Levomilnacipran ameliorates lipopolysaccharide-induced depression-like behaviors and suppressed the TLR4/Ras signaling pathway.

Levomilnacipran, a serotonin and norepinephrine reuptake inhibitor, has been reported to have anti-depressive effects. However, the detailed mechanisms underlying these effects are still unclear. This study aimed to investigate the antidepressant mechanisms of levomilnacipran to discover new perspectives on the treatment of depression in male rats. Intraperitoneal injection of lipopolysaccharide (LPS) was used to induce depressive behaviors in rats. Activation of microglia and apoptosis of neurons verified by immunofluorescence. Inflammatory related proteins and neurotrophic related proteins were verified by immunoblotting. The mRNA expression of apoptosis markers was verified by real-time quantitative PCR. Finally, electron microscopy analysis was used to observe the ultrastructural pathology of neuron. Here, we found that the anti-depression and anti-anxiety effects of levomilnacipran in the LPS-induced rat model of depression was resulted from the suppression of neuroinflammation and neuronal apoptosis within prefrontal cortex of rats. Furthermore, we found that levomilnacipran could decrease the number of microglia and suppress its activation in prefrontal cortex of rats. This effect may be mediated by suppressing the TLR4/NF-κB and Ras/p38 signaling pathways. In addition, levomilnacipran plays a neuroprotective role by increasing the expression of neurotrophic factors. Taken together, these results suggest that levomilnacipran exerts antidepressant effects by attenuating neuroinflammation to inhibit the damage in central nervous system and plays a neuroprotective role to improve depressive behaviors. These findings suggest that suppression of neuroinflammation in prefrontal cortex could ameliorate depressive behavioral disorder of rats induced by LPS, which provided a new perspective for the treatment of depression.

Levomilnacipran: More of the Same?

OBJECTIVE: The primary objective of this narrative review is to provide clinicians an in-depth analysis of the mechanism of action, pharmacokinetics, toxicology, and efficacy of levomilnacipran. We propose that unlike selective serotonin reuptake inhibitors (SSRIs), or even their precursor serotonin-norepinephrine reuptake inhibitors (SNRIs), levomilnacipran demonstrates a potentially unique ability to alleviate the fatigue symptom cluster of major depressive disorder (MDD). DATA SOURCES: A literature review was completed in PubMed using the MeSH term levomilnacipran. STUDY SELECTION: Inclusion criteria were English-language only, randomized controlled trials and systematic reviews published through March 2019. Analyses using product labels and anecdotal or uncontrolled reports of clinical applications were excluded. Only published data from short-term and long-term trials were analyzed. The search resulted in 73 articles. The evidence-based review comprises a total of 31 articles. DATA SYNTHESIS: The data analyzed suggest that levomilnacipran has evidence in the treatment of MDD. More specifically, data suggest that levomilnacipran may be unique among SSRI and SNRI antidepressants in its ability to improve the fatigue symptom cluster in MDD. CONCLUSIONS: Further investigations are warranted into levomilnacipran's potentially unique ability to alleviate the fatigue symptom cluster of MDD. Future head-to-head studies and studies that assess for clinically relevant improvements in fatigue are needed.