Ammoxetine attenuates diabetic neuropathic pain through inhibiting microglial activation and neuroinflammation in the spinal cord

Autor: Lei An, Juan Li, Qiong-Yin Fan, Lei Zhu, Fan Shiyong, Rui Xue, Li-Ming Zhang, Yun-Feng Li, Zhong Bohua, Ting-Ting Zhang, Yu-Hua Ran, Caiying Ye, You-Zhi Zhang
Rok vydání: 2018
Předmět:
Lipopolysaccharides
0301 basic medicine
MAPK/ERK pathway
Pharmacology
lcsh:RC346-429
0302 clinical medicine
Diabetic Neuropathies
Cell Line
Transformed
SNRI
Propylamines
Microglia
biology
Kinase
General Neuroscience
Microfilament Proteins
Myelitis
medicine.anatomical_structure
Neurology
Hyperalgesia
Mitogen-activated protein kinase
Neuropathic pain
Cytokines
Locomotion
p38 mitogen-activated protein kinases
Immunology
Duloxetine Hydrochloride
Streptozocin
03 medical and health sciences
Cellular and Molecular Neuroscience
Ammoxetine
Glia
medicine
Animals
Hypoglycemic Agents
Benzodioxoles
lcsh:Neurology. Diseases of the nervous system
Neuroinflammation
Dose-Response Relationship
Drug
business.industry
Calcium-Binding Proteins
Rats
Disease Models
Animal
030104 developmental biology
Exploratory Behavior
biology.protein
Diabetic neuropathic pain
Serotonin
business
030217 neurology & neurosurgery
Zdroj: Journal of Neuroinflammation, Vol 15, Iss 1, Pp 1-13 (2018)
ISSN: 1742-2094
Popis: 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.
Databáze: OpenAIRE
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