Sigma-1 receptor activation mediates the sustained antidepressant effect of ketamine in mice via increasing BDNF levels.

Sigma-1 receptor (S1R) is a unique multi-tasking chaperone protein in the endoplasmic reticulum. Since S1R agonists exhibit potent antidepressant-like activity, S1R has become a novel target for antidepression therapy. With a rapid and sustained antidepressant effect, ketamine may also interact with S1R. In this study, we investigated whether the antidepressant action of ketamine was related to S1R activation. Depression state was evaluated in the tail suspension test (TST) and a chronic corticosterone (CORT) procedure was used to induce despair-like behavior in mice. The neuronal activities and structural changes of pyramidal neurons in medial prefrontal cortex (mPFC) were assessed using fiber-optic recording and immunofluorescence staining, respectively. We showed that pharmacological manipulation of S1R modulated ketamine-induced behavioral effect. Furthermore, pretreatment with an S1R antagonist BD1047 (3 mg·kg-1·d-1, i.p., for 3 consecutive days) significantly weakened the structural and functional restoration of pyramidal neuron in mPFC caused by ketamine (10 mg·kg-1, i.p., once). Ketamine indirectly triggered the activation of S1R and subsequently increased the level of BDNF. Pretreatment with an S1R agonist SA4503 (1 mg·kg-1·d-1, i.p., for 3 consecutive days) enhanced the sustained antidepressant effect of ketamine, which was eliminated by knockdown of BDNF in mPFC. These results reveal a critical role of S1R in the sustained antidepressant effect of ketamine, and suggest that a combination of ketamine and S1R agonists may be more beneficial for depression patients.

Corrigendum: Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919).

[This corrects the article DOI: 10.3389/fphar.2023.1122541.].

Astrocytes underlie a faster-onset antidepressant effect of hypidone hydrochloride (YL-0919).

Introduction: Major depression disorder (MDD) is a common and potentially life-threatening mental illness; however, data on its pathogenesis and effective therapeutic measures are lacking. Pathological changes in astrocytes play a pivotal role in MDD. While hypidone hydrochloride (YL-0919), an independently developed antidepressant, has shown rapid action with low side effects, its underlying astrocyte-specific mechanisms remain unclear. Methods: In our study, mice were exposed to chronic restraint stress (CRS) for 14 days or concomitantly administered YL-0919/fluoxetine. Behavioral tests were applied to evaluate the depression model; immunofluorescence and immunohistochemistry staining were used to explore morphological changes in astrocytes; astrocyte-specific RNA sequencing (RNA-Seq) analysis was performed to capture transcriptome wide alterations; and ATP and oxygen consumption rate (OCR) levels of primary astrocytes were measured, followed by YL-0919 incubation to appraise the alteration of energy metabolism and mitochondrial oxidative phosphorylation (OXPHOS). Results: YL-0919 alleviated CRS-induced depressive-like behaviors faster than fluoxetine and attenuated the number and morphologic deficits in the astrocytes of depressed mice. The changes of gene expression profile in astrocytes after CRS were partially reversed by YL-0919. Moreover, YL-0919 improved astrocyte energy metabolism and mitochondrial OXPHOS in astrocytes. Conclusion: Our results provide evidence that YL-0919 exerted a faster-onset antidepressant effect on CRS-mice possibly via astrocyte structural remodeling and mitochondria functional restoration.

Essential role of microglia in the fast antidepressant action of ketamine and hypidone hydrochloride (YL-0919).

Introduction: Intracerebral microglia play a vital role in mediating central immune response, neuronal repair and synaptic pruning, but its precise role and mechanism in fast action of antidepressants have remained unknown. In this study, we identified that the microglia contributed to the rapid action of antidepressants ketamine and YL-0919. Methods: The depletion of microglia was achieved with the diet containing the colony-stimulating factor 1 receptor (CSF1R) inhibitor PLX5622 in mice. The tail suspension test (TST), forced swimming test (FST) and novelty suppressed feeding test (NSFT) were employed to evaluate the rapid acting antidepressant behavior of ketamine and YL-0919 in the microglia depletion model. The number of microglia in the prefrontal cortex (PFC) was assayed by the immunofluorescence staining. The expressions of synaptic proteins (synapsin-1, PSD-95, GluA1) and brain-derived neurotrophic factor (BDNF) in the PFC were tested by Western blot. Results: The immobility duration in FST and the latency to feed in NSFT were shortened 24 h after an intraperitoneal (i.p.) injection of ketamine (10 mg/kg). The microglial depletion of PLX3397 blocked the rapid antidepressant-like effect of ketamine in mice. In addition, the immobility time in TST and FST as well as latency to feed in NSFT were reduced 24 h after the intragastric (i.g.) administration of YL-0919 (2.5 mg/kg), and the rapid antidepressant effect of YL-0919 was also blocked by the microglial depletion using PLX5622. About 92% of microglia in the prefrontal cortex was depleted in PLX5622 diet-fed mice, while both ketamine and YL-0919 promoted proliferation on the remaining microglia. YL-0919 significantly increased the protein expressions of synapsin-1, PSD-95, GluA1 and BDNF in the PFC, all of which could be blocked by PLX5622. Conclusion: These results suggested the microglia underlying the rapid antidepressant-like effect of ketamine and YL-0919, and microglia would likely constitute in the rapid enhancing impact of synaptic plasticity in the prefrontal cortex by YL-0919.

Sigma-1 receptor agonist properties that mediate the fast-onset antidepressant effect of hypidone hydrochloride (YL-0919).

The most intriguing characteristic of the sigma-1 receptor is its ability to regulate multiple functional proteins directly via protein-protein interactions, giving the sigma-1 receptor the powerful ability to regulate several survival and metabolic functions in cells, fine tune neuronal excitability, and regulate the transmission of information within brain circuits. This characteristic makes sigma-1 receptors attractive candidates for the development of new drugs. Hypidone hydrochloride (YL-0919), a novel structured antidepressant candidate developed in our laboratory, possess a selective sigma-1 receptor agonist profile, as evidenced by molecular docking, radioligand receptor binding assays, and receptor functional experiments. In vivo studies have revealed that YL-0919 elicits a fast-onset antidepressant activity (within one week) that can be attenuated with pretreatment of the selective sigma-1 receptor antagonist, BD-1047. Taken together, the findings of the current study suggest that YL-0919 activates the sigma-1 receptor to partially mediate the rapid onset antidepressant effects of YL-0919. Thus, YL-0919 is a promising candidate as a fast-onset antidepressant that targets the sigma-1 receptor.

Creation of engineered cardiac tissue in vitro from mouse embryonic stem cells.

BACKGROUND: Embryonic stem (ES) cells can terminally differentiate into all types of somatic cells and are considered a promising source of seed cells for tissue engineering. However, despite recent progress in in vitro differentiation and in vivo transplantation methodologies of ES cells, to date, no one has succeeded in using ES cells in tissue engineering for generation of somatic tissues in vitro for potential transplantation therapy. METHODS AND RESULTS: ES-D3 cells were cultured in a slow-turning lateral vessel for mass production of embryoid bodies. The embryoid bodies were then induced to differentiate into cardiomyocytes in a medium supplemented with 1% ascorbic acid. The ES cell-derived cardiomyocytes were then enriched by Percoll gradient centrifugation. The enriched cardiomyocytes were mixed with liquid type I collagen supplemented with Matrigel to construct engineered cardiac tissue (ECT). After in vitro stretching for 7 days, the ECT can beat synchronously and respond to physical and pharmaceutical stimulation. Histological, immunohistochemical, and transmission electron microscopic studies further indicate that the ECTs both structurally and functionally resemble neonatal native cardiac muscle. Markers related to undifferentiated ES cell contamination were not found in reverse transcriptase-polymerase chain reaction analysis of the Percoll-enriched cardiomyocytes. No teratoma formation was observed in the ECTs implanted subcutaneously in nude mice for 4 weeks. CONCLUSIONS: ES cells can be used as a source of seed cells for cardiac tissue engineering. Additional work remains to demonstrate engraftment of the engineered heart tissue in the case of cardiac defects and its functional integrity within the host's remaining healthy cardiac tissue.

Response surface optimization and physicochemical properties of polysaccharides from Nelumbo nucifera leaves.

Dynamic high pressure microfluidization (DHPM)-assisted extraction (DHPMAE) of lotus (Nelumbo nucifera) leaves polysaccharides (LLPs) was optimized by response surface methodology. The optimal extraction conditions were: liquid/solid ratio of 35:1 (v/m, mL/g), processing pressure of 180 MPa, processed two times, extraction temperature of 76°C, extraction time of 50 min. Under the optimal extraction conditions, DHPMAE produced a higher polysaccharides yield (6.31%) than leaching (2.95%). Scanning electron microscope (SEM) analysis revealed that DHPM could reduce the particles size and make the surface more unconsolidated. The LLPs prepared by both methods showed similar FT-IR spectrum, and were consisted of the same monosaccharides, including rhamnose, fucose, arabinose, xylose, mannose, glucose and galactose. The content of each monosaccharide in extracts, however, was quite different. The average molecular weight of LLPs prepared by DHPMAE is 550 kDa, smaller than 578 kDa obtained by leaching. The LLPs prepared by DHPMAE exhibited stronger DPPH scavenging ability (IC50 value of 0.38 mg/mL), HO scavenging ability (IC50 value of 0.61 mg/mL) and reducing power. Therefore, DHPMAE can be a promising alternative to traditional extraction techniques for polysaccharides from plants, and lotus leaves might be a potential resource of natural antioxidants.