α-humulene improves schizophrenia via NRG1/ErbB4 signaling pathway / 中草药

Objective: To study the treating mechanism of α-humulene on the schizophrenic mice. Methods: The schizophrenic models were established by dizocilpine maleate (MK801), then different concentrations of α-humulene were used to treat the mice by intragastric administration. Open-field experiment and PPI test were carried out to evaluate the spontaneous activity and sensorimotor gating function of mice. Moreover, the frontal cortex MDA, NO levels and hippocampal NRG1, ErbB4 protein expression was detected. Results: The spontaneous activity, sensorimotor gating function, MDA, NO, NRG1 and ErbB4 levels were significantly changed in model mice when compared with normal mice (P < 0.01). Compared with model group, different concentrations of α-humulene notably inhibited spontaneous activity, improved PPI value, increased NO and MDA content, down-regulated ErbB4 and NRG1 protein expression (P < 0.05, P < 0.01). Conclusion: The schizophrenia abnormal behavior of mice was improved by α-humulene via down-regulating NRG1/ErbB4 signaling pathway, so as to achieve the purpose of treating schizophrenia.

Neuroprotective effects and underlying mechanism of preconditioning with MK-801 in cerebral ischemia/reperfusion injury in rats induced by cardiac arrest-cardiopulmonary resuscitation / 中国医师杂志

Objective To explore effects of dizocilpine (MK-801) preconditioning on excitatory amino acids and inflammatory response in rats induced by cardiac arrest-cardiopulmonary resuscitation (CACPR).Methods 18 male Sprague Dawley (SD) rats were randomly divided into three groups:control group,CA group and CA + MK-801 group.To establish rat models of CA-CPR and keep samples of serum and specimens of brain tissues for following detection.The injury of neurons was observed by HE staining and expression of N-methyl-D-aspartic acid receptor (NMDAR) in brain tissues was detected by Western blot.The concentrations of interleukin 1 beta (IL-1 β) and tumor necrosis factor (TNF)-α in serum were detected by enzyme linked immunosorbent assay (ELISA).Results Neurons in CA group were disorganized,cells shrank,nuclei pyknosis,and cytoplasmic eosinophilia,accompanied by inflammatory cell infiltration.Preconditioning with MK-801 reduced the pathological damage of neuron and degree of macrophage infiltration.The relative expression of NMDAR protein in CA group were significantly higher than that in control group (907.9 ±24.9 vs 321.6 ± 18.4,P ＜0.001).Preconditioning with MK-801 significantly decreased the expression of NMDAR in CA + MK-801 group compared with that in CA group (512.4 ± 21.1 vs 907.9 ± 24.9).The CA group showed significantly increased concentrations of IL-1 β and TNF-α than that in control group (P ＜ 0.001),and this effect was abolished by preconditioning with MK-801.CA rats treated with MK-801 showed higher concentrations of IL-1 β and TNF-α than the control group.Conclusions Cardiac arrest causes pathological injury of neurons,up-regulates expression of NMDAR and aggravates inflammatory response.These results induce the apoptosis of nerve cells.Blocking glutamate receptor with MK-801 can inhibit expression of NMDAR,decrease level of cytokines,down-regulate inflammatory reaction degree therefore to protect the brain.

Analysis on blood miRNA-132 expression in schizophrenia mice / 国际检验医学杂志

Objective To prepare the schizophrenia mouse model by using peritoneal injection of dizocilpine maleate(MK‐801) , then to study the peripheral blood miRNA‐132 abnormal expression in schizophrenia mouse model .Methods Adult male Kunming mice(KM) were selected and randomly divided into the normal saline group(control group) and MK‐801 group(experimental group) .The behaviors changes were observed .Real‐time PCR method was used to detect the miRNA‐132 expression in peripheral blood .Results (1) Compared with the control group ,the stereotyped behavior score in the experimental group was increased sig‐nificantly(P<0 .05) ,the spontaneous activity was increased significantly(P<0 .05) ,showing that the up‐right number was signifi‐cantly decreased ,while the walking‐grid number was significantly increased(P< 0 .05) ,which was consistent with the manifesta‐tions of schizophrenia mouse model .(2)Compared with the control group ,the miRNA‐132 expressed in the experimental group was down‐regulated ,the difference was statistically significant(P<0 .05) .Conclusion miRNA‐132 is abnormally expressed in blood of schizophrenia mouse .

The effects of neonatal MK-801 treatment on expression of NMDA receptors and NGF in rats / 中国神经精神疾病杂志

Objective To investigate the effects of repeated neonatal administration of dizocipline maleate (MK-801), the N-methyl-D-aspartate (NMDA) receptor antagonist, on the expression of NMDA receptor subunits NMDAR 1 (NR1), NMDAR2A (NR2A), NMDAR2B (NR2B) and the protein levels of nerve growth factor (NGF) in neonatal rats. Methods Neonatal Sprague-Dawley (SD) rats were randomly divided into research group and control group, with 15 ani-mals in each group. Rats were administrated subcutaneously with MK-801 or normal saline from postnatal day (PND) 5 to PND14 (0.25 mg/kg, twice a day). The expression levels of NR1, NR2A, NR2B and NGF were examined on PND15, PND42 and PND70 in the prefrontal cortex and hippocampus. Results At PND15 (neonatal period), there were no signifi-cant differences in the expression levels of NR1, NR2A, NR2B and NGF in the prefrontal cortex and hippocampus be- tween the two groups (P>0.05). At PND42 (adolescence), NGF protein levels in the prefrontal cortex was significantly low-er in research group than in control group [(56.19±37.87) vs. (152.54±53.92), P<0.01]. At PND70 (adulthood), the expres-sion of NR1, NR2A in the hippocampus was significantly higher in research group than in control group [NR1:(149.55%± 27.00%) vs. (100.00%±32.08%);NR2A:(171.54%±19.85%) vs. (100.00%±51.04%). P<0.05]. Conclusion Neonatal re-peated treatment of MK-801 increases the expression of NMDA receptor subunits NR1, NR2A in the hippocampus in adulthood while decreases the expression of NGF in the prefrontal cortex in adolescence, suggesting that neonatal block-ade of the NMDA receptor may influence the growth and development of the nervous system.

Comparison of effects of the different dosage MK-801 on recognition memory in rats / 中华行为医学与脑科学杂志

Objective To observe the behavioral effects of acute administration of dizocilpine (MK-801) in rats,and to determine an appropriate doses of the drug to mimicking memory deficits of schizophrenia.Methods 192 rats were randomly divided into model groups and control group,and given different doses of MK-801 or saline.Locomotor activity,pre-pulse inhibition (PPI) test and novel object recognition test were studied respectively.Results The spontaneous activity increased in a dose-dependent manner after the treatment of MK-801.The total distances of locomotor activity in 0.3 mg/kg group((127.04 ± 32.35) m) exhibited a significant difference compared with control group((35.34 ± 12.81) m,P ＜ 0.05).MK-801 decreased PPI in dose-dependent manner(P ＜ 0.01).MK-801 0.1 mg/kg((103.45 ± 68.04) ％) and 0.3 mg/kg ((41.55 ± 62.93) ％) groups showed significant differences compared to control group ((200.39 ± 30.97) ％) in PPI.The discrimination index of 0.03 mg/kg group((15.78 ± 6.23) ％) and 0.1 mg/kg group((22.42 ± 3.85) ％) were lower than that in control group((39.42 ±3.86)％,P＜0.05).Conclusion It is necessary for select right doses for model different endophenotypes of schizophrenia by MK-801.0.03 mg/kg of MK-801 is a relatively appropriate dosage to cause recognition memory damage.

Expression analysis of neuregulin 1 gene in schizophrenia model rats / 中华行为医学与脑科学杂志

ObjectiveTo analyze the gene expression of neuregulin1 (Nrg1)mRNA and protein in encephalic region and peripheral blood,and to explore the consistency of the expression in central and peripheral in schizophrenia model rat induced by dizocilpine maleate ( MK801 ).Methods30 adult male SD rats were randomly divided into 3 groups ( 10 cases per group):model group injected with MK801 (0.6 mg/kg and 100μl/20 g)on the right rear of ventrolateral compartment,control group 1 ( no treatment) and control group 2 injected with equal volume normal saline.Nrg1 mRNA was measured in peripheral blood and in prefrontal lobe by using semiquantitative RT-PCR in 3 groups,and Nrg1 protein was measured in encephalic region (prefrontal lobe,dentate band and hippocamp) by using immunohistochemistry.ResultsThere was significant difference of the amount of Nrg1 mRNA among 3 groups (for center:F=9.141,P =0.001 ;for peripheral blood F =8.389,P =0.001 ),and it was higher in model group ( center:2.08 ± 0.64; peripheral blood:1.43 ± 0.46) than that in two control groups ( control group1,center:1.17 ± 0.42,peripheral blood:0.78 ± 0.39 ; control group 2,center:1.31 ± 0.44,peripheral blood:0.79 ± 0.37 ),but no statistical significant difference existed between two control groups.There was positive correlation of Nrg1 mRNA between center and periphery.There was significant difference of Nrg1 protein in prefrontal lobe,dentate band and hippocamp among 3 groups ( F value was 7.275,21.50 and 4.619,and P value was 0.003,0.000 and 0.019,respectively),and it was higher in model( 7.71 ± 2.55,11.67 ± 1.83and 10.18 ±2.08,respectively)than that in two control groups( control group 1:4.89 ± 1.06,7.53 ± 1.14 and 7.10 ± 2.52,respectively; control group 2:5.31 ± 1.39,8.10 ± 1.60 and 7.81 ± 2.50),but no statistical significant difference existed between two control groups.ConclusionMK801 can effect on the expression of Nrg1 gene,Nrg1 mRNA and protein increase in MK801 model rat,and the change is synchronous between center and periphery.

Antinociceptive Interactions between Intrathecal Gabapentin and MK801 or NBQX in Rat Formalin Test

Antagonists for spinal N-methyl-D-aspartate (NMDA) and amino-hydroxy-methtyl-isoxazolepropionate (AMPA) receptors are effective in attenuating acute nociception or injury-induced hyperalgesia. The antinociception of spinal gabapentin is developed in injury-induced hyperalgesia without affecting acute nociception. The authors evaluated the effects of intrathecal gabapentin, NMDA antagonist (MK801) and AMPA antagonist (NBQX) in the formalin test which shows injury-induced hyperalgesia as well as acute pain. We further assessed the interactions between gabapentin and either MK801 or NBQX. Male Sprague-Dawley rats were implanted with intrathecal catheters. To evoke pain, 50 microliter of 5% formalin solution was injected into the hindpaw. The interaction was investigated by a fixed dose analysis or an isobolographic analysis. MK801 and NBQX suppressed flinching responses during phase 1 of the formalin test, while gabapentin had little effect on phase 1. All three agents decreased the phase 2 flinching response. A fixed dose analysis in phase 1 showed that gabapentin potentiated the antinociceptive effect of MK801 and NBQX. Isobolographic analysis in phase 2 revealed a synergistic interaction after coadministration of gabapentin-MK801 or gabapentin-NBQX. Correspondingly, spinal gabapentin with NMDA or AMPA antagonist may be useful in managing acute pain and injury-induced hyperalgesia.

The Ototoxicity of Cisplatin is Mediated by NO: A Study using L-NAME and MK-801 in Guinea pigs / 대한이비인후과학회지

BACKGROUND AND OBJECTIVES: Nitric oxide has been suggested to play an important role in the pathogenesis of cisplatin ototoxicity. L-NAME (NG-Nitroarginine Methyl Ester) is an inhibitor of nitric oxide synthase. MK-801 (Dizocilpine Maleate) is a NMDA receptor antagonist. To evaluate a role of nitric oxide in cisplatin ototoxicity, we investigated whether L-NAME and MK-801 can block the cisplatin ototoxicity in guinea pigs. MATERIALS AND METHOD: In the Group 1, normal saline was injected intraperitoneally as a control group. Group 2, 3, 4, and 5 were injected intraperitoneally as described in the following: Group 2, cisplatin only; Group 3, L-NAME+isplatin; Group 4, MK-801+cisplatin; Group 5, L-NAME+K-801+cisplatin. Using an auditory brainstem response, hearing threshold was tested before cisplatin administration and 5 days after cisplatin injection in each group. The morphological changes of the cochlea were observed by scanning electron microscopy. RESULTS: In the Group 2, a significant hearing loss was observed comparing to Group 1. In contrast , Group 3, 4, and 5 did not demonstrate any significant hearing loss compared to Group 1. In the scanning electron microscopy, the Group 2 showed distorsion and loss of stereocilia of the hair cells. However, the Group 1, 3, 4, and 5 demonstrated well preserved cochlear hair cell morphology. CONCLUSION: Hearing loss induced by ototoxicity of cisplatin was prevented by L-NAME and MK-801. This study suggests that NO may mediate cisplatin ototoxicity.

Antagonism of Dizocilpine Maleate and Taurine to Methylmercury-induced Glutamate Metabolism Disturbance in Cerebrum of Rats / 环境与健康杂志

Objective To determine the antagonism of dizocilpine maleate(MK-801) and taurine to glutamate metabolism disturbance induced by methylmercury(MeHg) in cerebrum.Methods Forty Wistar rats were randomly divided into five groups.The first group was the control group,the second one was low dose MeHg-exposed group and the third was high dose MeHg-exposed group,these three groups were given physiological saline respectively.The fourth group was subcutaneously injected with 0.3 ?mol/kg of MK-801 and the five group was subcutaneously injected with 1 mmol/kg of taurine.Two hours later,the control group was intraperitoneally given physiological saline,the second group was intraperitoneally given 4 ?mol/kg of methylmercury chloride,the third,fourth and five groups were given 12 ?mol/kg of methylmercury chloride.The administration above was given five times a week for 4 weeks.The contents of mercury and Glu and Gln and the activities of GS and PAG in pallium were determined.Results Compared with the control group,the activities of PAG and the contents of mercury and Glu in MeHg-exposed groups increased significantly,the activities of GS and the contents of Gln decreased significantly.Compared with high dose MeHg group,in MK-801 and taurine treated groups,no significant differences were seen in the contents of mercury,and the contents of Glu,the activities of PAG were decreased significantly,the contents of Gln and the activities of GS were increased significantly.Conclusion Methylmercury can disorder glutamate metabolism in cerebrum of rats,and MK-801 and taurine can effectively counteract the adverse effects of methylmercury.

Effect of ischemia/reperfusion on expression of endothelin in the rat ventral prostate and preventive measure / 中国病理生理杂志

AIM: Effect of ischemia/reperfusion on expression of endothelin-1(ET-1) in the rat prostate and preventive measure were studied. METHODS: The abdominal aorta of rat was clipped briefly and repeatedly so as to treat the prostate with ischemia/reperfusion and expression of ET-1 mRNA in the ventral prostate was determined by RT-PCR.RESULTS: Expression of ET-1 mRNA in the ventral prostate was significantly increased at 1 h and 3 h after 90 min repeated ischemia/reperfusion ( P 0 05). CONCLUSIONS: Expression of ET-1 in the prostate can be affected by repeated brief ischemia/reperfusion and it may play a role in the development of benign prostatic hyperplasia. Ischemia-reperfusion-induced ET-1 expression in the prostate of rats can be inhibited by prectreatment of MK-801.