BackgroundDiabetic 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.MethodsThe 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.ResultsTreatment 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.ConclusionOur 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.

Selective serotonin reuptake inhibitors (SSRIs) bind 5-HT transporters, leading to the accumulation of 5-HT and amelioration of depression. Although different mouse strains show varying sensitivity to SSRIs in mouse models of depression, the underlying mechanism of these strain differences remains unclear. Here, the SSRI citalopram dose-dependently reduced immobility time in both the FST and TST in DBA/2J mice but not C57BL/6J mice, whereas fluoxetine showed the opposite results. Paroxetine similarly reduced immobility time in both strains. The affinity of citalopram for the 5-HT transporter was 700-fold higher in DBA/2J mice than in C57BL/6J mice, whereas the affinity of fluoxetine was 100-fold higher in C57BL/6J mice than in DBA/2J mice. Furthermore, high citalopram concentrations were required for [3H]5-HT uptake in C57BL/6J but not in DBA/2J mouse cortical synaptosomes, whereas fluoxetine showed the opposite results. The effects of paroxetine on 5-HT transporter binding and synaptosomal 5-HT uptake were similar in the two strains. These results suggest that immobility duration depends on 5-HT transporter binding levels, which lead to apparent strain differences in immobility time in the FST and TST. Furthermore, differences in 5-HT transporter binding may cause variations in SSRI effects on behaviors.

No abstract

YL-0919 has been identified as a novel dual 5-HT partial agonist and serotonin reuptake inhibitor. In the current study, we demonstrated that YL-0919 produced prominent antidepressant-like and anxiolytic-like effects in a chronic unpredictable stress (CUS) rat model. Male SD rats were exposed to CUS for 5 weeks; YL-0919 (1.25 and 2.5 mg/kg) or a positive control fluoxetine (Flx, 10 mg/kg) was orally administered daily. YL-0919 or Flx treatment significantly increased the sucrose preference rate, the locomotor activity in an open field test (OFT), the latency to feed in a novelty-suppressed feeding test (NSFT), and both the percentage of time spent in the open arms and the number of entries into the open arms in an elevated plus-maze test. YL-0919 or Flx treatment significantly suppressed the serum levels of ACTH and corticosterone in CUS-exposed rats. Additionally, YL-0919 or Flx treatment significantly enhanced the levels of cAMP, the expression of phosphorylated cAMP response element-binding protein (pCREB) and brain-derived neurotrophic factor (BDNF) in the hippocampus of CUS-exposed rats. Similar to Flx, YL-0919 treatment significantly enhanced the dendritic complexity, and increased the number of dendritic nodes as well as the spine length and number of branch nodes in the hippocampal pyramidal neurons of CUS-exposed rats. Overall, our results reveal that YL-0919 suppresses the HPA axis and exerts antidepressant-like and anxiolytic-like effects in CUS-exposed rats, which are associated with the enhanced cAMP signaling and hippocampal dendritic complexity.

These data suggest that YL-0919 is probably a fast-onset potent antidepressant with few side effects.