Skip to main content
NCBI home page
Frontiers in Pharmacology logoLink to Frontiers in Pharmacology
. 2026 Jun 1;17:1786578. doi: 10.3389/fphar.2026.1786578

Human placental extract, melsmon, suppresses stress-induced neuroinflammation and peripheral inflammation in a mouse model of depression

Naomi Oka 1,*, Kazuya Shimada 1, Azusa Ishii 1, Yohei Watanabe 1, Kazuhiro Kondo 2, Takeshi Yamamoto 3
PMCID: PMC13265502  PMID: 42305446

Abstract

Neuroinflammation and hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis triggered by stress have been implicated in the pathophysiology of depression, highlighting the need for novel therapeutic approaches targeting these mechanisms. Placental extracts have been reported in clinical studies to alleviate fatigue and depressive symptoms, suggesting their potential to modulate stress-induced neuroinflammatory responses and HPA-axis activation, although this has not been adequately investigated. In this study, we used a stress-sensitive depression model mouse (SITH-1 mouse), which expresses the human herpesvirus 6 (HHV-6)-derived protein SITH-1 specifically in astrocytes, and subjected it to mild stress via water immersion cage stress (WICS) to induce inflammatory cytokine expression in the brain and peripheral organs. We further examined the effects of intramuscular administration of the human placental extract “Melsmon” (20 μL per injection, administered every other day for four doses) on neuroinflammation and HPA-axis hyperactivity in this model. As a result, WICS exposure led to increased expression of inflammatory cytokines in the brain and in peripheral organs such as the liver, colon, and heart, along with elevated expression of steroidogenic acute regulatory protein (StAR), a marker of HPA-axis activation, in the adrenal gland. These changes were suppressed by Melsmon treatment. Collectively, our findings suggest that Melsmon exerts anti-inflammatory effects in both central and peripheral tissues, potentially contributing to the stabilization of the HPA axis and attenuation of stress-related inflammatory responses involved in the pathogenesis of depression. These findings suggest that placental extracts may serve as a novel therapeutic strategy for treating stress-related neuroinflammatory disorders such as depression.

Keywords: depression, inflammation, melsmon, neuroinflammation, placental extract, stress

1. Introduction

Depression is a psychiatric disorder that arises from a complex interplay of multiple factors, including chronic stress, genetic predisposition, environmental influences, and neurophysiological changes (Tafet and Nemeroff, 2016). Although the pathophysiology of depression remains incompletely understood, the monoamine hypothesis has long been dominant. However, recent studies have proposed more multifactorial hypotheses, including hyperactivation of the hypothalamic–pituitary–adrenal (HPA) axis, neuroinflammation, reduced neurogenesis, and impaired neuroplasticity (Dean and Keshavan, 2017; Ferrari and Villa, 2017; Cui et al., 2024), with particular attention being paid to the “neuroinflammation hypothesis” and the “neuroplasticity hypothesis”.

Neuroinflammation refers to the activation of glial cells such as microglia and astrocytes, leading to the production and release of inflammatory cytokines (e.g., IL-1β, IL-6, TNF-α) in the brain (Kwon and Koh, 2020). In animal models, chronic stress has been shown to activate microglia via the innate immune receptors TLR2/4, resulting in increased production of inflammatory cytokines that impair neuronal plasticity and induce depression-like behavior (Nie et al., 2018). Additionally, stress-induced activation of the sympathetic nervous system promotes the secretion of catecholamines and activates TLR4, thereby enhancing NF-κB signaling and upregulating the transcription of pro-inflammatory cytokines (Johnson et al., 2005; Gárate et al., 2013; Kuebler et al., 2015). In parallel, stress robustly activates the hypothalamic–pituitary–adrenal (HPA) axis, leading to sustained glucocorticoid release. Although glucocorticoids exert anti-inflammatory effects under physiological conditions, prolonged HPA-axis activation can lead to glucocorticoid resistance in immune cells, thereby impairing negative feedback regulation and promoting inflammatory cytokine production (Walsh, Bovbjerg, and Marsland, 2021; Hassamal, 2023).

These findings suggest that stress-induced neuroinflammatory processes, particularly when sustained, may contribute to the pathogenesis of depression (Koo and Wohleb, 2021). Inflammatory cytokines have been shown to suppress brain-derived neurotrophic factor (BDNF) expression and impair neurogenesis, dendritic growth, and synaptogenesis, thereby disrupting neural circuits involved in emotional regulation (Khairova et al., 2009; Calabrese et al., 2014; Zheng et al., 2021). Indeed, clinical studies have reported elevated levels of inflammatory cytokines in the blood of patients with depression (Maes et al., 1992; Zorrilla et al., 2001), suggesting that the stress-induced neuroinflammatory mechanisms observed in animal models may also be relevant to the pathophysiology of human depression. Based on this background, there is growing interest in developing antidepressants that target neuroinflammation and neuroplasticity. For example, glutamatergic agents such as ketamine and psilocybin have been reported to exert rapid antidepressant effects in treatment-resistant depression by promoting neuroplasticity (Rosas-Sánchez et al., 2024). Furthermore, anti-inflammatory compounds such as non-steroidal anti-inflammatory drugs (NSAIDs), cytokine inhibitors, and dipeptides that suppress microglial activation have demonstrated antidepressant-like effects (Kohler et al., 2016; Ano et al., 2019).

Our previous work demonstrated that the human herpesvirus 6 (HHV-6)-derived protein SITH-1, expressed during latent infection, activates the HPA axis and induces depression-like behavior in mice (Kobayashi et al., 2020). Mice expressing SITH-1 exhibit heightened stress sensitivity, showing depression-like behavior in response to mild stress. However, it remains unclear whether this model also displays neuroinflammatory responses, and the relationship between SITH-1 expression and neuroinflammation has not been fully explored. Given the established link between HPA-axis dysregulation and immune activation, we hypothesized that SITH-1 expression may create a stress-vulnerable state in which stress exposure triggers sustained inflammatory responses in the brain.

Among the emerging therapeutic bioproducts, placental extracts derived from mammalian placentae (e.g., human, horse, pig) have attracted increasing attention. These extracts, known to possess anti-inflammatory properties (Akagi et al., 2016; Ghoneum and El-Gerbed, 2021), have been used as pharmaceuticals and dietary supplements, particularly in several Asian countries (Yi Pan et al., 2017; Shen et al., 2022; Gwam et al., 2023). Clinical studies have suggested that various placental extracts may alleviate fatigue (Lee et al., 2012), improve osteoarthritis symptoms (Park and Cho, 2017), and reduce depressive symptoms (Kovalenko and Atalyan, 2016), indicating potential central nervous system activity of these extracts. One such extract, Melsmon®, a human placental preparation, has been reported to improve depressive symptoms and emotional instability in clinical trials (Kovalenko and Atalyan, 2016).

In this study, we investigated whether SITH-1–mediated stress vulnerability is accompanied by enhanced stress-induced inflammatory responses by applying water immersion cage stress (WICS) to SITH-1 mice and quantifying inflammatory cytokine expression in the brain and peripheral organs. We further evaluated whether administration of the human placental preparation Melsmon could attenuate these inflammatory responses. By focusing on the interplay between stress sensitivity, neuroinflammation, and HPA-axis activation, this study aimed to provide foundational evidence supporting the potential therapeutic application of placental preparations in stress-related psychiatric disorders.

2. Materials and methods

2.1. Animals

All experiments were conducted using male C57BL/6NCrSlc mice aged 8–9 weeks (body weight 22–27 g; n = 3‐5 per group), obtained from Sankyo Laboratories (Tokyo, Japan). Mice were housed under standard laboratory conditions with a 12-h light/dark cycle (lights on at 8:00 a.m.) and given ad libitum access to food and water. Mice were randomly assigned to experimental groups. All experimental procedures were approved by the Animal Experiment Committee of Jikei University School of Medicine and performed in accordance with institutional guidelines for animal care.

2.2. Production of recombinant adenovirus vectors

Recombinant adenovirus vectors were prepared as described previously (Kobayashi et al., 2020). An adenovirus expressing the HHV-6-derived SITH-1 protein under the control of the astrocyte-specific GFAP promoter was constructed using an adenovirus expression vector kit (Takara Bio Inc., Shiga, Japan) according to the manufacturer’s protocol. The GFAP promoter and PCR-amplified SITH-1 gene were cloned into an adenoviral cosmid vector (Ad-GFAP-SITH1) by standard molecular biology techniques. Recombinant adenoviruses (SITH-Ad or Vector-Ad) were generated by transfecting HEK293 A cells with the Ad-GFAP-SITH1 cosmid and a helper cosmid (pAxcwit) lacking the target gene. Viruses were purified using the Adeno-X Virus Purification Kit (Takara Bio Inc.), and viral titers were determined using the Adeno-X Rapid Titer Kit (Takara Bio Inc.).

2.3. Nasal inoculation of adenovirus vectors

Intranasal administration of adenovirus vectors was performed as previously described (Kobayashi et al., 2020). Briefly, male C57BL/6 mice aged 8–9 weeks were anesthetized with 3% isoflurane. Recombinant adenoviruses were diluted in sterile distilled water (not isotonic buffer). A total volume of 20 μL of viral solution (containing 1 × 109 infectious units [ifu]/mL of either SITH-Ad or Vector-Ad) was applied dropwise to the nostrils in multiple aliquots. The solution was passively inhaled into the nasal cavity by spontaneous breathing.

2.4. Water immersion cage stress (WICS)

Water immersion cage stress (WICS) was applied as a prolonged stress paradigm. Mice were placed in standard cages containing 1 cm of water at the bottom without bedding and maintained under these conditions for 30 h (from 10:00 to 16:00 the following day). Animals had free access to food and water during the exposure period. WICS was initiated on day 6 after SITH-1 administration, as neurobiological alterations, including olfactory bulb apoptosis, reduced hippocampal neurogenesis, and HPA-axis activation, have been shown to occur within 7 days in this model (Kobayashi et al., 2020). After 30 h of water exposure, mice were returned to standard cages with dry bedding and allowed to recover for 18 h (from 16:00 to 10:00 the next day). Following the recovery period, mice were deeply anesthetized with an overdose of isoflurane and euthanized. Brain and peripheral organs were immediately collected for subsequent analyses. This stress paradigm was selected because preliminary experiments indicated that WICS induced a transient inflammatory response in control mice, whereas inflammatory cytokine expression persisted in SITH-1 mice during the recovery period.

2.5. Drugs

The Melsmon® preparation was kindly provided by Melsmon Pharmaceutical Co., Ltd (Tokyo, Japan). The vehicle for diluting Melsmon was prepared by mixing the following components: 65 mM NaCl, 198 μM CaCl2, 129 μM MgCl2, 7.09 μM FeCl2, and 1.16 mM phosphate buffer (pH 7.0), followed by sterile filtration.

2.6. Administration of melsmon preparation

For Melsmon-treated mice, a total volume of 50 μL containing 20 μL of Melsmon and 30 μL of Melsmon vehicle was injected intramuscularly into the hind limb every other day (Figure 1A). Control mice received 50 μL of the Melsmon vehicle alone via the same route and schedule. The dose of Melsmon administered in this study was determined with reference to previously published in vivo studies using Melsmon (Park et al., 2010; Oh, Jung and Sul, 2023), in which 20 μL was administered intramuscularly under comparable experimental conditions.

FIGURE 1.

Panel A presents a timeline showing treatment of mice with Melsmon on days zero, one, two, four, and six, intranasal viral inoculation, and water immersion cage stress on day seven. Two groups of mice are depicted: one receiving SITH-1/Adv and one receiving Vector/Adv, with schematic representation of the constructs. Panel B displays a scatter plot comparing TNF-α mRNA expression in brain tissue between the vector and SITH-1 groups, showing higher expression in the SITH-1 group with statistical significance indicated by double asterisks.

Open in a new tab

Experimental protocol and elevation of brain inflammatory cytokines in SITH-1 mice following water immersion cage stress (WICS). (A) Schematic representation of the experimental protocol used in this study. Recombinant adenovirus vectors were intranasally administered, and WICS was initiated 6 days later. After 18 h of rest in the home cage, tissue samples were collected. For Melsmon treatment experiments, intramuscular injections were administered on days 0, 2, 4, and 6. (B) TNFα mRNA expression in whole brain tissue. TNFα expression in the brains of SITH-1 mice (n = 8) was significantly increased after WICS compared to control mice (n = 8). Bars represent median values. Mann–Whitney U test. **p < 0.01. Data represent pooled results from two independent experiments (4 mice per group per experiment).

2.7. Real-time PCR

Total RNA was extracted from animal tissues using the RNeasy Mini QIAcube Kit (Qiagen, Hilden, Germany). For brain samples, whole brain tissue was collected and used for RNA extraction. Complementary DNA (cDNA) was synthesized from total RNA using the PrimeScript RT Reagent Kit (Takara Bio Inc., Shiga, Japan). Quantification of mRNA levels was performed using Premix Ex Taq (Perfect Real Time; Takara Bio Inc.) on a QuantStudio Real-Time PCR System (Thermo Fisher Scientific, Waltham, MA, United States). The thermal cycling conditions were as follows: 95 °C for 30 s, followed by 45 cycles of 95 °C for 5 s and 60 °C for 31 s. Gene expression analyses were performed by a technician who was blinded to the experimental conditions. Data analysis was conducted using QuantStudio Design and Analysis Software (Thermo Fisher Scientific). The following TaqMan Gene Expression Assays (Thermo Fisher Scientific) were used: mouse TNF-α (Mm00443258_m1), mouse StAR (Mm00441558_m1), mouse IL-6 (Mm00446190_m1), and eukaryotic 18 S rRNA (Hs99999901_s1) as the internal control.

2.8. Statistical analysis

Statistical analyses were performed using GraphPad Prism software (GraphPad Software, San Diego, CA, United States). Statistical outliers were excluded using the software. For comparisons between two groups, the non-parametric Mann–Whitney U test was used. For comparisons among multiple groups, the Kruskal–Wallis test followed by Dunn’s post hoc test was employed. Red horizontal bars in the figures represent median values. A p-value of less than 0.05 was considered statistically significant.

3. Results

3.1. Induction of neuroinflammatory cytokine expression in the brains of SITH-1 mice by water immersion cage stress (WICS)

To investigate whether neuroinflammatory cytokines are induced in SITH-1 mice, which exhibit depression-like behavior under mild stress conditions, we administered an adenovirus encoding SITH-1 under an astrocyte-specific promoter via intranasal inoculation. Control mice were treated with an empty adenoviral vector. Six days after inoculation, mice were subjected to 30 h of water immersion cage stress (WICS), and brain tissues were collected 18 h after the end of stress exposure (Figure 1A). Quantitative reverse transcription real-time PCR (qRT-PCR) analysis revealed that the expression of the proinflammatory cytokine TNF-α was significantly increased in the brains of SITH-1 mice following WICS (Figure 1B). Based on this result, we next investigated whether administration of the human placental extract Melsmon could suppress this stress-induced cytokine expression.

3.2. Comparison of neuroinflammatory cytokine and adrenal StAR expression between melsmon-treated and untreated SITH-1 mice

To evaluate the effect of Melsmon on stress-induced neuroinflammation, SITH-1 mice were intramuscularly administered Melsmon every other day for a total of four doses prior to WICS exposure (Figure 1A). Following WICS, brain tissues were analyzed, and the elevated TNF-α expression observed in the brains of SITH-1 mice was significantly reduced in the Melsmon-treated group (Figure 2A). In addition, expression of the steroidogenic acute regulatory protein (StAR), a marker of HPA axis activation in the adrenal glands, was also decreased by Melsmon administration (Figure 2B).

FIGURE 2.

Figure with two scatter plots shows relative mRNA expression levels in mouse brain and adrenal gland. Panel A: TNFα mRNA in brain with significantly higher expression in the SITH-1 vehicle group compared to other groups; melsmon treatment reduces expression. Panel B: StAR mRNA in adrenal gland with significantly higher expression in the SITH-1 vehicle group compared to vector vehicle; melsmon treatment lowers expression. Statistical significance is indicated by †, *, and **.

Open in a new tab

Effects of Melsmon treatment on brain TNFα and adrenal StAR expression in WICS-exposed SITH-1 mice. (A) TNFα mRNA expression in whole brain tissue. WICS induced an increase in TNFα expression in the brains of vehicle-treated SITH-1 mice, whereas Melsmon administration significantly suppressed this elevation. Bars represent median values. Kruskal–Wallis test followed by Dunn’s post hoc test. ☨p < 0.1; **p < 0.01. Group sizes were as follows: Vector + Vehicle (n = 9), SITH-1 + Vehicle (n = 10), Vector + Melsmon (n = 10), and SITH-1 + Melsmon (n = 9). Data represent pooled results from two independent experiments (4-5 mice per group per experiment). (B) StAR mRNA expression in adrenal gland tissue. WICS significantly increased adrenal StAR expression in vehicle-treated SITH-1 mice, but this elevation was not observed in the Melsmon-treated group. Bars represent median values. Kruskal–Wallis test followed by Dunn’s post hoc test. *p < 0.05. Group sizes were as follows: Vector + Vehicle (n = 10), SITH-1 + Vehicle (n = 10), Vector + Melsmon (n = 10), and SITH-1 + Melsmon (n = 10). Data represent pooled results from two independent experiments (5 mice per group per experiment).

3.3. Comparison of peripheral inflammatory cytokine expression between melsmon-treated and untreated SITH-1 mice

Chronic activation of the HPA axis observed in SITH-1 mice has been reported to promote inflammatory cytokine production in peripheral organs (Zunszain et al., 2011; Walsh, Bovbjerg and Marsland, 2021). Moreover, peripheral inflammation can in turn promote neuroinflammation (Kempuraj et al., 2017; Hassamal, 2023). Therefore, we examined whether Melsmon could attenuate inflammatory cytokine expression in peripheral organs of WICS-exposed SITH-1 mice. qRT-PCR analysis revealed that WICS-induced expression of IL-6 in the liver (Figure 3A), TNF-α in the colon (Figure 3B), and IL-6 in the heart (Figure 3C) were all reduced in the Melsmon-treated group.

FIGURE 3.

Three grouped scatter plots display mRNA expression relative ratios for IL-6 or TNFα in liver (A), colon (B), and heart (C) among mouse groups treated with vehicle or melsmon, showing significant differences marked by symbols.

Open in a new tab

Effects of Melsmon treatment on inflammatory cytokine expression in the liver, colon, and heart of WICS-exposed SITH-1 mice. (A) IL-6 expression in the liver of vehicle-treated SITH-1 mice showed an increasing trend after WICS, which was significantly suppressed by Melsmon treatment. Bars represent median values. Kruskal–Wallis test followed by Dunn’s post hoc test. ☨p < 0.1; *p < 0.05. Group sizes were as follows: Vector + Vehicle (n = 9), SITH-1 + Vehicle (n = 10), Vector + Melsmon (n = 10), and SITH-1 + Melsmon (n = 9). Data represent pooled results from two independent experiments (4-5 mice per group per experiment). (B) TNFα expression in the colon was increased in vehicle-treated SITH-1 mice following WICS and was significantly reduced by Melsmon treatment. Bars represent median values. Kruskal–Wallis test followed by Dunn’s post hoc test. ***p < 0.001. Group sizes were as follows: Vector + Vehicle (n = 9), SITH-1 + Vehicle (n = 9), Vector + Melsmon (n = 10), and SITH-1 + Melsmon (n = 9). Data represent pooled results from two independent experiments (4-5 mice per group per experiment). (C) IL-6 expression in the heart was elevated after WICS in vehicle-treated SITH-1 mice, and this was attenuated by Melsmon treatment. Bars represent median values. Kruskal–Wallis test followed by Dunn’s post hoc test. Group sizes were as follows: Vector + Vehicle (n = 10), SITH-1 + Vehicle (n = 10), Vector + Melsmon (n = 10), and SITH-1 + Melsmon (n = 7). Data represent pooled results from two independent experiments (3-5 mice per group per experiment).

4. Discussion

In the present study, we demonstrated that 18 h after exposure to water immersion cage stress (WICS), inflammatory cytokine expression was elevated in both the brain (Figures 1, 2) and peripheral organs (Figure 3) of a stress-sensitive depression model mouse expressing SITH-1 specifically in astrocytes. To our knowledge, this is the first report showing that, in this stress-sensitive model, inflammatory responses are concurrently induced and maintained in both central and peripheral tissues following stress exposure. These findings support the concept that neuroinflammation and systemic inflammation may be bidirectionally involved in the pathophysiology of depression. In the present experimental design, tissues were collected 18 h after WICS exposure to allow transient stress responses to subside. Under these conditions, inflammatory responses remained elevated in SITH-1 mice, whereas they were attenuated in control mice, suggesting sustained inflammatory activation in the stress-vulnerable state.

Administration of the human placental extract Melsmon significantly suppressed not only neuroinflammatory cytokine expression in the brain but also the expression of steroidogenic acute regulatory protein (StAR) in the adrenal gland. StAR is a key rate-limiting factor in adrenal steroidogenesis, and its reduced expression suggests attenuation of HPA-axis hyperactivation. Inflammatory cytokine receptors are expressed in HPA-axis–related structures such as the hypothalamus and pituitary gland, and centrally produced inflammatory cytokines have been shown to stimulate corticotropin-releasing hormone (CRH) neurons and pituitary corticotrophs, thereby promoting the secretion of adrenocorticotropic hormone (ACTH) and glucocorticoids (Turnbull and Rivier, 1995; Gądek-Michalska et al., 2013). Thus, the HPA-axis hyperactivation observed in SITH-1 mice may be driven, at least in part, by neuroinflammatory cytokines. Our findings suggest that Melsmon may contribute to the maintenance of HPA-axis homeostasis through suppression of stress-induced neuroinflammation.

Notably, Melsmon administration also reduced inflammatory cytokine expression in peripheral organs, including the liver, colon, and heart (Figure 3). Chronic stress is known to induce inflammatory cytokine production in these organs (Mann, 2003; Miller et al., 2019; Wei et al., 2019). However, in SITH-1 mice, elevated inflammatory cytokine expression persisted in peripheral tissues even after a single stress exposure, and this sustained inflammatory response was suppressed by Melsmon treatment. Notably, this sustained inflammatory response was observed after a single episode of stress exposure, suggesting that SITH-1 expression may prolong stress-induced inflammatory activation beyond the transient responses typically observed in control animals. Peripheral inflammation has been reported to induce neuroinflammatory cytokine expression through humoral and neural pathways (Raghavendra et al., 2004; Silverman et al., 2015; Talley et al., 2021). Taken together, our results suggest that Melsmon may interrupt the vicious cycle linking stress, neuroinflammation, and peripheral inflammation.

Various biological functions of human placental extracts have been reported, including anti-inflammatory activity (Alimu, Yamamoto, and Nakahata, 2025). For example, in vitro studies have shown that one placental extract, Laennec, induces macrophage polarization toward an anti-inflammatory M2 phenotype (Ishikawa et al., 2025). In addition, both Laennec and Melsmon have been reported to exert anti-inflammatory effects through antioxidant mechanisms. Laennec treatment increases the expression of antioxidant genes such as Hmox1, Nqo1, Cat, and Sod1, and enhances the activity of nuclear factor erythroid 2–related factor 2 (NRF2), a key regulator of antioxidant pathways (Yamauchi et al., 2020). Similarly, Melsmon has been shown to upregulate antioxidant genes including CYGB, APOE, NQO1, and PTGS1, and to increase NRF2 protein levels (Huang et al., 2022). NRF2 activation has been reported to suppress the expression of inflammatory cytokines such as IL-6 and IL-1β (Kobayashi et al., 2016), which may counteract oxidative stress–induced activation of transcription factors such as NF-κB and AP-1 that promote inflammation (Chatterjee, 2016; Liu et al., 2023). Although the present study did not directly assess antioxidant gene expression or NRF2 activity, the observed suppression of inflammatory cytokines in both central and peripheral tissues, along with reduced adrenal StAR expression, is consistent with the involvement of antioxidant pathways.

Clinical studies in humans have reported that continuous administration of Melsmon alleviates depressive mood, anxiety, and fatigue-related symptoms (Kovalenko and Atalyan, 2016). The anti-inflammatory effects observed in the present study are therefore consistent with these reported clinical benefits.

Several limitations of this study should be acknowledged. First, inflammatory cytokine expression was assessed only at the mRNA level, and protein expression and cellular localization were not examined. Second, HPA-axis activation was evaluated based on adrenal StAR mRNA expression as a molecular marker of steroidogenic activity. Circulating corticosterone levels were not measured, and the chronicity of HPA-axis activation was not directly assessed. Future studies incorporating endocrine measurements will be necessary to further characterize HPA-axis dynamics in this model. Third, the present analysis focused primarily on molecular endpoints, and functional outcomes such as changes in neuroplasticity markers or depression-like behaviors were not evaluated. Fourth, although no obvious intestinal bleeding or severe physical abnormalities were observed during the experiment, potential stress-related pathological changes such as gastric ulcer formation were not systematically evaluated and therefore cannot be excluded. Future studies incorporating behavioral assessments, analyses of neuronal structural plasticity, and comprehensive investigation of molecular mechanisms, including antioxidant pathways, will be required to further clarify the therapeutic potential of Melsmon in psychiatric disorders. In addition, although both Melsmon and Laennec have been reported to enhance NRF2 activity and suppress inflammatory cytokine expression, the specific bioactive components responsible for NRF2 activation remain unidentified. Despite differences in manufacturing processes, both preparations involve acid hydrolysis of human placenta (Alimu, Yamamoto, and Nakahata, 2025), suggesting that acid-hydrolyzed placental components may contribute to NRF2 activation. Elucidating these active constituents will be an important goal for future research.

In conclusion, this study demonstrates that Melsmon exerts multifaceted suppressive effects on stress-induced neuroinflammation and peripheral inflammation, thereby highlighting a novel therapeutic potential of human placental extracts for stress-related psychiatric disorders.

Funding Statement

The author(s) declared that financial support was received for this work and/or its publication. This work received funding support from Melsmon Pharmaceutical Co. Ltd.

Footnotes

Edited by: Chen Li, Binzhou Medical University Hospital, China

Reviewed by: Shingo Miyata, Kindai University, Japan

Sara Taha Elazab, Mansoura University, Egypt

Data availability statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Ethics statement

The animal study was approved by the Animal Experiment Committee of Jikei University School of Medicine. Experiments involving recombinant adenovirus vectors were approved by the Recombinant DNA Experiment Safety Committee of Jikei University School of Medicine. The study was conducted in accordance with local legislation and institutional requirements.

Author contributions

NO: Data curation, Software, Writing – original draft, Conceptualization, Visualization, Investigation, Methodology, Validation, Writing – review and editing, Project administration, Formal Analysis, Resources. KS: Writing – review and editing, Formal Analysis, Data curation. AI: Formal Analysis, Data curation, Writing – review and editing. YW: Formal Analysis, Data curation, Writing – review and editing. KK: Supervision, Funding acquisition, Writing – review and editing, Methodology. TY: Investigation, Conceptualization, Supervision, Funding acquisition, Writing – review and editing, Writing – original draft, Methodology, Data curation.

Conflict of interest

Author TY was employed by Corporate Planning Division, Melsmon Pharmaceutical Co. Ltd.

The remaining author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Generative AI statement

The author(s) declared that generative AI was not used in the creation of this manuscript.

Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

References

  1. Akagi H., Imamura Y., Makita Y., Nakamura H., Hasegawa N., Fujiwara S. I., et al. (2016). Evaluation of collagen type-1 production and anti-inflammatory activities of human placental extracts in human gingival fibroblasts. J. Hard Tissue Biology 25 (3), 277–281. 10.2485/jhtb.25.277 [DOI] [Google Scholar]
  2. Alimu Y., Yamamoto T., Nakahata Y. (2025). Biological effects of human placental extracts - variations in manufacturing methods and compositions. Front. Pharmacol. 16 (1707890), 1707890. 10.3389/fphar.2025.1707890 [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Ano Y., Kita M., Kitaoka S., Furuyashiki T. (2019). Leucine-histidine dipeptide attenuates microglial activation and emotional disturbances induced by brain inflammation and repeated social defeat stress. Nutrients 11 (9), 2161. 10.3390/nu11092161 [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Calabrese F., Rossetti A. C., Racagni G., Gass P., Riva M. A., Molteni R. (2014). Brain-derived neurotrophic factor: a bridge between inflammation and neuroplasticity. Front. Cellular Neuroscience 8, 430. 10.3389/fncel.2014.00430 [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chatterjee S. (2016). “Oxidative stress, inflammation, and disease,” in Oxidative Stress and Biomaterials (Elsevier; ), 35–58. 10.1016/b978-0-12-803269-5.00002-4 [DOI] [Google Scholar]
  6. Cui L., Li S., Wang S., Wu X., Liu Y., Yu W., et al. (2024). Major depressive disorder: hypothesis, mechanism, prevention and treatment. Signal Transduction Targeted Therapy 9 (1), 30. 10.1038/s41392-024-01738-y [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Dean J., Keshavan M. (2017). The neurobiology of depression: an integrated view. Asian Journal Psychiatry 27, 101–111. 10.1016/j.ajp.2017.01.025 [DOI] [PubMed] [Google Scholar]
  8. Ferrari F., Villa R. F. (2017). The neurobiology of depression: an integrated overview from biological theories to clinical evidence. Mol. Neurobiology 54 (7), 4847–4865. 10.1007/s12035-016-0032-y [DOI] [PubMed] [Google Scholar]
  9. Gądek-Michalska A., Tadeusz J., Rachwalska P., Bugajski J. (2013). Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems. Pharmacol. Rep. 65 (6), 1655–1662. 10.1016/s1734-1140(13)71527-5 [DOI] [PubMed] [Google Scholar]
  10. Gárate I., Garcia-Bueno B., Madrigal J. L. M., Caso J. R., Alou L., Gomez-Lus M. L., et al. (2013). Stress-induced neuroinflammation: role of the Toll-like receptor-4 pathway. Biol. Psychiatry 73 (1), 32–43. 10.1016/j.biopsych.2012.07.005 [DOI] [PubMed] [Google Scholar]
  11. Ghoneum M., El-Gerbed M. S. A. (2021). Human placental extract ameliorates methotrexate-induced hepatotoxicity in rats via regulating antioxidative and anti-inflammatory responses. Cancer Chemotherapy Pharmacology 88 (6), 961–971. 10.1007/s00280-021-04349-4 [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Gwam C., Ohanele C., Hamby J., Chughtai N., Mufti Z., Ma X. (2023). Human placental extract: a potential therapeutic in treating osteoarthritis. Ann. Translational Medicine 11 (9), 322. 10.21037/atm.2019.10.20 [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Hassamal S. (2023). Chronic stress, neuroinflammation, and depression: an overview of pathophysiological mechanisms and emerging anti-inflammatories. Front. Psychiatry 14, 1130989. 10.3389/fpsyt.2023.1130989 [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Huang L., Chin L. C., Kimura K., Nakahata Y. (2022). Human placental extract delays in vitro cellular senescence through the activation of NRF2-mediated antioxidant pathway. Antioxidants Basel, Switz. 11 (8), 1545. 10.3390/antiox11081545 [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Ishikawa N., Watanabe Y., Maeda Y., Yoshida T., Kimura N., Abe H., et al. (2025). Human placental extract improves liver cirrhosis in mice with regulation of macrophages and senescent cells. Regen. Ther. 28, 509–516. 10.1016/j.reth.2025.01.017 [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Johnson J. D., Campisi J., Sharkey C. M., Kennedy S. L., Nickerson M., Greenwood B. N., et al. (2005). Catecholamines mediate stress-induced increases in peripheral and central inflammatory cytokines. Neuroscience 135 (4), 1295–1307. 10.1016/j.neuroscience.2005.06.090 [DOI] [PubMed] [Google Scholar]
  17. Kempuraj D., Thangavel R., Selvakumar G. P., Zaheer S., Ahmed M. E., Raikwar S. P., et al. (2017). Brain and peripheral atypical inflammatory mediators potentiate neuroinflammation and neurodegeneration. Front. Cellular Neuroscience 11, 216. 10.3389/fncel.2017.00216 [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Khairova R. A., Machado-Vieira R., Du J., Manji H. K. (2009). A potential role for pro-inflammatory cytokines in regulating synaptic plasticity in major depressive disorder. International Journal Neuropsychopharmacology 12 (4), 561–578. 10.1017/S1461145709009924 [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Kobayashi E. H., Suzuki T., Funayama R., Nagashima T., Hayashi M., Sekine H., et al. (2016). Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nat. Commun. 7 (1), 11624. 10.1038/ncomms11624 [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Kobayashi N., Oka N., Takahashi M., Shimada K., Ishii A., Tatebayashi Y., et al. (2020). Human herpesvirus 6B greatly increases risk of depression by activating hypothalamic-pituitary -adrenal axis during latent phase of infection. iScience 23 (6), 101187. 10.1016/j.isci.2020.101187 [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Kohler O., Krogh J., Mors O., Benros M. E. (2016). Inflammation in depression and the potential for anti-inflammatory treatment. Curr. Neuropharmacology 14 (7), 732–742. 10.2174/1570159x14666151208113700 [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Koo J. W., Wohleb E. S. (2021). How stress shapes neuroimmune function: implications for the neurobiology of psychiatric disorders. Biol. Psychiatry 90 (2), 74–84. 10.1016/j.biopsych.2020.11.007 [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Kovalenko I. I., Atalyan A. V. (2016). The experience of using the placenta hydrolyzate in women with climacteric syndrome in perimenopausal period. GYNECOLOGY 18 (5), 20–25. 10.26442/2079-5696_18.5.20-25 [DOI] [Google Scholar]
  24. Kuebler U., Zuccarella-Hackl C., Arpagaus A., Wolf J. M., Farahmand F., von Känel R., et al. (2015). Stress-induced modulation of NF-κB activation, inflammation-associated gene expression, and cytokine levels in blood of healthy men. Brain, Behavior, Immunity 46, 87–95. 10.1016/j.bbi.2014.12.024 [DOI] [PubMed] [Google Scholar]
  25. Kwon H. S., Koh S.-H. (2020). Neuroinflammation in neurodegenerative disorders: the roles of microglia and astrocytes. Transl. Neurodegeneration 9 (1), 42. 10.1186/s40035-020-00221-2 [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Lee K.-K., Choi W. S., Yum K. S., Song S. W., Ock S. M., Park S. B., et al. (2012). Efficacy and safety of human placental extract solution on fatigue: a double-blind, randomized, placebo-controlled study. Evidence-based Complementary Alternative Medicine eCAM 2012, 130875. 10.1155/2012/130875 [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Liu J., Han X., Zhang T., Tian K., Li Z., Luo F. (2023). Reactive oxygen species (ROS) scavenging biomaterials for anti-inflammatory diseases: from mechanism to therapy. J. Hematol. and Oncol. 16 (1), 116. 10.1186/s13045-023-01512-7 [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Maes M., Van der Planken M., Stevens W. J., Peeters D., DeClerck L. S., Bridts C. H., et al. (1992). Leukocytosis, monocytosis and neutrophilia: hallmarks of severe depression. J. Psychiatric Research 26 (2), 125–134. 10.1016/0022-3956(92)90004-8 [DOI] [PubMed] [Google Scholar]
  29. Mann D. L. (2003). Stress-activated cytokines and the heart: from adaptation to maladaptation. Annu. Rev. Physiology 65 (1), 81–101. 10.1146/annurev.physiol.65.092101.142249 [DOI] [PubMed] [Google Scholar]
  30. Miller E. S., Apple C. G., Kannan K. B., Funk Z. M., Plazas J. M., Efron P. A., et al. (2019). Chronic stress induces persistent low-grade inflammation. Am. J. Surg. 218 (4), 677–683. 10.1016/j.amjsurg.2019.07.006 [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Nie X., Kitaoka S., Tanaka K., Segi-Nishida E., Imoto Y., Ogawa A., et al. (2018). The innate immune receptors TLR2/4 mediate repeated social defeat stress-induced social avoidance through prefrontal microglial activation. Neuron 99 (3), 464–479. 10.1016/j.neuron.2018.06.035 [DOI] [PubMed] [Google Scholar]
  32. Oh E., Jung W.-W., Sul D. (2023). DNA damage and protective effects of placental extracts in blood lymphocytes and lymphoid organs of mice exposed to gamma irradiation. J. Radiat. Res. Appl. Sci. 16 (2), 100557. 10.1016/j.jrras.2023.100557 [DOI] [Google Scholar]
  33. Park K. M., Cho T. H. (2017). Therapeutic effect of acupuncture point injection with placental extract in knee osteoarthritis. J. Integrative Medicine 15 (2), 135–141. 10.1016/s2095-4964(17)60316-9 [DOI] [PubMed] [Google Scholar]
  34. Park S. Y., Phark S., Lee M., Lim J. Y., Sul D. (2010). Anti-oxidative and anti-inflammatory activities of placental extracts in benzo[a]pyrene-exposed rats. Placenta 31 (10), 873–879. 10.1016/j.placenta.2010.07.010 [DOI] [PubMed] [Google Scholar]
  35. Raghavendra V., Tanga F. Y., DeLeo J. A. (2004). Complete freunds adjuvant-induced peripheral inflammation evokes glial activation and proinflammatory cytokine expression in the CNS. Eur. J. Neurosci. 20 (2), 467–473. 10.1111/j.1460-9568.2004.03514.x [DOI] [PubMed] [Google Scholar]
  36. Rosas-Sánchez G. U., Germán-Ponciano L. J., Guillen-Ruiz G., Cueto-Escobedo J., Limón-Vázquez A. K., Rodríguez-Landa J. F., et al. (2024). Neuroplasticity and mechanisms of action of acute and chronic treatment with antidepressants in preclinical studies. Biomedicines 12 (12), 2744. 10.3390/biomedicines12122744 [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Shen L.-H., Fan L., Zhang Y., Zhu Y. K., Zong X. L., Peng G. N., et al. (2022). Protective effect and mechanism of placenta extract on liver. Nutrients 14 (23), 5071. 10.3390/nu14235071 [DOI] [PMC free article] [PubMed] [Google Scholar]
  38. Silverman H. A., Dancho M., Regnier-Golanov A., Nasim M., Ochani M., Olofsson P. S., et al. (2015). Brain region-specific alterations in the gene expression of cytokines, immune cell markers and cholinergic system components during peripheral endotoxin-induced inflammation. Mol. Med. Camb. Mass. 20 (1), 601–611. 10.2119/molmed.2014.00147 [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Tafet G. E., Nemeroff C. B. (2016). The links between stress and depression: psychoneuroendocrinological, genetic, and environmental interactions. Journal Neuropsychiatry Clinical Neurosciences 28 (2), 77–88. 10.1176/appi.neuropsych.15030053 [DOI] [PubMed] [Google Scholar]
  40. Talley S., Valiauga R., Anderson L., Cannon A. R., Choudhry M. A., Campbell E. M. (2021). DSS-Induced inflammation in the Colon drives a proinflammatory signature in the brain that is ameliorated by prophylactic treatment with the S100A9 inhibitor paquinimod. J. Neuroinflammation 18 (1), 263. 10.1186/s12974-021-02317-6 [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Turnbull A. V., Rivier C. (1995). Regulation of the HPA axis by cytokines. Brain, Behav. Immun. 9 (4), 253–275. 10.1006/brbi.1995.1026 [DOI] [PubMed] [Google Scholar]
  42. Walsh C. P., Bovbjerg D. H., Marsland A. L. (2021). Glucocorticoid resistance and β2-adrenergic receptor signaling pathways promote peripheral pro-inflammatory conditions associated with chronic psychological stress: a systematic review across species. Neurosci. Biobehavioral Reviews 128, 117–135. 10.1016/j.neubiorev.2021.06.013 [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Wei L., Li Y., Tang W., Sun Q., Chen L., Wang X., et al. (2019). Chronic unpredictable mild stress in rats induces colonic inflammation. Front. Physiology 10, 1228. 10.3389/fphys.2019.01228 [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Yamauchi A., Tone T., Toledo A. d., Igarashi K., Sugimoto K., Miyai H., et al. (2020). Placental extract ameliorates liver fibrosis in a methionine- and choline-deficient diet-induced mouse model of non-alcoholic steatohepatitis. Biomed. Res. Tokyo, Jpn. 41 (1), 1–12. 10.2220/biomedres.41.1 [DOI] [PubMed] [Google Scholar]
  45. Yi Pan S., K.S. Chan M., B. F. Wong M., Klokol D., Chernykh V. (2017). Placental therapy: an insight to their biological and therapeutic properties. J. Medicine Therapeutics 1 (4). 10.15761/jmt.1000118 [DOI] [Google Scholar]
  46. Zheng Z.-H., Tu J. L., Li X. H., Hua Q., Liu W. Z., Liu Y., et al. (2021). Neuroinflammation induces anxiety- and depressive-like behavior by modulating neuronal plasticity in the basolateral amygdala. Brain, Behavior, Immunity 91, 505–518. 10.1016/j.bbi.2020.11.007 [DOI] [PubMed] [Google Scholar]
  47. Zorrilla E. P., Luborsky L., McKay J. R., Rosenthal R., Houldin A., Tax A., et al. (2001). The relationship of depression and stressors to immunological assays: a meta-analytic review. Brain, Behavior, Immunity 15 (3), 199–226. 10.1006/brbi.2000.0597 [DOI] [PubMed] [Google Scholar]
  48. Zunszain P. A., Anacker C., Cattaneo A., Carvalho L. A., Pariante C. M. (2011). Glucocorticoids, cytokines and brain abnormalities in depression. Prog. Neuro-Psychopharmacology Biol. Psychiatry 35 (3), 722–729. 10.1016/j.pnpbp.2010.04.011 [DOI] [PMC free article] [PubMed] [Google Scholar]

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

The original contributions presented in this study are included in the article. Further inquiries can be directed to the corresponding author.

Articles from Frontiers in Pharmacology are provided here courtesy of Frontiers Media SA

RESOURCES