Depression is a devastating mental disorder and major depressive disorder (MDD) that afflicts 16％ of the global population at some point in their lives. Currently available classical antide-pressants (SSRIs, SNRIs, TCAs and MOIs), require a minimum of 2–4 weeks of continuous treat-ment to elicit therapeutic relief in depressed patients and are associated with high rates of non-respon-siveness, and limited duration of efficacy. Therefore, faster-acting antidepressant therapies are need-ed,particularly for patients at risk for suicide for current therapies for depression.Although the molecu-lar mechanisms underlying the pathogenesis of depression are still largely unclear, previous studies have suggested that modulators of mammalian target of rapamycin complex 1 (mTORC1) signaling may have beneficial neuroprotective and antidepressant effects. Here, we review recent advances in understanding mTORC1 signaling in depression and potential therapeutic strategies resulting from modulation of the mTORC1 signaling network. We also highlight recent studies considered to support mTORC1 signaling modulation as a rapid-acting antidepressant therapy (e.g. ketamine, scopolamine, GLYX-13, (2R,6R)-HNK, Ro-256891 etc.) and discuss future research directions. Studies on prospec-tive next-generation rapid-acting antidepressant therapies should focus on developing more selective glutamate receptors(e.g.α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid receptors(AMPARs) agonists or activators)that activate the mTORC1 signaling pathway free of ketamine's adverse effects.

Depression is one of the diseases with the highest disability rate in the world. A large number of studies have shown that the intake of unsaturated fatty acids can deal with depression while chronic overconsumption of saturated fatty acids is a risk factor for depression. It was suggested that the mechanism of saturated fatty acids inducing depression is related to the following four aspects: regulating the function which links to depression in whole brain and specific brain regions, including the hippocampus, the hypothalamic-pituitary-adrenal axis, the striatum, and the prefrontal cortex; stimulating the secretion of inflammatory factors; affecting the balance and function of metabolic regulatory hormones, including leptin, adiponectin, glucocorticoid, and insulin; inducing the disturbance of intestinal flora. This article reviews the relationship between dietary fatty acids and depression, and the possible mechanisms by which saturated fatty acids induce depression from the four aspects mentioned above.

Objective To evaluate the effects of different doses of lidocaine on suppressing fentanyl-induced cough and determine a safe suppressing dose.Methods Two hundred patients undergoing general anesthesia were randomized to four groups evenly.The following medications were given within ten seconds:normal saline 10ml (groupⅠ,control group),lidocaine 1 mg/kg (groupⅡ),lidoeaine 1.5 mg/kg(groupⅢ),lidocaine 2mg/kg (groupⅣ).Toxic symptoms of lidocaine were recorded within lmin after the administration of lidocaine,then fentanyl 3?g/ kg was given intravenously within 5 seconds.Cough incidence and cough grade were recorded within 2rain after the administration of fentanyl.Systolic blood pressure (SBP),diastolic blood pressure (DBP),heart rates (HR),and satu- ration of pulse oximeter(SpO2) were recorded during different time points of induction,all recorded data were anal- ysed by the statistical software,P value

The study reports the detection of neuroprotective effect of 10 kinds of coumarin derivatives and explores their possible mechanism. MTT method was used to screen the neuroprotective effect of 10 coumarin derivatives on neurotoxic agents (Aβ25-35 and rotenone) or OGD (oxygen-glucose deprivation). A compound with better protective effect was obtained. Then the effect of this compound on neurotoxic agents on PC12 was detected by the morphological observation. Furthermore, the effect of compound 3 on microglia with lipopolysaccharide (LPS) induced inflammation was detected. And the inflammatory factor was tested. Finally, direct free radical scavenging ability was detected. Compound 3 was found to be the best compound through three neurons toxic models. Not only compound 3 ameliorated cell viability reduced by three neurons toxic models, but also significantly inhibited the production of inflammatory factor (TNF-α and IL-1β). And its free radical scavenging ability is very good, especially the effect on superoxide anion, which is comparable with vitamin C. The significant scavenging effect of compound 3 on superoxide anion might be the mechanism of the neuroprotection. Compound 3 as a potential neural cell protective agent merits further investigation.
Animals ; Coumarins ; chemistry ; Free Radical Scavengers ; chemistry ; Inflammation ; Microglia ; drug effects ; Neurons ; drug effects ; Neuroprotective Agents ; chemistry ; PC12 Cells ; Rats

OBJECTIVE ① To estimate the value of the subacute MPTP mouse model in aspects of behavioral performance, biochemical changes and pathological abnormalities. ② To find effective positive drugs. METHODS Male C57BL/6 mice were injected with MPTP (30 mg·kg- 1 ·d- 1, ip) for 5 consecutive days. Three days before MPTP injection, the mice were orally administered selegiline (3 mg·kg-1·d-1), pramipexole (3 mg·kg-1·d-1), or medopar (100 mg·kg-1·d-1) for 18 d. Behavioral perfor?mance was assessed in the open field test, pole test and rotarod test. Neurotransmitters in the striatum were detected using HPLC. Protein levels were measured by Western blot. Pathological characteristics were examined by immunohistochemistry. Ultrastructure changes were observed by electron microscopy. RESULTS The subacute MPTP treatment did not induce evident motor defects despite severe injuries in the dopaminergic system. Additionally, MPTP significantly increased the α-synuclein levels and the number of astrocytes in the striatum, and destroyed the blood-brain barrier (BBB) in the substantianigra pars compacta. Both selegiline and pramipexole were able to protect the mice against MPTP injuries. CONCLUSION The subacute MPTP mouse model does not show visible motor defects; it is not enough to evaluate the validity of a candidate just based on behavioral examination, much attention should also be paid to the alterations in neurotransmitters, astrocytes, α- synuclein and the BBB. In addition, selegiline or pramipexole is a better choice than medopar as an effective positive control for the subacute MPTP model.

Parkinson's disease (PD) is a degenerative disease of the central nervous system due to the loss or death of dopaminergic neurons in the substantia nigra. Clinically, levodopa is the most effective and commonly used drug for PD treatment. However, long-term levodopa therapy is prone to motor complications and other side effects caused by excessive peripheral dopamine production, which has become an urgent problem to be solved in PD treatment. Dopamine receptor (DR) agonists are similar to dopamine. They can directly stimulate postsynaptic dopamine receptors, produce the same effect as dopamine, delay the application of levodopa as much as possible, and reduce complications caused by long-term use of levodopa. Therefore, screening effective dopamine receptor agonists has become a key issue in the study and treatment of PD. In order to establish a rapid, stable and reliable method for dopamine receptor agonist screening, this study used the human dopamine receptor 2 (DRD2) gene fused with a circular permuted EGFP (cpEGFP) to construct a recombinant gene, packaged with lentiviral vector, and the vector replaced the parted inner transmembrane domain of the third intracellular loop (ICL3) of genetically-encoded GPCR-activation based (GRAB) sensors. The fluorescence of GPCR-fused cpEGFP is regulated by conformational changes mediated by the interaction of dopamine receptor agonists with GPCRs without altering GPCR activity. The HEK293T cells were infected with viral vector, screened by puromycin to select highly expressed cells. Dopamine receptor agonists (including dopamine, bromocriptine mesylate, cabergoline, pramipexole) were used as positive drugs to explore the best screening and detection conditions, establishing a stable model to evaluate the dopamine receptor agonist. The results showed that the optimal filter for the dopamine receptor agonist in this study was the cell seeding count of 7×10⁴, and the effective concentration of the positive drug was 1-100 µmol·L^-1. In addition, pretreated with 10 µmol·L^-1 dopamine receptor antagonists (including chlorprothixol hydrochloride, domperidone, and sulpiride), the positive fluorescence signal of overexpressed DRD2-cpEGFP HEK293T cells could not be detected when exposed to 10 µmol·L^-1 dopamine receptor agonists, which proved that dopamine receptor antagonists could block the activity of dopamine receptor agonists, so they cannot activate dopamine receptor allosteric, indicating that the model has good specificity and can also be used for the screening and detection of new dopamine receptor antagonists. In summary, the study constructs a stable dopamine sensor detection system, which can effectively screen potential dopamine receptor agonists. The operation procedures are simple and rapid. And it can be used for a large-scale screening providing a fundamental methodology for drug development and PD treatment targeted on DRD2.

This study investigates the protective role of IMM-H004, a novel coumarin derivative, on hepatic ischemia-reperfusion injury (HIRI) in mice. All animal experiments in this paper have been approved by the Ethics Committee of Institute of Materia Medica, Chinese Academy of Medical Sciences. The experimental animals were divided into three groups, including sham group, model group, and IMM-H004 treatment group. Serum biochemical indicators were detected and H&E staining was used to assess liver damage. Real-time quantitative PCR (qPCR) was performed to analysis the mRNA content of inflammatory factors. Immunohistochemistry and immunofluorescence were used to observe neutrophil infiltration. Western blot was used to examine the protein levels of NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), cysteinyl aspartate specific proteinase-1 (caspase-1), and interleukin-1β (IL-1β). The results showed that IMM-H004 could significantly reduce the serum levels of alanine transaminase (ALT), aspartate transaminase (AST), lactate dehydrogenase (LDH). H&E results showed IMM-H004 could alleviate liver damage caused by HIRI. The mRNA expression of tumor necrosis factor-α (TNF-α), IL-1β, and interleukin-6 (IL-6) were decreased by IMM-H004 administration. Meanwhile, IMM-H004 could markedly inhibit neutrophil infiltration. Furthermore, IMM-H004 could significantly down-regulate the protein expression of NLRP3, ASC, caspase-1, and IL-1β, inhibiting the activation of NLRP3 inflammasome pathway. Our results confirmed that IMM-H004 could protect mice from HIRI and provide a theoretical foundation for IMM-H004 application for treating HIRI.

OBJECTIVETo explore the protective effect of baicalin against rotenone-induced injury on PC12 cells, and the po-tential mechanism of action action was also explored.

METHODPC12 cells were injured by rotenone and were treated with different concentrations (0.1, 1, 10 μmol x L(-1)) of baicalin at the same time. Cell viability was analyzed by MTT, and morphology was observed by phase-contrast microscopy. The cell apoptosis was detected by flow cytometry by Annexin V-FITC/PI staining. The intracellular ROS level was determined by fluorescence microscope with DCF-DA staining. The expression of Bcl-2, Bax and Caspase-3 was analyzed by Western blot.

RESULTThe viability of PC12 cells exposure to rotenone for 24 hour was gradually decreased with dose escalating and 1.5 μmol x L was adopted to do the following experiment. Baicalin increased cell viability, improved cell morphology and decreased intracellular ROS level. Moreover, FACS indicated baicalin attenuated the apoptosis induced by rotenone significantly. Western blot showed that Bcl-2, Bax and Caspase-3 expression in rotenone-induced PC12 cells was reversed by baicalin.

CONCLUSIONThis study has demonstrated that baicalin protects PC12 cells against rotenone-induced apoptosis, at least in part, by scavenging excessive ROS and inhibiting the mitochondrion-dependent apoptotic pathway.

Animals ; Apoptosis ; drug effects ; Caspase 3 ; metabolism ; Cell Survival ; drug effects ; Cytoprotection ; drug effects ; Flavonoids ; pharmacology ; Gene Expression Regulation ; drug effects ; Intracellular Space ; drug effects ; metabolism ; PC12 Cells ; Proto-Oncogene Proteins c-bcl-2 ; metabolism ; Rats ; Reactive Oxygen Species ; metabolism ; Rotenone ; pharmacology ; bcl-2-Associated X Protein ; metabolism

Cyclin-dependent kinase 5 (Cdk5),as a key neuro-nal regulator,has received extensively attention. In our previous experiments, we have preliminary confirmed the importance of the regulation on neuronal apoptosis after cerebral ischemia by Cdk5 signal path. According to the documents reported, we found that there were signal transductions between apoptosis and autophagy, which acted the"rapier"position after cerebral is-chemia. Furthermore,Cdk5 could mediate protein kinase B(Akt or PKB) to play bidirectional regulation on the intercross be-tween apoptosis and autophagy. So,there would be of great sig-nificance to reveal the signal transduction relationship between apoptosis and autophagy mediated by Cdk5. Owing to the impor-tance of the intercross-effect between the two programmed cell death paths,we aimed at the imparity viewpoints between apop-tosis and autophagy after cerebral ischemia, raising the sugges-tions as follows:it is appropriate to reveal the effects of Cdk5 on Akt kinase dynamically, and discuss the double regulation mechanism of co-regulators between apoptosis and autophagy af-ter cerebral ischemia, which would provide references for the following researches.

20C, a bibenzyl compound isolated from Gastrodia elata, possesses antioxidative properties in PC12 cells, but its in-depth molecular mechanisms against rotenone-induced neurotoxicity remains unknown. Recent studies indicate that without intact DJ- 1, nuclear factor erythroid 2- related factor (Nrf2) protein becomes unstable, and the activity of Nrf2-mediated downstream antioxidant enzymes are thereby suppressed. Therefore, increasing the nuclear translocation of Nrf2 by DJ-1 may present a helpful means for the prevention and treatment of chronic diseases related to oxidative stress. Our results showed that 20C clearly protected PC12 and SH-SY5Y cells against rotenone-induced oxidative injury in a concentration-dependent manner. Furthermore, 20C markedly up-regulated the levels of DJ-1, which in turn activated phosphoinositide-3-kinase (PI3K)/Akt signaling and inhibited glycogen synthase kinase 3β (GSK3β) activation, eventually promoting Nrf2 nuclear translocation and inducing the expression of Nrf2-mediated downstream antioxidative enzymes such as HO-1. The antioxidative effects of 20C could be partially blocked by ShRNA-mediated knockdown of DJ-1 and inhibition of the PI3K/Akt pathways with Akt1/2 kinase inhibitor in PC12 and SH-SY5Y cells, respectively. Conclusively, our findings confirm that DJ- 1 is necessary for 20C- mediated protection against rotenone- induced oxidative damage, at least in part, by activating PI3K/Akt signaling, and subsequently enhancing the nuclear accumulation of Nrf2. The findings from our investigation suggest that 20C should be developed as a novel candidate for preventing or alleviating the consequences of PD in the future.