Schizophrenia is one of the most serious mental disorders affecting around 1% of the world population, yet the pathophysiology of this disorder remains largely unknown. Nitric oxide (NO) has recently been discovered to be an important intracellular messenger in the glutamatergic NMDA pathway of brain and may also operate as an intercellular messenger. There is a growing interest in the role of NO in schizophrenia in that NO has been functionally linked to glutamatergic and dopaminergic systems both of which are strongly implicated in the pathophysiology of schizophrenia. Three lines of evidence have strongly implicated NO in the pathophysiology of schizophrenia. First, NO is intimately connected with glutamatergic and dopaminergic systems which are thought to be dysfunctional in schizophrenia. The second line of evidence is the finding that distribution of nitric oxide synthase (NOS) and NO metabolism are altered in schizophrenic patients. Third, NOS inhibitors may have some antipsychotic action. In conclusion, a novel direction of schizophrenia research might benefit from a more thorough understanding of the glutamate/NMDA-NO pathway. And also, compounds targeting the glutamate/NMDA-NO pathway may provide a new approach to the treatment of schizophrenia.
Brain ; Humans ; Mental Disorders ; Metabolism ; N-Methylaspartate ; Nitric Oxide Synthase ; Nitric Oxide* ; Schizophrenia*

Experimental autoimmune prostatitis (EAP)-induced persistent inflammatory immune response can significantly upregulate the expression of N-methyl-D-aspartic acid (NMDA) receptors in the paraventricular nucleus (PVN). However, the mechanism has not yet been elucidated. Herein, we screened out the target prostate-derived inflammation cytokines (PDICs) by comparing the inflammatory cytokine levels in peripheral blood and cerebrospinal fluid (CSF) between EAP rats and their controls. After identifying the target PDIC, qualified males in initial copulatory behavior testing (CBT) were subjected to implanting tubes onto bilateral PVN. Next, they were randomly divided into four subgroups (EAP-1, EAP-2, Control-1, and Control-2). After 1-week recovery, EAP-1 rats were microinjected with the target PDIC inhibitor, Control-1 rats were microinjected with the target PDIC, while the EAP-2 and Control-2 subgroups were only treated with the same amount of artificial CSF (aCSF). Results showed that only interleukin-1β(IL-1β) had significantly increased mRNA-expression in the prostate of EAP rats compared to the controls (P < 0.001) and significantly higher protein concentrations in both the serum (P = 0.001) and CSF (P < 0.001) of the EAP groups compared to the Control groups. Therefore, IL-1β was identified as the target PDIC which crosses the blood-brain barrier, thereby influencing the central nervous system. Moreover, the EAP-1 subgroup displayed a gradually prolonged ejaculation latency (EL) in the last three CBTs (all P < 0.01) and a significantly lower expression of NMDA NR1 subunit in the PVN (P = 0.043) compared to the respective control groups after a 10-day central administration of IL-1β inhibitors. However, the Control-1 subgroup showed a gradually shortened EL (P < 0.01) and a significantly higher NR1 expression (P = 0.004) after homochronous IL-1β administration. Therefore, we identified IL-1β as the primary PDIC which shortens EL in EAP rats. However, further studies should be conducted to elucidate the specific molecular mechanisms through which IL-1β upregulates NMDA expression.
Animals ; Cytokines/metabolism* ; Disease Models, Animal ; Ejaculation/physiology* ; Interleukin-1beta/metabolism* ; Male ; N-Methylaspartate/metabolism* ; Prostate/metabolism* ; Prostatitis/metabolism* ; Rats ; Receptors, N-Methyl-D-Aspartate/metabolism*

OBJECTIVETo observe changes of learning and memory ability (LMA) in burn rats with depression, and study the relationship between LMA and expression of hippocampal NMDA.

METHODSAccording to simple random method, 46 Wistar rats were divided into burn group (B, with 30% TBSA deep partial-thickness burn, n = 10), depression group (D, with moderate stress stimulation in chronic and unpredictable, n = 12), B + D group (with the same stress stimulation inflicted to B group after burn, n = 12), healthy control group ( HC, without treatment, n = 12). Changes in escape latency was examined in water maze test. Expression of hippocampal NMDA in CA1, CA2 regions and dentate gyrus were observed with immunohistochemistry.

RESULTSCompared with that of HC group (22 +/- 20 s), water maze escape latency in B, D, B + D groups on 2 day after training prolonged (38 +/- 31, 41 +/- 36, 42 +/- 33 s, respectively, P < 0.05 or P < 0.01). Water maze escape latency in B + D group on 4th day after training was longer than that of other groups (P < 0.01). There was no obvious difference in positive expression of NMDA in CA1, CA2 regions among groups (P > 0.05). The positive count of NMDA in dentate gyrus in D group (198 +/- 14) and B + D group (191 +/- 6) were lower than that of HC group (224 +/- 23, P < 0.05 or P < 0.01), but there was no obvious difference between HC group and B group (219 +/- 25, P > 0.05).

CONCLUSIONSBurn complicated with depression can reduce LMA, which may be due to a decrease in NMDA in dentate gyrus.

Animals ; Burns ; complications ; metabolism ; psychology ; Depression ; complications ; Hippocampus ; metabolism ; Maze Learning ; physiology ; Memory ; N-Methylaspartate ; metabolism ; Rats ; Rats, Wistar

Animals ; Female ; Gene Expression Regulation, Developmental ; Inferior Colliculi ; metabolism ; N-Methylaspartate ; genetics ; metabolism ; RNA, Messenger ; genetics ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; genetics ; metabolism

OBJECTIVE: To determine the regulation of the expression of NMDA receptor-1 induced by NMDA in the brain of neonatal SD rats. METHODS: Neonatal SD rats (n=90) were randomly divided into normal control (n=6) and NMDA injected group (subdivided into 10 nmol-0 min, 15 min, 30 min, 1 h, 2 h, 4 h groups, and 10, 20, 50 nmol groups, each n=6). NMDA fluorescent inmmunohistological staining and TTC (2,3,5-triphenyltetrazoliun chloride) staining techniques were used. RESULTS: At 30 min after the injection of 10 nmol NMDA, a few NR1 positive cells could be observed along the injection tract. At 1 h after the injection, NR1 positive cells in large quantity could be observed in the hippocampal CA1 region and paraventricular thalamus of the ipsilateral hemisphere. The number and location of positive cells at 2 h and 4 h after the injection were not much different from that at 1 h after the injection. At 2 h after injection, stronger NR1 expression was observed in the 50 nmol injection group. In addition, slight crinkle of the cell wall with mild condensation of the nuclei was also observed in the 50 nmol injection group. At 2 h after the injection, no abnormality was observed in 10, 20, or 50 nmol group after TTC staining. CONCLUSION The NR1 induced by NMDA is expressed in a time-dependent and dose-dependent pattern after a short period of "delay", providing a possible "therapeutic window" for using NMDA receptor antagonist to treat diseases relating to the NMDA receptor activation.
Animals ; Animals, Newborn ; Brain ; metabolism ; Dose-Response Relationship, Drug ; Mice ; N-Methylaspartate ; pharmacology ; Random Allocation ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; biosynthesis ; Time Factors

AIMTo investigate the relation between Glu-R and the protective effect of hypothermia on oxygen and glucose deprivation (OGD) injury in hippocampal slices of rat.

METHODS(1) We had established OGD injury model in rat hippocampal slices. The changes of orthodromic population spike(OPS) during OGD and after administration of hypothermia (32 degrees C, 25 degrees C) were observed. (2) We had established Glu excitatory toxicity injury model in rat hippocampal slices. The changes of OPS after exposure to Glu and the effect of hypothermia (32 degrees C, 25 degrees C) against the Glu excitatory toxicity injury were observed. The non-NMDA receptor-mediated excitatory postsynaptic potentials (EPSP) in the CA1 area were recorded via adding the GABA-R specific agonists bicuculline (BMI) and NMDAR agonists D-(-)-2-Amino-5-phosphonopentanoic Acid (AP5) in normal artificial cerebrospinal fluid (nACSF), the NMDA receptor-mediated EPSP were recorded via adding the BMI and non-NMDA-R agonists 6,7-Dinitroquinoxaline-2, 3(1H,4H)-dione(CNQX) in nACSF. The variety of the changes of OPS during OGD14min in nACSF groups and added BMI compounded AP5 or BMI compounded CNQX ACSF groups were observed after administration of 25 degrees C hypothermia 28 min. (3) The changes of ultrastructure of CA1 area after OGD 1 h and the effect of hypothermia (25 degrees C) on it were observed.

RESULTS(1) OPS reduced and abolished quickly during OGD14min, and the recovery amplitude of OPS was very low after reoxygenation/glucose 1 h. While the time of OPS abolishing significantly elongated and the recovery of OPS was higher in hypothermia (32 degrees, 25 degrees C) groups. The effect in groups 25 degrees C was more significant than those in groups 32 degrees C. (2) In control groups, Glu (2 mmol/L, 14 min) decreased the amplitude of OPS, after the end of Glu exposure the recovery amplitude of OPS was very low. After administration of hypothermia (32 degrees C, 25 degrees C), the recovery amplitude and rate of OPS were significantly higher than those in the control groups, while the antagonism on Glu excitatory toxicity injury in H 25 degrees C was more significant than those in H 32 degrees C. The changes of OPS during OGD 14 min were no distinct difference in nACSF groups and added BMI (50 micromol/L) compounded AP5(20 micromol/L) or BMI (50 micromol/L) compounded CNQX (100 micromol/L) ACSF groups. The protection of hypothermia (25 degrees C) could not be cancelled by added AP5 compounded BMI or BMI compounded CNQX in nACSF. (3) After OGD (14 min) 1 h, the nuclear membrane of pyramidal cells in CA1 area was irregular, nucleus were homogenized, the organelle in the cytoplasm was degenerate, even more to necrosis or loss, mitochondrion swelled, ridge was vacuoles. In H 25 degrees C the nuclear membrane was regular, mitochondrion swelled only lightly. Small chromatin gathered to edge.

CONCLUSIONHypothermia shows the protective effects of against OGD injury in hippocampal slices. The mechanism is related to the antagonism of Glu excitor toxicity and maintenance the ATP level in cells, and the antagonism perhaps is mediated by NMDA-R and non-NMDA-R.

Animals ; Cell Hypoxia ; Glucose ; metabolism ; Glutamic Acid ; toxicity ; Hippocampus ; metabolism ; Hypothermia ; Membrane Potentials ; N-Methylaspartate ; metabolism ; Neurons ; metabolism ; Organ Culture Techniques ; Oxygen ; metabolism ; Rats ; Rats, Sprague-Dawley

OBJECTIVETo explore the effects of different liquid therapies on the intracranial pressure, brain water content, and expressions of aquaporin-4 and N-methyl-D-aspartate-1 in the brain tissue.

METHODSTwo intervention factors including the colloids (two levels: 4% gelofusine; 6% hydroxyethyl starch and sodium chloride injection) and the crystal/gel ratios (two levels: 0:1; 1:1) were set based on the results of the analysis of variance of factorial design. Thirty-two patient who had undergone epilepsy surgery were equally and randomly divided into four groups: group A (4% gelofusine, crystal/gel ratio 0:1); group B (6% hydroxyethyl starch and sodium chloride injection, crystal/gel ratio 0:1); group C (4% gelofusine, crystal/gel ratio 1:1); and group D (6% hydroxyethyl starch and sodium chloride injection, crystal/gel ratio 1:1). The intracranial pressure during operation was recorded. After the operation, the intracranial pressure and brain water content were measured and the expressions of aquaporin-4 and N-methyl-D-aspartate-1 in the brain tissue were determined with Western blot. Glasgow coma scores were obtained 2 hours after operation.

RESULTSThe intracranial pressure (F=55.714, P=0.000; F=142.432, P=0.000) and the brain water content (F=31.477, P=0.000; F=84.896, P=0.000) significantly increased after the application of the 6% hydroxyethyl starch and sodium chloride injection and crystal/gel ratio 1:1, and the expressions of aquaporin-4 (F=37.205, P=0.000; F=149.652, P=0.014) and N-methyl-D-aspartate-1(F=29.664, P=0.000; F=65.951, P=0.000) in the brain tissue significantly increased. There were additive effects between two of them (the intracranial pressure: F=11.056, P=0.002; the brain water content: F=8.007, P=0.008; the expression of aquaporin-4: F=9.845, P=0.004; and the expression of N-methyl-D-aspartate-1: F=5.020, P=0.033). However, the Glasgow coma score showed no significant difference after the administration (P>0.05).

CONCLUSIONThe liquid therapy with 4% gelofusine and crystal/gel ratio 0:1 can result in better control on the intracranial pressure, brain water content and expressions of aquaporin-4 and N-methyl-D-aspartate-1 in the brain tissue better than the liquid therapy with 6% hydroxyethyl starch and crystal/gel ratio 1:1 during neurosurgery, although it may not improve the coma status.

Adolescent ; Adult ; Aquaporin 4 ; metabolism ; Brain ; drug effects ; metabolism ; Female ; Fluid Therapy ; methods ; Humans ; Intracranial Pressure ; drug effects ; Male ; Middle Aged ; N-Methylaspartate ; metabolism ; Water ; metabolism ; Young Adult

OBJECTIVETo study the effect and the possible mechanism of IL-6 on NMDA-excited neuronal discharges of rats in vitro.

METHODSThe cerebellar slices were prepared and spontaneous discharges of single cerebellar interposed nuclear (IN) neurons were recorded by extracellular recordings. The cerebellar slices were perfused with artificial cerebral spinal fluid (ACSF) containing N-methyl-D-aspartate (NMDA), IL-6, JAK inhibitor AG490. The changes in firing activities of the neurons treated with the drugs were recorded. The levels of phosphorylation at serine 897 site of NMDA receptor subunit 1 (NR1) in the neurons treated with various drugs mentioned above were detected by Western blot.

RESULTSThe discharge rates of the neurons that were treated with IL-6 together with NMDA were significantly lower than those of the neurons treated with NMDA alone. AG490 partially blocked the inhibitory effect of IL-6 on the NMDA-stimulated neuronal firing activity. The treatment of the neurons with IL6 and NMDA led to a concentration-dependent suppression of the phospho-NR1 expression relative to those neurons treated with NMDA alone. AG490 blocked the effect of the IL-6-induced depression of phospho-NR1 expression.

CONCLUSIONIL-6 inhibits NMDA-stimulated neuronal firing activity, and simultaneously down-regulates the phosphorylation of NR1 at serine 897 site.

Animals ; Cerebellum ; drug effects ; metabolism ; In Vitro Techniques ; Interleukin-6 ; pharmacology ; N-Methylaspartate ; pharmacology ; Nerve Growth Factors ; metabolism ; Neurons ; drug effects ; metabolism ; physiology ; Phosphorylation ; Rats ; Rats, Sprague-Dawley ; Receptors, N-Methyl-D-Aspartate ; metabolism

CaMKII is essential for long-term potentiation (LTP), a process in which synaptic strength is increased following the acquisition of information. Among the four CaMKII isoforms, γCaMKII is the one that mediates the LTP of excitatory synapses onto inhibitory interneurons (LTP_E→I). However, the molecular mechanism underlying how γCaMKII mediates LTP_E→I remains unclear. Here, we show that γCaMKII is highly enriched in cultured hippocampal inhibitory interneurons and opts to be activated by higher stimulating frequencies in the 10-30 Hz range. Following stimulation, γCaMKII is translocated to the synapse and becomes co-localized with the postsynaptic protein PSD-95. Knocking down γCaMKII prevents the chemical LTP-induced phosphorylation and trafficking of AMPA receptors (AMPARs) in putative inhibitory interneurons, which are restored by overexpression of γCaMKII but not its kinase-dead form. Taken together, these data suggest that γCaMKII decodes NMDAR-mediated signaling and in turn regulates AMPARs for expressing LTP in inhibitory interneurons.
Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism* ; Hippocampus/metabolism* ; Interneurons/physiology* ; Long-Term Potentiation/physiology* ; N-Methylaspartate/metabolism* ; Receptors, AMPA/physiology* ; Receptors, N-Methyl-D-Aspartate/metabolism* ; Synapses/physiology*

AIMTo investigate the effect of ciliary neurotrophic factor (CNTF) on the nuclear translocation of protein kinase C (PKC) following NMDA administration in the primary cultured hippocampal neurons.

METHODS(1) PKCGAMMA or PKCepsilon- immunocytochemistry staining method was used after treating neurons with NMDA or CNTF. (2) The gray of the nucleus of the PKC-positive neurons were measured under the image pattern analysis system.

RESULTS(1) After NMDA administration of different concentration and time, Nucleus appear PKCgamma and PKCepsilon activities, especially the 100 micromol/L NMDA 30 min group. (2) The gray of nucleus in CNTF + 500 micromol/L NMDA group is similar to control group.

CONCLUSIONNMDA can induce nuclear translocation of PKC in the primary cultured hippocampal neurons, and CNTF can inhibit the translocation. It suggests that the inhibition of PKC translocation induced by NMDA is one of the important reasons for the neuro-protective effects of CNTF.

Animals ; Cells, Cultured ; Ciliary Neurotrophic Factor ; pharmacology ; Hippocampus ; cytology ; N-Methylaspartate ; pharmacology ; Neurons ; drug effects ; metabolism ; Protein Kinase C ; metabolism ; Protein Transport ; Rats ; Rats, Sprague-Dawley