N-methyl-D-aspartate receptors and thymoquinone induce apoptosis and alteration in mitochondria in colorectal cancer cells.

Colon cancer is on the rise in both men and women. In addition to traditional treatment methods, herbal treatments from complementary and alternative medicine are actively followed. Naturally derived from plants, thymoquinone (TQ) has drawn a lot of attention in the field of cancer treatment. MK-801, an N-methyl-D-aspartate agonist, is used to improve memory and plasticity, but it has also lately been explored as a potential cancer treatment. This study aimed to determine the roles of N-Methyl-D-Aspartate agonists and Thymoquinone on mitochondria and apoptosis. HT-29 cells were treated with different TQ and MK-801 concentrations. We analyzed cell viability, apoptosis, and alteration of mitochondria. Cell viability significantly decreased depending on doses of TQ and MK-801. Apoptosis and mitochondrial dysfunctions induced by low and high doses of TQ and MK-801. Our study emphasizes the need for further safety evaluation of MK-801 due to the potential toxicity risk of TQ and MK-801. Optimal and toxic doses of TQ and MK-801 were determined for the treatment of colon cancer. It should be considered as a possibility that colon cancer can be treated with TQ and MK-801.

[Effect of Suanzaoren Decoction on expression of ionotropic glutamate receptors and synaptic plasticity in hippocampus of anxiety rats].

This study investigated the effect of Suanzaoren Decoction on the expression of N-methyl-D-aspartate receptors(NMDAR) and α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptors(AMPAR) in the hippocampus and synaptic plasticity in rats with conditioned fear-induced anxiety. The effect of Suanzaoren Decoction on rat behaviors were evaluated through open field experiment, elevated plus maze experiment, and light/dark box experiment. Enzyme-linked immunosorbent assay(ELISA) was used to measure the levels of glutamate(Glu) and γ-aminobutyric acid(GABA) in the rat hippocampus. Real-time fluorescence quantitative PCR(qRT-PCR) and Western blot were employed to assess the gene and protein expression of ionotropic glutamate receptors in the hippocampal region. Transmission electron microscopy was utilized to observe the changes in the ultrastructure of synaptic neurons in the hippocampal region. Long-term potentiation(LTP) detection technique was employed to record the changes in population spike(PS) amplitude in the hippocampal region of mice in each group. The behavioral results showed that compared with the model group, the Suanzaoren Decoction group effectively increased the number of entries into open arms, time spent in open arms, percentage of time spent in open arms out of total movement time, number of entries into open arms out of total entries into both arms(P<0.01), and significantly increased the time spent in the light box and the number of shuttle crossings(P<0.01). There was an increasing trend in the number of grid crossings, entries into the center grid, and time spent in the center grid, indicating a significant anxiolytic effect. ELISA results showed that compared with the model group, the Suanzaoren Decoction group exhibited significantly reduced levels of Glu, Glu/GABA ratio(P<0.01), and significantly increased levels of GABA(P<0.01) in the rat hippocampus. Furthermore, Suanzaoren Decoction significantly decreased the gene and protein expression of NMDAR(GluN2B and GluN2A) and AMPAR(GluA1 and GluA2) compared with the model group. Transmission electron microscopy results demonstrated improvements in synapses, neuronal cells, and organelles in the hippocampal region of the Suanzaoren Decoction group compared with the model group. LTP detection results showed a significant increase in the PS amplitude changes in the hippocampal region of Suanzaoren Decoction group from 5 to 35 min compared with the model group(P<0.05, P<0.01). In conclusion, Suanzaoren Decoction exhibits significant anxiolytic effects, which may be attributed to the reduction in NMDAR and AMPAR expression levels and the improvement of synaptic plasticity.

Amorphous selenium inhibits oxidative stress injury of neurons in vascular dementia rats by activating NMDAR pathway.

Vascular dementia (VD) is one of the most common causes of dementia, taking account for about 20% of all cases. Although studies have found that selenium supplementation can improve the cognitive ability of Alzheimer's patients, there is currently no research on the cognitive impairment caused by VD. This study aimed to investigate the role and mechanism of Amorphous selenium nanodots (A SeNDs) in the prevention of VD. The bilateral common carotid artery occlusion (BCCAO) method was used to establish a VD model. The neuroprotective effect of A SeNDs was evaluated by Morris water maze, Transcranial Doppler TCD, hematoxylin-eosin (HE) staining, Neuron-specific nuclear protein (Neu N) staining and Golgi staining. Detect the expression levels of oxidative stress and Calcium-calmodulin dependent protein kinase II (CaMK II), N-methyl-D-aspartate receptor subunit NR2A, and postsynaptic dense protein 95 (PSD95). Finally, measure the concentration of calcium ions in neuronal cells. The results showed that A SeNDs could significantly improve the learning and memory ability of VD rats, restore the posterior arterial blood flow of the brain, improve the neuronal morphology and dendritic remodeling of pyramidal cells in hippocampal CA1 area, reduce the level of oxidative stress in VD rats, increase the expression of NR2A, PSD95, CaMK II proteins and reduce intracellular calcium ion concentration, but the addition of selective NR2A antagonist NVP-AAMO77 eliminated these benefits. It suggests that A SeNDs may improve cognitive dysfunction in vascular dementia rats by regulating the NMDAR pathway.

Chinese Tuina remodels the synaptic structure in neuropathic pain rats by downregulating the expression of N-methyl D-aspartate receptor subtype 2B and postsynaptic density protein-95 in the spinal cord dorsal horn.

OBJECTIVE: To investigate whether the Chinese massage system, Tuina, exerts analgesic effects in a rat model of chronic constriction injury (CCI) by remodeling the synaptic structure in the spinal cord dorsal horn (SCDH). METHODS: Sixty-nine male Sprague-Dawley rats were randomly and evenly divided into the normal group, sham group, CCI group, CCI + Tuina group, CCI + MK-801 [an -methyl D-aspartate receptor subtype 2B (NR2B) antagonist] group, and CCI + MK-801 + Tuina group. The neuropathic pain model was established using CCI with right sciatic nerve ligation. Tuina was administered 4 d after CCI surgery, using pressing manipulation for 10 min, once daily. Motor function was observed with the inclined plate test, and pain behaviors were observed by the Von Frey test and acetone spray test. At 19 d after surgery, the L3-L5 spinal cord segments were removed. Glutamate, interleukin 1ß (IL-1ß), and tumor necrosis factor-α (TNF-α) levels were detected by enzyme-linked immunosorbent assay. The protein expression levels of NR2B and postsynaptic density protein-95 (PSD-95) were detected by Western blot, and the synaptic structure was observed by transmission electron microscopy (TEM). RESULTS: CCI reduced motor function and caused mechanical and cold allodynia in rats, increased glutamate concentration and TNF-α and IL-1ß levels, and increased expression of synapse-related proteins NR2B and PSD-95 in the SCDH. TEM revealed that the synaptic structure of SCDH neurons was altered. Most of these disease-induced changes were reversed by Tuina and intrathecal injection of MK-801 ( < 0.05 or < 0.01). For the majority of experiments, no significant differences were found between the CCI + MK-801 and CCI + MK-801 + Tuina groups. CONCLUSIONS: Chinese Tuina can alleviate pain by remodeling the synaptic structure, and NR2B and PSD-95 receptors in the SCDH may be among its targets.

Exploring the effect of Tuina on the dendritic structure of spinal cord dorsal horn in rats with lumbar disc herniation based on NR2B/PSD-95 pathway / 针灸推拿医学（英文版）

Objective: To investigate the analgesic mechanism of Tuina (Chinese therapeutic massage) by observing the effect of the N-methyl-D-aspartate receptor subunit 2B (NR2B)/postsynaptic density-95 (PSD-95) pathway on the dendritic structure of spinal cord dorsal horn in rats with lumbar disc herniation. Methods: Fifty Sprague-Dawley rats were randomly divided into a blank group, a model group, a Tuina group, a blocker agent group, and a blocker agent + Tuina group. The sciatic nerve chronic constriction injury (CCI) model was prepared by the sciatic nerve ligation method. From the 4th day after modeling, rats in the Tuina group and the blocker agent + Tuina group were subject to daily Tuina intervention, and those in the blocker agent group and the blocker agent + Tuina group were daily intrathecally injected with NR2B blocker agent (MK-801). The spontaneous pain score was used to observe the pain behavior of all rats. The expression levels of NR2B and downstream PSD-95 were measured by immunohistochemistry, and the dendritic structure changes were observed by Golgi staining for rat spinal cord dorsal horn after 14 d of continuous intervention. Results: Compared with the blank group, the degree of rat spontaneous pain after CCI was elevated in both the model and the Tuina groups (P<0.01) and was reduced in the Tuina group after the Tuina intervention compared with the model group (P<0.05). Compared with the model group, the rat spontaneous pain level after blocking NR2B was reduced in both the blocker agent group and the blocker agent + Tuina group (P<0.05). The NR2B and PSD-95 protein levels were significantly higher in the model group compared with the blank group (P<0.01); the total number of dendritic branches was increased (P<0.01), and the total dendritic length became longer (P<0.01) in the spinal cord dorsal horn. The rat NR2B and PSD-95 protein levels were significantly decreased in the Tuina group compared with the model group (P<0.01); the total dendritic branch number was reduced (P<0.01) and the total length was shortened (P<0.01) in the spinal cord dorsal horn. After blocking NR2B, the expression levels of NR2B and downstream PSD-95 protein were significantly lower in both the blocker agent group and the blocker agent + Tuina group compared to the model group (P<0.01). The total branch number was significantly reduced (P<0.01), and the total length was significantly shortened (P<0.01) of the dendrites in the spinal cord dorsal horn. Conclusion: Tuina may exert an analgesic effect by remodeling the dendritic structure in the spinal cord dorsal horn in rats with lumbar disc herniation, and its mechanism may be related to the inhibition of NR2B/PSD-95 signaling pathway.

Jing-an oral liquid alleviates Tourette syndrome via the NMDAR/MAPK/CREB pathway in vivo and in vitro.

CONTEXT: Jing-an oral liquid (JA) is a Chinese herbal formula used in the treatment of Tourette syndrome (TS); however, its mechanism is unclear. OBJECTIVE: To investigate the effects of JA on amino acid neurotransmitters and microglia activation in vivo and in vitro. MATERIALS AND METHODS: Sixty male Sprague-Dawley rats were divided into a control group and 5 TS groups. TS was induced in rats with intraperitoneal injection of 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (1 mg/kg) and in BV2 cells with lipopolysaccharide. Control and model rats were administered saline, whereas treatment groups were administered JA (5.18, 10.36, or 20.72 g/kg) or tiapride (a benzamide, 23.5 mg/kg) by gavage once daily for 21 days. Stereotypic behaviour was tested. The levels of N-methyl-d-aspartate receptor (NMDAR)/mitogen-activated protein kinase/cAMP response element-binding protein (CREB)-related proteins in striatum and BV2 cells were measured via western blots. CD11b and IBa1 levels were also measured. Ultra-high-performance liquid-chromatography was used to determine γ-aminobutyric acid (GABA), glutamic acid (Glu), and aspartic acid (ASP) levels. RESULTS: JA markedly alleviated the stereotype behaviour (25.92 ± 0.35 to 13.78 ± 0.47) in rats. It also increased NMDAR1 (0.48 ± 0.09 to 0.67 ± 0.08; 0.54 ± 0.07 to 1.19 ± 0.18) expression and down-regulated the expression of p-ERK, p-JNK, p-P38, and p-CREB in BV2 cells and rat striatum. Additionally, Glu, ASP, GABA, CD11b, and IBa1 levels were significantly decreased by JA. DISCUSSION AND CONCLUSIONS: JA suppressed microglia activation and regulated the levels of amino acid neurotransmitters, indicating that it could be a promising therapeutic agent for TS.

Late relapse of anti-N-methyl-d-aspartate receptor encephalitis with amusia and transiently reduced uptake in 123I-iomazenil single-photon emission computed tomography.

INTRODUCTION: Anti-N-methyl-d-aspartate receptor (NMDAR) encephalitis has a high relapse rate at approximately 10-20%. Most relapses occur within 2 years from onset, and 5 years after onset is rare. We report a case of anti-NMDAR encephalitis relapse with amusia 10 years after the initial encephalitis and discuss the usefulness of 123I-iomazenil single-photon emission computerized tomography (IMZ-SPECT) for its diagnosis. CASE: A 13-year-old left-handed girl presented with a depressed level of consciousness and focal to bilateral tonic-clonic seizures. Cerebrospinal fluid (CSF) analysis showed a mildly increased white blood cell count, elevated neopterin levels, and positive oligoclonal bands. Brain MRI was normal. IMZ-SPECT revealed reduced uptake in the right frontoparietal region. She received intravenous pulse methylprednisolone (IVMP) and high-dose intravenous immunoglobulin for autoimmune encephalitis; her symptoms resolved without neurological deficits. At 23 years old, she had mild right-sided numbness, dysarthria, amusia, and tonic-clonic seizures. Although the CSF analysis and brain MRI were normal, IMZ-SPECT revealed reduced uptake, indicating a relapse of encephalitis. IVMP administration resolved the symptoms. After discharge, the initial and relapse CSF analysis revealed anti-NMDAR antibodies. CONCLUSION: An anti-NMDAR encephalitis relapse 10 years after onset has never been reported. IMZ-SPECT may help in the diagnosis of anti-NMDAR encephalitis.

In vivo neuronal and astrocytic activation in somatosensory cortex by acupuncture stimuli.

Acupuncture is a medical treatment that has been widely practiced in China for over 3000 years, yet the neural mechanisms of acupuncture are not fully understood. We hypothesized that neurons and astrocytes act independently and synergistically under acupuncture stimulation. To investigate this, we used two-photon in vivo calcium recording to observe the effects of acupuncture stimulation at ST36 (Zusanli) in mice. Acupuncture stimulation in peripheral acupoints potentiated calcium signals of pyramidal neurons and astrocytes in the somatosensory cortex and resulted in late-onset calcium transients in astrocytes. Chemogenetic inhibition of neurons augmented the astrocytic activity. These findings suggest that acupuncture activates neuronal and astrocytic activity in the somatosensory cortex and provide evidence for the involvement of both neurons and astrocytes in acupuncture treatment.

Dietary zinc supplementation rescues fear-based learning and synaptic function in the Tbr1+/- mouse model of autism spectrum disorders.

BACKGROUND: Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterised by a dyad of behavioural symptoms-social and communication deficits and repetitive behaviours. Multiple aetiological genetic and environmental factors have been identified as causing or increasing the likelihood of ASD, including serum zinc deficiency. Our previous studies revealed that dietary zinc supplementation can normalise impaired social behaviours, excessive grooming, and heightened anxiety in a Shank3 mouse model of ASD, as well as the amelioration of synapse dysfunction. Here, we have examined the efficacy and breadth of dietary zinc supplementation as an effective therapeutic strategy utilising a non-Shank-related mouse model of ASD-mice with Tbr1 haploinsufficiency. METHODS: We performed behavioural assays, amygdalar slice whole-cell patch-clamp electrophysiology, and immunohistochemistry to characterise the synaptic mechanisms underlying the ASD-associated behavioural deficits observed in Tbr1+/- mice and the therapeutic potential of dietary zinc supplementation. Two-way analysis of variance (ANOVA) with Sídák's post hoc test and one-way ANOVA with Tukey's post hoc multiple comparisons were performed for statistical analysis. RESULTS: Our data show that dietary zinc supplementation prevents impairments in auditory fear memory and social interaction, but not social novelty, in the Tbr1+/- mice. Tbr1 haploinsufficiency did not induce excessive grooming nor elevate anxiety in mice. At the synaptic level, dietary zinc supplementation reversed α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) and N-methyl-D-aspartate receptor (NMDAR) hypofunction and normalised presynaptic function at thalamic-lateral amygdala (LA) synapses that are crucial for auditory fear memory. In addition, the zinc supplemented diet significantly restored the synaptic puncta density of the GluN1 subunit essential for functional NMDARs as well as SHANK3 expression in both the basal and lateral amygdala (BLA) of Tbr1+/- mice. LIMITATIONS: The therapeutic effect of dietary zinc supplementation observed in rodent models may not reproduce the same effects in human patients. The effect of dietary zinc supplementation on synaptic function in other brain structures affected by Tbr1 haploinsufficiency including olfactory bulb and anterior commissure will also need to be examined. CONCLUSIONS: Our data further the understanding of the molecular mechanisms underlying the effect of dietary zinc supplementation and verify the efficacy and breadth of its application as a potential treatment strategy for ASD.

N-methyl-D-aspartate receptor antagonism impairs sensory gating in the auditory cortex in response to speech stimuli.

Deficits in early auditory sensory processing in schizophrenia have been linked to N-methyl-D-aspartate receptor (NMDAR) hypofunction, but the role of NMDARs in aberrant auditory sensory gating (SG) in this disorder is unclear. This study, conducted in 22 healthy humans, examined the acute effects of a subanesthetic dose of the NMDAR antagonist ketamine on SG as measured electrophysiologically by suppression of the P50 event-related potential (ERP) to the second (S2) relative to the first (S1) of two closely paired (500 ms) identical speech stimuli. Ketamine induced impairment in SG indices at sensor (scalp)-level and at source-level in the auditory cortex (as assessed with eLORETA). Together with preliminary evidence of modest positive associations between impaired gating and dissociative symptoms elicited by ketamine, tentatively support a model of NMDAR hypofunction underlying disturbances in auditory SG in schizophrenia.

[Effect of moxibustion on inflammatory pain and N-methyl-D aspartic acid receptor-nitric oxide-cyclic GMP pathway in spinal cord of adjuvant arthritis rats].

OBJECTIVE: To observe the effect of moxibustion on pain and N-methyl-D aspartic acid receptor/nitric oxide/cyclic guanosine monophosphate (NMDA-NO-cGMP) signaling pathway in the spinal cord of rats with adjuvant arthritis (AA), so as to explore its underlying mechanisms in relieving inflammatory pain of rheumatoid arthritis (RA). METHODS: SD rats were randomly divided into normal, model, moxibustion (Moxi), Moxi +NMDA receptor antagonist AP-5 (Moxi+AP-5) and Moxi +NMDA receptor agonist (NMDA) groups, with 20 rats in each group. The AA model was established by placing the rats in a wind, cold and damp environment for 12 h, once daily for 20 days and by injection of complete Freund's adjuvant into the right hind paw. Rats of the three Moxi groups received ignited moxa-stick stimulation of "Zusanli"(ST36) and "Shenshu"(BL23) alternately for 20 min, once a day for 15 days. The Moxi + AP-5 group and Moxi +NMDA group received intraperitoneal injection of AP-5 (0.7 mg·kg-1·d-1) and NMDA (5 mg·kg-1·d-1), respectively, once a day, for a total of 15 days. Mechanical pain thres-hold (MPT) was measured before and after modeling and interventions. The spinal cord tissue was sampled for detecting the expression of iNOS mRNA and protein, content of cGMP and NO, and the activity of NOS by using fluorescence quantitative PCR, Western blot, ELISA,nitrate reductase method and colorimetric method, respectively. RESULTS: Before modeling, there was no significant difference in MPT among all the 5 groups (P>0.05). After modeling, the MPT was remarkably decreased (P<0.01), the expression levels of iNOS mRNA and protein,the contents of cGMP and NO, the activity of NOS were significantly increased in the model group relevant to the normal group (P<0.01). After the interventions, the MPT was obviously increased (P<0.01), while the expression levels of iNOS mRNA and protein, the contents of cGMP and NO, the activity of NOS were significantly down-regulated in the Moxi, Moxi-AP-5 and Moxi+NMDA groups (P<0.05, P<0.01). The effect of Moxi+AP-5 group was significantly superior to that of Moxi group in raising MPT and down-regulating the expression levels of iNOS mRNA and protein, and the content of NO (P<0.05, P<0.01). The effect of Moxi+NMDA group was obviously inferior to that of Moxi group in up-regulating MPT and down-regulating the levels of iNOS mRNA and protein, and the contents of cGMP and NO, and the activity of NOS (P<0.01), suggesting a reduction of the therapeutic effects in raising MPT and down-regulating expression of iNOS mRNA and protein after administration of AP-5. CONCLUSION: Moxibustion can relieve RA inflammatory pain in AA rats, which may be related to its function in down-regulating the NMDA/NO/cGMP signaling pathway in the spinal cord.

Anesthetic Pharmacology of the Mint Extracts L-Carvone and Methyl Salicylate.

INTRODUCTION: Hydrocarbons with sufficient water solubility allosterically modulate anesthetic-sensitive ion channels. Mint extracts L-carvone and methyl salicylate water solubility exceeds modulation cutoff values for γ-amino butyric acid type A (GABAA) receptors, N-methyl-D-aspartate (NMDA) receptors, and type-2 voltage-gated sodium (Nav1.2) channels. We hypothesized that mint extracts modulate these channels at concentrations that anesthetize rats. METHODS: Channels were expressed separately in frog oocytes and studied using 2-electrode voltage clamp techniques at drug concentrations up to 10 mM. Normalized current effects were fit to Hill equations. Mint compounds were formulated in a lipid emulsion and administered IV to rats. When unresponsive to the tail clamp, rats were exsanguinated, and plasma drug concentrations were measured. RESULTS: Both mint compounds caused concentration-dependent inhibition of all channels except for methyl salicylate which inhibited GABAA receptors at low concentrations and potentiated at high concentrations. Plasma drug concentrations in anesthetized rats were 7.9 mM for L-carvone and 2.7 mM for methyl salicylate. This corresponded to ≥53% NMDA receptor inhibition and ≥78% Nav1.2 channel inhibition by both compounds and 30% potentiation of GABAA receptors by methyl salicylate. CONCLUSION: L-Carvone and methyl salicylate allosterically modulate cell receptor targets important to molecular actions of conventional anesthetics at concentrations that also induce general anesthesia in rats.

Tongluo Huatan capsule improves cognitive function by regulating the endocytosis of N-methyl-D-aspartic acid receptors mediated by clathrin in a rat model of vascular dementia.

OBJECTIVE: To explore the neuroprotective mechanisms of Tongluo Huatan capsule (THC) in a rat model of vascular dementia (VD). METHODS: A rat model of VD was established by repeated clamping of bilateral common carotid arteries with the intraperitoneal injection of sodium nitroprusside solution. VD rats were administered THC, memantine hydrochloride, or distilled water daily for 14 d after operation. Learning and memory abilities were assessed using the step-down passive avoidance test, novel object recognition (NOR) test, and Morris water maze (MWM) test. Pathological changes in the hippocampus were observed through hematoxylin and eosin and Nissl staining. The expression levels of clathrin, RAB5B, and N-methyl-D-aspartic acid receptor 1 (NMDAR1) were measured by immunohistochemistry staining, real-time quantitative polymerase chain reaction and Western blot. RESULTS: Rats in VD group showed impaired learning and memory abilities (step-down passive avoidance, NOR, and MWM) and abnormalities in neuronal morphology (light microscopy) in the hippocampus. The mRNA or protein expression levels of clathrin and RAB5B were decreased, and NMDAR1 was increased in hippocampal tissues (P < 0.05). Administration of THC promoted the learning and memory abilities and the morphological structure of hippocampal neurons in VD rats. Besides, THC enhanced mRNA or protein expression levels of clathrin and RAB5B, and decreased NMDAR1 (P < 0.05). CONCLUSION: THC may improve cognitive functions by regulating the endocytosis of NMDA receptors mediated by clathrin.

Establishing a high throughput drug screening system for cerebral ischemia using zebrafish larvae.

We previously generated an ischemic stroke in a zebrafish model using N2 gas perfusion; however, this model was an unsuitable drug screening system due to low throughput. In this study, we examined a zebrafish ischemic stroke model using an oxygen absorber to assess drug effects. Hypoxic exposure more than 2 h using the oxygen absorber significantly induced cell death in the brain and damage to the neuronal cells. To confirm the utility of the ischemic model induced by the oxygen absorber, we treated zebrafish with neuroprotective agents. MK-801, an N-methyl-d-aspartate (NMDA) receptor antagonist, significantly suppressed cell death in the brain, and edaravone, a free radical scavenger, significantly reduced the number of dead cells. These results suggest that the activation of NMDA receptors and the production of reactive oxygen species induce neuronal cell damage in accordance with previous mammalian reports. We demonstrate the suitability of an ischemic stroke model in zebrafish larvae using the oxygen absorber, enabling a high throughput drug screening.

Effect of Korean Red Ginseng on metabolic syndrome.

Metabolic syndrome (MS) refers to a clustering of at least three of the following medical conditions: high blood pressure, abdominal obesity, hyperglycemia, low high-density lipoprotein level, and high serum triglycerides. MS is related to a wide range of diseases which includes obesity, diabetes, insulin resistance, cardiovascular disease, dyslipidemia, or non-alcoholic fatty liver disease. There remains an ongoing need for improved treatment strategies for MS. The most important risk factors are dietary pattern, genetics, old age, lack of exercise, disrupted biology, medication usage, and excessive alcohol consumption, but pathophysiology of MS has not been completely identified. Korean Red Ginseng (KRG) refers to steamed/dried ginseng, traditionally associated with beneficial effects such as anti-inflammation, anti-fatigue, anti-obesity, anti-oxidant, and anti-cancer effects. KRG has been often used in traditional medicine to treat multiple metabolic conditions. This paper summarizes the effects of KRG in MS and related diseases such as obesity, cardiovascular disease, insulin resistance, diabetes, dyslipidemia, or non-alcoholic fatty liver disease based on experimental research and clinical studies.

Influence of progestational stress on BDNF and NMDARs in the hippocampus of male offspring and amelioration by Chaihu Shugan San.

BACKGROUND: Progestational stress has been proven to be a risk for the neural development of offspring, especially in the hippocampus. However, whether Chaihu Shugan San (CSS) can ameliorate hippocampal neural development via the regulation of brain-derived neurotrophic factor (BDNF), and N-methyl-D-aspartate receptors (NMDAR) 2A (NR2A) and 2B (NR2B), and the mechanism of such action remains unclear. METHODS: Thirty-six female rats were randomly allocated into control, chronic immobilization stress (CIS) and CSS groups according to the random number table, respectively. The male offspring were fed for 21 days after birth then randomly divided into the same three groups (6 rats/group) as the female rats. Female rats, except for the control group, underwent 21-day CIS to established a progestational stress anxiety-like model which was evaluated by body weight, the elevated plus-maze (EPM) test and serum dopamine (DA) measured using an enzyme-linked immunosorbent assay (ELISA). The expression levels of estrogen receptors (ERα/ERß) and progesterone receptor (PR) in female rat ovaries were quantified by real-time fluorescence quantitative polymerase chain reaction (RT-qPCR) and Western blot analysis. The hippocampal tissue in the 21-day offspring was observed by hematoxylin-eosin (HE) staining. The concentration of BDNF, NR2A, and NR2B were measured by RT-qPCR and immunohistochemistry in the CA3 and dentate gyrus (DG) regions of offsprings' hippocampus. RESULTS: Compared with the female control group, significant differences in body weight, EPM test and DA concentration were observed in the CIS group, meanwhile, the concentration of ERα (P < 0.05), PR (P < 0.05) and ERß in the ovaries were decreased. In the offsprings' hippocampus of the CIS group, the chromatin of the nucleus was edge set and with condensed and irregular morphology nucleus, and the cytoplasm was unevenly stained with spaces around the cells, moreover, the expression levels of BDNF, NR2A, and NR2B were also declined (P < 0.05). However, Chaihu Shugan San reversed these changes, especially the BDNF in the DG region (P < 0.05), and NR2A and NR2B in the CA3 and DG region (P < 0.05). CONCLUSIONS: CSS could ameliorate the neural development of the hippocampus in offspring damaged by anxiety-like progestational stress in female rats via regulating the expression levels of ERα, ERß, and PR in female rat ovaries and BDNF, NR2A, and NR2B in the hippocampus of their offspring.

Deficiency of SHANK3 isoforms impairs thermal hyperalgesia and dysregulates the expression of postsynaptic proteins in the spinal cord.

SHANK3 is one of the scaffolding proteins in the postsynaptic density (PSD). Pain perception and underlying mechanisms were investigated in Shank3 exon 21 deficient (Shank3△C) mice. Sixty-six mice were attributed according to their genotype to three groups: (1) wild-type (WT), (2) heterozygous Shank3△C/+, and (3) homozygous Shank3△C/△C. Complete Freund's adjuvant (CFA) was used to induce inflammatory pain, and thermal hyperalgesia was determined. CFA treatment reduced the thermal threshold in the WT group; groups expressing mutations of Shank3 (△C/+ and △C/△C) had higher thresholds after CFA administration compared to the WT group. Mice with Shank3 mutations (△C/+ or △C/△C) had a lower expression of GluN2A and IP3R proteins and a higher expression of mGluR5 protein in the PSD compared to WT mice without changes in GluN1, GluN2B, and Homer expression. The crosslinking of Homer-IP3R, but not Homer-mGluR5, was decreased in the total lysate. Deficit of Shank3 exon 21 may lead to impaired perception of thermal pain in mice under inflammatory conditions. This impairment may result from protein dysregulation in the PSD like downregulation of the GluN2A subunit, which may reduce NMDAR-mediated currents, and/or decreased crosslinking between Homer and IP3R, which may reduce the release of Ca2+ from intracellular stores.

Selenium Restores Synaptic Deficits by Modulating NMDA Receptors and Selenoprotein K in an Alzheimer's Disease Model.

Aims: Strong evidence has implicated synaptic failure as a direct contributor to cognitive decline in Alzheimer's disease (AD), and selenium (Se) supplementation has demonstrated potential for AD treatment. However, the exact roles of Se and related selenoproteins in mitigating synaptic deficits remain unclear. Results: Our data show that selenomethionine (Se-Met), as the major organic form of Se in vivo, structurally restored synapses, dendrites, and spines, leading to improved synaptic plasticity and cognitive function in triple transgenic AD (3 × Tg-AD) mice. Furthermore, we found that Se-Met ameliorated synaptic deficits by inhibiting extrasynaptic N-methyl-d-aspartate acid receptors (NMDARs) and stimulating synaptic NMDARs, thereby modulating calcium ion (Ca2+) influx. We observed that a decrease in selenoprotein K (SELENOK) levels was closely related to AD, and a similar disequilibrium was found between synaptic and extrasynaptic NMDARs in SELENOK knockout mice and AD mice. Se-Met treatment upregulated SELENOK levels and restored the balance between synaptic and extrasynaptic NMDAR expression in AD mice. Innovation: These findings establish a key signaling pathway linking SELENOK and NMDARs with synaptic plasticity regulated by Se-Met, and thereby provide insight into mechanisms by which Se compounds mediate synaptic deficits in AD. Conclusion: Our study demonstrates that Se-Met restores synaptic deficits through modulating Ca2+ influx mediated by synaptic and extrasynaptic NMDARs in 3 × Tg-AD mice, and suggests a potentially functional interaction between SELENOK and NMDARs. Antioxid. Redox Signal. 35, 863-884.

Bilateral thalamic changes in anti-NMDAR encephalitis presenting with hemichorea and dystonia and acute transient psychotic disorder.

Anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis is one of the most common causes of autoimmune encephalitis. Both movement disorders and neuropsychiatric manifestations are considered core features of anti-NMDAR encephalitis. Strong clinical suspicion, along with NMDAR antibody positivity in paired sample of serum and cerebrospinal fluid, with supportive MRI changes clinch diagnosis in majority. We herein report a case of a middle-aged woman with subacute behavioral abnormalities, which were so severe that forced her to attempt suicide. Hemichorea and dystonia, which appeared later in course, are not previously reported movement disorders in combination in anti-NMDAR encephalitis. Further, magnetic resonance imaging showed bilateral thalamic hyperintensities with diffusion restriction, which are in turn not described in this entity. After amalgamation of history, especially the presence of neuropsychiatric symptoms, clinical features, physical examination, and investigations, the diagnosis of anti-NMDAR encephalitis could be established. Our case not only highlights that the combination of hemichorea and dystonia can be features of anti-NMDAR encephalitis, but adds novelty by bilateral symmetric thalamic changes.

Interaction between Mesocortical and Mesothalamic Catecholaminergic Transmissions Associated with NMDA Receptor in the Locus Coeruleus.

Noncompetitive N-methyl-D-aspartate/glutamate receptor (NMDAR) antagonists contribute to the pathophysiology of schizophrenia and mood disorders but improve monoaminergic antidepressant-resistant mood disorder and suicidal ideation. The mechanisms of the double-edged sword clinical action of NMDAR antagonists remained to be clarified. The present study determined the interaction between the NMDAR antagonist (MK801), α1 adrenoceptor antagonist (prazosin), and α2A adrenoceptor agonist (guanfacine) on mesocortical and mesothalamic catecholaminergic transmission, and thalamocortical glutamatergic transmission using multiprobe microdialysis. The inhibition of NMDAR in the locus coeruleus (LC) by local MK801 administration enhanced both the mesocortical noradrenergic and catecholaminergic coreleasing (norepinephrine and dopamine) transmissions. The mesothalamic noradrenergic transmission was also enhanced by local MK801 administration in the LC. These mesocortical and mesothalamic transmissions were activated by intra-LC disinhibition of transmission of γ-aminobutyric acid (GABA) via NMDAR inhibition. Contrastingly, activated mesothalamic noradrenergic transmission by MK801 enhanced intrathalamic GABAergic inhibition via the α1 adrenoceptor, resulting in the suppression of thalamocortical glutamatergic transmission. The thalamocortical glutamatergic terminal stimulated the presynaptically mesocortical catecholaminergic coreleasing terminal in the superficial cortical layers, but did not have contact with the mesocortical selective noradrenergic terminal (which projected terminals to deeper cortical layers). Furthermore, the α2A adrenoceptor suppressed the mesocortical and mesothalamic noradrenergic transmissions somatodendritically in the LC and presynaptically/somatodendritically in the reticular thalamic nucleus (RTN). These discrepancies between the noradrenergic and catecholaminergic transmissions in the mesocortical and mesothalamic pathways probably constitute the double-edged sword clinical action of noncompetitive NMDAR antagonists.