Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord
Abstract Background Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for...
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | Journal of Neuroinflammation |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12974-018-1216-3 |
| _version_ | 1818041834458316800 |
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| author | Ting-Ting Zhang Rui Xue Shi-Yong Fan Qiong-Yin Fan Lei An Juan Li Lei Zhu Yu-Hua Ran Li-Ming Zhang Bo-Hua Zhong Yun-Feng Li Cai-Ying Ye You-Zhi Zhang |
| author_facet | Ting-Ting Zhang Rui Xue Shi-Yong Fan Qiong-Yin Fan Lei An Juan Li Lei Zhu Yu-Hua Ran Li-Ming Zhang Bo-Hua Zhong Yun-Feng Li Cai-Ying Ye You-Zhi Zhang |
| author_sort | Ting-Ting Zhang |
| collection | DOAJ |
| description | Abstract Background Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. Methods The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. Results Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. Conclusion Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism. |
| first_indexed | 2024-12-10T08:36:43Z |
| format | Article |
| id | doaj.art-390fc61dea9e4a97a7ad99cd4387098f |
| institution | Directory Open Access Journal |
| issn | 1742-2094 |
| language | English |
| last_indexed | 2024-12-10T08:36:43Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Neuroinflammation |
| spelling | doaj.art-390fc61dea9e4a97a7ad99cd4387098f2022-12-22T01:55:56ZengBMCJournal of Neuroinflammation1742-20942018-06-0115111310.1186/s12974-018-1216-3Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cordTing-Ting Zhang0Rui Xue1Shi-Yong Fan2Qiong-Yin Fan3Lei An4Juan Li5Lei Zhu6Yu-Hua Ran7Li-Ming Zhang8Bo-Hua Zhong9Yun-Feng Li10Cai-Ying Ye11You-Zhi Zhang12Institute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyDepartment of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyDepartment of Pharmacology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical CollegeInstitute of Pharmacology and Toxicology, Beijing Key laboratory of NeuropsychopharmacologyAbstract Background Diabetic neuropathic pain (DNP) is a common and distressing complication in patients with diabetes, and the underlying mechanism remains unclear. Tricyclic antidepressants (TCAs) and serotonin and norepinephrine reuptake inhibitors (SNRIs) are recommended as first-line drugs for DNP. Ammoxetine is a novel and potent SNRI that exhibited a strong analgesic effect on models of neuropathic pain, fibromyalgia-related pain, and inflammatory pain in our primary study. The present study was undertaken to investigate the chronic treatment properties of ammoxetine on DNP and the underlying mechanisms for its effects. Methods The rat model of DNP was established by a single streptozocin (STZ) injection (60 mg/kg). Two weeks after STZ injection, the DNP rats were treated with ammoxetine (2.5, 5, and 10 mg/kg/day) for 4 weeks. The mechanical allodynia and locomotor activity were assayed to evaluate the therapeutic effect of ammoxetine. In mechanism study, the activation of microglia, astrocytes, the protein levels of pro-inflammatory cytokines, the mitogen-activated protein kinases (MAPK), and NF-κB were evaluated. Also, microglia culture was used to assess the direct effects of ammoxetine on microglial activation and the signal transduction mechanism. Results Treatment with ammoxetine for 4 weeks significantly relieved the mechanical allodynia and ameliorated depressive-like behavior in DNP rats. In addition, DNP rats displayed increased activation of microglia in the spinal cord, but not astrocytes. Ammoxetine reduced the microglial activation, accumulation of pro-inflammatory cytokines, and activation of p38 and c-Jun N-terminal kinase (JNK) in the spinal cord of DNP rats. Furthermore, ammoxetine displayed anti-inflammatory effects upon challenge with LPS in BV-2 microglia cells. Conclusion Our results suggest that ammoxetine may be an effective treatment for relieving DNP symptoms. Moreover, a reduction in microglial activation and pro-inflammatory release by inhibiting the p-p38 and p-JNK pathways is involved in the mechanism.http://link.springer.com/article/10.1186/s12974-018-1216-3AmmoxetineSNRIDiabetic neuropathic painGliaCytokinesMitogen-activated protein kinase |
| spellingShingle | Ting-Ting Zhang Rui Xue Shi-Yong Fan Qiong-Yin Fan Lei An Juan Li Lei Zhu Yu-Hua Ran Li-Ming Zhang Bo-Hua Zhong Yun-Feng Li Cai-Ying Ye You-Zhi Zhang Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord Journal of Neuroinflammation Ammoxetine SNRI Diabetic neuropathic pain Glia Cytokines Mitogen-activated protein kinase |
| title | Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| title_full | Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| title_fullStr | Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| title_full_unstemmed | Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| title_short | Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| title_sort | ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord |
| topic | Ammoxetine SNRI Diabetic neuropathic pain Glia Cytokines Mitogen-activated protein kinase |
| url | http://link.springer.com/article/10.1186/s12974-018-1216-3 |
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