI (P < 0. 05). On d 9, compared to group II, % MPE was significantly increased while p-p38MAPK, LCN2 and Ibal were markedly reduced in group IV (P <0. 05). Conclusion Using LCN2 siRNA to knockdown spinal LCN2 relieves the development of morphine tolerance in normal rats possibly through inhibiting the activation of microglia and p38 MAPK in the spinal cord.


Ye X.,The Affiliated Hospital of Xuzhou Medical University | Kong D.,The Affiliated Hospital of Xuzhou Medical University | Wang J.,Emory University | Ishrat T.,Emory University | And 6 more authors.
Biochemical and Biophysical Research Communications | Year: 2016

Myeloid differentiation primary-response protein-88 (MyD88) is one of adaptor proteins mediating Toll-like receptors (TLRs) signaling. Activation of MyD88 results in the activation of nuclear factor kappa B (NFκB) and the increase of inflammatory responses. Evidences have demonstrated that TLRs signaling contributes to cerebral ischemia/reperfusion (I/R) injury. However, the role of MyD88 in this mechanism of action is disputed and needs to be clarified. In the present study, in a mouse model of cerebral I/R, we examined the activities of NFκB and interferon factor-3 (IRF3), and the inflammatory responses in ischemic brain tissue using ELISA, Western blots, and real-time PCR. Neurological function and cerebral infarct size were also evaluated 24 h after cerebral I/R. Our results showed that NFκB activity increased in ischemic brains, but IRF3 was not activated after cerebral I/R, in wild-type (WT) mice. MyD88 deficit inhibited the activation of NFκB, and the expression of interleukin-1β (IL-1β), IL-6, Beclin-1 (BECN1), pellino-1, and cyclooxygenase-2 (COX-2) increased by cerebral I/R compared with WT mice. Interestingly, the expression of interferon Beta 1 (INFB1) and vascular endothelial growth factor (VEGF) increased in MyD88 KO mice. Unexpectedly, although the neurological function improved in the MyD88 knockout (KO) mice, the deficit of MyD88 failed to reduce cerebral infarct size compared to WT mice. We concluded that MyD88-dependent signaling contributes to the inflammatory responses induced by cerebral I/R. MyD88 deficit may inhibit the increased inflammatory response and increase neuroprotective signaling. © 2016 The Authors

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