NMDA Receptor Antagonist MK801 Protects Against 1-Bromopropane-Induced Cognitive Dysfunction / 神经科学通报·英文版

Occupational exposure to 1-bromopropane (1-BP) induces learning and memory deficits. However, no therapeutic strategies are currently available. Accumulating evidence has suggested that N-methyl-D-aspartate receptors (NMDARs) and neuroinflammation are involved in the cognitive impairments in neurodegenerative diseases. In this study we aimed to investigate whether the noncompetitive NMDAR antagonist MK801 protects against 1-BP-induced cognitive dysfunction. Male Wistar rats were administered with MK801 (0.1 mg/kg) prior to 1-BP intoxication (800 mg/kg). Their cognitive performance was evaluated by the Morris water maze test. The brains of rats were dissected for biochemical, neuropathological, and immunological analyses. We found that the spatial learning and memory were significantly impaired in the 1-BP group, and this was associated with neurodegeneration in both the hippocampus (especially CA1 and CA3) and cortex. Besides, the protein levels of phosphorylated NMDARs were increased after 1-BP exposure. MK801 ameliorated the 1-BP-induced cognitive impairments and degeneration of neurons in the hippocampus and cortex. Mechanistically, MK801 abrogated the 1-BP-induced disruption of excitatory and inhibitory amino-acid balance and NMDAR abnormalities. Subsequently, MK801 inhibited the microglial activation and release of pro-inflammatory cytokines in 1-BP-treated rats. Our findings, for the first time, revealed that MK801 protected against 1-BP-induced cognitive dysfunction by ameliorating NMDAR function and blocking microglial activation, which might provide a potential target for the treatment of 1-BP poisoning.

Effects of Ketamine on Basal Gamma Band Oscillation and Sensory Gating in Prefrontal Cortex of Awake Rats / 神经科学通报·英文版

Gamma band oscillation (GBO) and sensory gating (SG) are associated with many cognitive functions. Ketamine induces deficits of GBO and SG in the prefrontal cortex (PFC). However, the time-courses of the effects of different doses of ketamine on GBO power and SG are poorly understood. Studies have indicated that GBO power and SG have a common substrate for their generation and abnormalities. In this study, we found that (1) ketamine administration increased GBO power in the PFC in rats differently in the low- and high-dose groups; (2) auditory SG was significantly lower than baseline in the 30 mg/kg and 60 mg/kg groups, but not in the 15 mg/kg and 120 mg/kg groups; and (3) changes in SG and basal GBO power were significantly correlated in awake rats. These results indicate a relationship between mechanisms underlying auditory SG and GBO power.

The preventive effects of ascorbic acid supplementation on locomotor and acetylcholinesterase activity in an animal model of schizophrenia induced by ketamine

ABSTRACT Studies have shown that schizophrenic patients seem to have nutritional deficiencies. Ascorbic acid (AA) has an important antioxidant effect and neuromodulatory properties. The aim of this study was to evaluate the effects of AA on locomotor activity and the acetylcholinesterase activity (AChE) in an animal model of schizophrenia (SZ). Rats were supplemented with AA (0.1, 1, or 10 mg/kg), or water for 14 days (gavage). Between the 9th and 15th days, the animals received Ketamine (Ket) (25 mg/kg) or saline (i.p). After the last administration (30 min) rats were subjected to the behavioral test. Brain structures were dissected for biochemical analysis. There was a significant increase in the locomotor activity in Ket treated. AA prevented the hyperlocomotion induced by ket. Ket also showed an increase of AChE activity within the prefrontal cortex and striatum prevented by AA. Our data indicates an effect for AA in preventing alterations induced by Ket in an animal model of SZ, suggesting that it may be an adjuvant approach for the development of new therapeutic strategies within this psychiatric disorder.

Dual control of the vestibulosympathetic reflex following hypotension in rats

Orthostatic hypotension (OH) is associated with symptoms including headache, dizziness, and syncope. The incidence of OH increases with age. Attenuation of the vestibulosympathetic reflex (VSR) is also associated with an increased incidence of OH. In order to understand the pathophysiology of OH, we investigated the physiological characteristics of the VSR in the disorder. We applied sodium nitroprusside (SNP) to conscious rats with sinoaortic denervation in order to induce hypotension. Expression of pERK in the intermediolateral cell column (IMC) of the T4~7 thoracic spinal regions, blood epinephrine levels, and blood pressure were evaluated following the administration of glutamate and/or SNP. SNP-induced hypotension led to increased pERK expression in the medial vestibular nucleus (MVN), rostral ventrolateral medullary nucleus (RVLM) and the IMC, as well as increased blood epinephrine levels. We co-administered either a glutamate receptor agonist or a glutamate receptor antagonist to the MVN or the RVLM. The administration of the glutamate receptor agonists, AMPA or NMDA, to the MVN or RVLM led to elevated blood pressure, increased pERK expression in the IMC, and increased blood epinephrine levels. Administration of the glutamate receptor antagonists, CNQX or MK801, to the MVN or RVLM attenuated the increased pERK expression and blood epinephrine levels caused by SNP-induced hypotension. These results suggest that two components of the pathway which maintains blood pressure are involved in the VSR induced by SNP. These are the neurogenic control of blood pressure via the RVLM and the humoral control of blood pressure via epinephrine release from the adrenal medulla.

The effects of memantine on recovery, cognitive functions, and pain after propofol anesthesia / Efeitos da memantina sobre a recuperação, funções cognitivas e dor após a anestesia com propofol

Abstract Objectives: Postoperative cognitive dysfunction refers to the problems associated with thought and memory that are often experienced after major surgery. The aim of this study is to evaluate the effects of intraperitoneally administered memantine on recovery, cognitive functions, and pain after propofol anesthesia. Methods: The study was conducted in Gazi University Animal Research Laboratory, Ankara, Turkey in January 2012. Twenty-four adult female Wistar Albino rats weighing 170-270 g were educated for 300 s in the radial arm maze (RAM) over three days. Group P was administered 150 mg kg−1 of intraperitoneal (IP) propofol; Group M was given 1 mg kg−1 of IP memantine; and Group MP was given 1 mg kg−1 of IP memantine before being administered 150 mg kg−1 of IP propofol. The control group received only IP saline. RAM and hot plate values were obtained after recovery from the groups that received propofol anesthesia and 30 min after the administration of drugs in other two groups. Results: The duration of recovery for Group MP was significantly shorter than Group P (p < 0.001), and the number of entries and exits in the RAM by Group MP was significantly higher during the first hour when compared to Group P (p < 0.0001). Hot plate values, on the other hand, were found to be significantly increased in all groups when compared to the control values, aside from Group C (p < 0.0001). Conclusion: In this study, memantine provided shorter recovery times, better cognitive functions, and reduced postoperative pain. From this study, we find that memantine has beneficial effects on recovery, cognitive functions, and pain after propofol anesthesia.

Resumo Objetivos: A disfunção cognitiva no pós-operatório refere-se a problemas associados ao pensamento e à memória que são frequentemente manifestados após uma cirurgia de grande porte. O objetivo deste estudo foi avaliar os efeitos da memantina administrada por via intraperitoneal sobre a recuperação, as funções cognitivas e a dor após a anestesia com propofol. Métodos: O estudo foi feito no Laboratório de Pesquisa com Animais da Universidade de Gazi, Ankara, Turquia, em janeiro de 2012. Vinte e quatro ratos albinos do sexo feminino, adultos, da linhagem Wistar, com 170-270 g, foram treinados durante 300 segundos no labirinto radial de oito braços (LRB) durante três dias. O Grupo P recebeu 150 mg/kg−1 de propofol por via intraperitoneal (IP), o Grupo H recebeu 1 mg/kg−1 de memantina IP e o Grupo MP recebeu 1 mg/kg−1 de memantina IP antes da administração de 150 mg/kg−1 de propofol (IP). O grupo controle recebeu apenas solução salina IP. Os valores do LRB e da placa quente foram obtidos após a recuperação dos grupos que receberam propofol e 30 minutos após a administração dos fármacos nos outros dois grupos. Resultados: O tempo de recuperação do Grupo MP foi significativamente menor do que o do Grupo P (p < 0,001) e o número de entradas e saídas do LRB do Grupo MP foi significativamente maior durante a primeira hora, em comparação com o Grupo P (p < 0,0001). Os valores da placa quente, por outro lado, foram significativamente maiores em todos os grupos, em comparação com os valores do grupo controle, exceto pelo Grupo C (p < 0,0001). Conclusão: No presente estudo, memantina proporcionou tempos mais curtos de recuperação, funções cognitivas melhores e reduziu a dor no pós-operatório. A partir deste estudo, descobrimos que a memantina tem efeitos benéficos sobre a recuperação, as funções cognitivas e a dor após anestesia com propofol.

Historia de los terrenos del Hospital Clínico y la Facultad de Medicina de la Universidad de Chile / History of the University of Chile Faculty of Medicine and clinical hospital location

The history of the location of the University of Chile Faculty of Medicine North Campus is derived from a farm of Pedro de Valdivia founder of the city of Santiago de la Nueva Extremadura and governor of the “Reyno de Chile”. This work narrates succinctly the history of this particular location from the Spanish Conquest period to present days.

Functional Connections of the Vestibulo-spino-adrenal Axis in the Control of Blood Pressure Via the Vestibulosympathetic Reflex in Conscious Rats

Significant evidence supports the role of the vestibular system in the regulation of blood pressure during postural movements. In the present study, the role of the vestibulo-spino-adrenal (VSA) axis in the modulation of blood pressure via the vestibulosympathetic reflex was clarified by immunohistochemical and enzyme immunoassay methods in conscious rats with sinoaortic denervation. Expression of c-Fos protein in the intermediolateral cell column of the middle thoracic spinal regions and blood epinephrine levels were investigated, following microinjection of glutamate receptor agonists or antagonists into the medial vestibular nucleus (MVN) and/or sodium nitroprusside (SNP)-induced hypotension. Both microinjection of glutamate receptor agonists (NMDA and AMPA) into the MVN or rostral ventrolateral medullary nucleus (RVLM) and SNP-induced hypotension led to increased number of c-Fos positive neurons in the intermediolateral cell column of the middle thoracic spinal regions and increased blood epinephrine levels. Pretreatment with microinjection of glutamate receptor antagonists (MK-801 and CNQX) into the MVN or RVLM prevented the increased number of c-Fos positive neurons resulting from SNP-induced hypotension, and reversed the increased blood epinephrine levels. These results indicate that the VSA axis may be a key component of the pathway used by the vestibulosympathetic reflex to maintain blood pressure during postural movements.

Effect of Glutamate on the Vestibulo-Solitary Projection after Sodium Nitroprusside-Induced Hypotension in Conscious Rats

Orthostatic hypotension is most common in elderly people, and its prevalence increases with age. Attenuation of the vestibulo-sympathetic reflex (VSR) is commonly associated with orthostatic hypotension. In this study, we investigated the role of glutamate on the vestibulo-solitary projection of the VSR pathway to clarify the pathophysiology of orthostatic hypotension. Blood pressure and expression of both pERK and c-Fos protein were evaluated in the nucleus tractus solitarius (NTS) after microinjection of glutamate into the medial vestibular nucleus (MVN) in conscious rats with sodium nitroprusside (SNP)-induced hypotension that received baroreceptor unloading via sinoaortic denervation (SAD). SNP-induced hypotension increased the expression of both pERK and c-Fos protein in the NTS, which was abolished by pretreatment with glutamate receptor antagonists (MK801 or CNQX) in the MVN. Microinjection of glutamate receptor agonists (NMDA or AMPA) into the MVN increased the expression of both pERK and c-Fos protein in the NTS without causing changes in blood pressure. These results indicate that both NMDA and AMPA receptors play a significant role in the vestibulo-solitary projection of the VSR pathway for maintaining blood pressure, and that glutamatergic transmission in this projection might play a key role in the pathophysiology of orthostatic hypotension.

Activation of group II metabotropic glutamate receptors blocks zinc release from hippocampal mossy fibers

BACKGROUND: The hippocampal CA3 area contains large amounts of vesicular zinc in the mossy fiber terminals which is released during synaptic activity, depending on presynaptic calcium. Another characteristic of these synapses is the presynaptic localization of high concentrations of group II metabotropic glutamate receptors, specifically activated by DCG-IV. Previous work has shown that DCG-IV affects only mossy fiber-evoked responses but not the signals from associational-commissural afferents, blocking mossy fiber synaptic transmission. Since zinc is released from mossy fibers even for single stimuli and it is generally assumed to be co-released with glutamate, the aim of the work was to investigate the effect of DCG-IV on mossy fiber zinc signals. RESULTS: Studies were performed using the membrane-permeant fluorescent zinc probe TSQ, and indicate that DCG-IV almost completely abolishes mossy fiber zinc changes as it does with synaptic transmission. CONCLUSIONS: Zinc signaling is regulated by the activation of type II metabotropic receptors, as it has been previously shown for glutamate, further supporting the corelease of glutamate and zinc from mossy fibers.

µ-opioid receptors in the central nucleus of the amygdala regulate food rather than water intake in rats / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the effect of µ-opioid receptors (µ-ORs) in the central nucleus of the amygdala (CeA) on feeding and drinking behaviors in rats and evaluate the role of glutamate signaling in opioid-mediated ingestive behaviors.</p><p><b>METHODS</b>Stainless steel cannulas were implanted in the unilateral CeA for microinjection of different doses of the selective µ-OR agonist DAMGO in satiated or water-deprived male SD rats. The subsequent food intake or water intake of the rats was measured at 60, 120, and 240 min after the injection. The rats receiving microinjections of naloxone (NTX, a nonselective opioid antagonist) or D-AP-5 (a selective N-methyl-D-aspartic acid-type glutamate receptor antagonist) prior to DAMGO microinjection were tested for food intake at 60, 120, and 240 min after the injections.</p><p><b>RESULTS</b>Injections of DAMGO (1-4 nmol in 0.5 µl) into the CeA significantly increased food intake in satiated rats, but did not affect water intake in rats with water deprivation. NTX (26.5 nmol in 0.5 µl) injected into the CeA antagonized DAMGO-induced feeding but D-AP-5 (6.3-25.4 nmol in 0.5 µl) injections did not produce such an effect.</p><p><b>CONCLUSION</b>µ-ORs in the CeA regulate food intake rather than water intake in rats, and the orexigenic role of µ-ORs is not dependent on the activation of the NMDA receptors in the CeA.</p>

Inibição do receptor de glutamato do tipo NMDA em um modelo de hipóxia-isquemia prenatal: avaliação morfofuncional do cerebelo / Inhibition of glutamate NMDA receptor in a prenatal hipoxia-ischemia model: morphofunctional analises of cerebellum

Lesões sistêmicas peri e pré-natais alteram o desenvolvimento do SNC, levando a problemas cognitivos e motores em crianças que podem perdurar por toda a vida. Um tipo particular de lesão é a hipóxia-isquemia (HI), caracterizada pela interrupção momentânea ou permanente do fluxo sanguíneo. Um dos mecanismos propostos para as lesões decorrentes da HI é a excitotoxicidade glutamatérgica. O uso de inibidores da neurotransmissão glutamatérgica tem sido estudados em diversos modelos de HI. Neste trabalho, avaliamos os efeitos morfofuncionais da administração de um antagonista não-competitivo do receptor de glutamato NMDA sobre o desenvolvimento do cerebelo. Ratas no 18º dia de gestação foram anestesiadas, os cornos uterinos expostos e as 4 artérias uterinas obstruídas por 45 minutos (Grupo H). Animais controle tiveram os úteros expostos, sem a obstrução (Grupo S). Após a cirurgia a gestação prosseguiu. Somente animais nascidos a termo foram utilizados. Um dia após o nascimento, metade de cada ninhada foi designada para receber MK801, 0,3mg/kg/dia, (grupos SM e HM) e a outra metade recebeu solução salina (grupos SS e HS), por 5 dias. Após anestesia e perfusão-fixação com paraformaldeído 4% aos 9, 23, 30 e 60 dias pós-natais, cortes parassagitais do cerebelo foram obtidos em criótomo e submetidos à imunohistoquímica para calbindina, GFAP, GLAST, PDGFRα e MBP. A partir de 45 dias de vida, os animais foram testados em vários de testes comportamentais: labirinto em cruz elevado (LCE), campo vazado (CV), ROTAROD, teste de caminhada sobre barras (ladder test) e teste do comprimento da passada (stride length). Aos 9 dias, a espessura da árvore dendrítica era menor nos animais SM, HS/HM, demonstrando efeitos deletérios tanto do MK801 quanto da HI. Menor número de células PDGFRα+ foi observado nos animais HS/HM, sem efeitos da administração de MK801. Aos 23 dias, maior número de células PDGFRα+ foi observado nos animais HM comparado aos outros 3 grupos, indicando efeito ...

Peri and prenatal systemic lesions alter CNS development leading to motor and cognitive problems in children that might persist throughout life. A particular kind of injury, the hypoxic ischemic (HI), is characterized by a permanent or temporary blockage of blood flow. One of the proposed mechanisms downstream from a HI event is called glutamatergic excitotoxicity. The administration of glutamate inhibitors has been studied in HI models for several years. In this work, we evaluated the effects of administration of a non-competitive antagonist of glutamate receptor, NMDA, on cerebellar development and behavioral tests of HI animals. Pregnant rats in the 18th gestational day were anesthetized, the uterine horns were exposed and the four uterine arteries were clamped for 45 minutes (group H). Sham controls had the uterine horns exposed, but no arteries were clamped (group S). Gestation proceeded after surgery. Only full term animals were used. One day after birth half the animals was assigned to receive either SALINE (groups SS and HS) or MK801 (groups SM and HM). Animals were anesthetized and perfused with 4% paraformaldehyde at 9, 23, 30 and 60 days of age. Parasagittal cerebellar sections were submitted to Calbindin, GFAP, GLAST, PDGFRα and MBP immunohistochemistry. Beginning at P45 animals were subjected to a battery of behavioral tests: elevated plus maze (EPM), hole board (HB), ROTAROD, ladder test and stride length. At P9 the dendritic tree of Purkinje cells were thinner in SM, HS/HM animals, indicating that both HI and MK801 are deleterious regarding this Purkinje cell differentiation. A lower number of PDGFRα+ cells was observed in HS/HM animals, with no effects of MK801 administration. At P23 a greater number of PDGFRα+ cells was found in HM animals when compared to the other 3 groups, demonstrating a neuroprotector effect of MK801. A lower number of myelinated fibers (MBP+) was observed in HS animals at P9, and MK801 administration reverse this ...

Malnutrition affects the pressor response to microinjection of L-glutamate into the RVLM of awake rats

Post-weaning protein malnutrition is often related to the development of cardiovascular and metabolic diseases in humans, as well to changed content of neurotransmitters in the central nervous system under experimental conditions. The rostral ventrolateral medulla (RVLM) is a bulbar region that contains sympathetic premotor neurons; the excitatory amino acid L-glutamate seems to be the main neurotransmitter at this level. The aim of the present study was to evaluate the possible change in the L-glutamate sensitivity of the RVLM neurons of malnourished animals. Male Fischer rats were divided into two groups: control (n = 15) and malnourished (n = 19). Four days before the experiments, guide cannulas were implanted bilaterally in direction of the RVLM for microinjection of L-glutamate. Twenty-four hours before the experiments, the femoral artery was cannulated for cardiovascular recordings. The results showed that the baseline heart rate increased in malnourished compared to control animals (412.18 ± 16.03 bpm vs. 370.74 ± 9.59 bpm, respectively). Malnourished animals presented a dissimilar concentration-dependent pressor response curve to L-glutamate and an attenuated baroreflex gain. Our results suggest that post-weaning protein restriction affects glutamatergic neurotransmission of the baroreflex at the RVLM level.

MK-801 or DNQX reduces electroconvulsive shock-induced impairment of learning-memory and hyperphosphorylation of Tau in rats / 生理学报

This study explored the effect of the excitatory amino acid receptor antagonists on the impairment of learning-memory and the hyperphosphorylation of Tau protein induced by electroconvulsive shock (ECT) in depressed rats, in order to provide experimental evidence for the study on neuropsychological mechanisms improving learning and memory impairment and the clinical intervention treatment. The analysis of variance of factorial design set up two intervention factors which were the electroconvulsive shock (two level: no disposition; a course of ECT) and the excitatory amino acid receptor antagonists (three level: iv saline; iv NMDA receptor antagonist MK-801; iv AMPA receptor antagonist DNQX). Forty-eight adult Wistar-Kyoto (WKY) rats (an animal model for depressive behavior) were randomly divided into six experimental groups (n = 8 in each group): saline (iv 2 mL saline through the tail veins of WKY rats ); MK-801 (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats) ; DNQX (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats ); saline + ECT (iv 2 mL saline through the tail veins of WKY rats and giving a course of ECT); MK-801 + ECT (iv 2 mL 5 mg/kg MK-801 through the tail veins of WKY rats and giving a course of ECT); DNQX + ECT (iv 2 mL 5 mg/kg DNQX through the tail veins of WKY rats and giving a course of ECT). The Morris water maze test started within 1 day after the finish of the course of ECT to evaluate learning and memory. The hippocampus was removed from rats within 1 day after the finish of Morris water maze test. The content of glutamate in the hippocampus of rats was detected by high performance liquid chromatography. The contents of Tau protein which included Tau5 (total Tau protein), p-PHF1(Ser396/404), p-AT8(Ser199/202) and p-12E8(Ser262) in the hippocampus of rats were detected by immunohistochemistry staining (SP) and Western blot. The results showed that ECT and the glutamate ionic receptor blockers (NMDA receptor antagonist MK-801 and AMPA receptor antagonist DNQX) induced the impairment of learning and memory in depressed rats with extended evasive latency time and shortened space exploration time. And the two factors presented a subtractive effect. ECT significantly up-regulated the content of glutamate in the hippocampus of depressed rats which were not affected by the glutamate ionic receptor blockers. ECT and the glutamate ionic receptor blockers did not affect the total Tau protein in the hippocampus of rats. ECT up-regulated the hyperphosphorylation of Tau protein in the hippocampus of depressed rats, while the glutamate ionic receptor blockers down-regulated it, and combination of the two factors presented a subtractive effect. Our results indicate that ECT up-regulates the content of glutamate in the hippocampus of depressed rats, which up-regulates the hyperphosphorylation of Tau protein resulting in the impairment of learning and memory in depressed rats.

Study on protective effect of salvianolic acid B on glutamate-induced excitotoxicity in pheochromocytoma PC12 cells / 中国中药杂志

<p><b>OBJECTIVE</b>To study the protective effect and mechanism of salvianolic acid B (Sal B) on glutamate-induced excito-toxicity.</p><p><b>METHOD</b>Glutamate-induced PC12 cell injury model was established to detect the cell survival rate by MTT, the leakage rate of lactic dehydrogenases using LDH, and the cell apoptosis by using AO/EB double staining for fluorescence microscope and PI single staining flow cytometry which was also used to detect the content of intracellular reactive oxygen species. The expression of Caspase-3 protein was also detected by the Western blotting method.</p><p><b>RESULT</b>Sal B is proved to inhibit glutamate-induced PC12 cells from injury and prevent them from releasing LDH within the range from 50 micromol x L(-1) to 200 micromol x L(-1). Meanwhile, Sal B has an effect on significantly reducing the expression of inhibit glutamate-induced active Caspase-3 protein, inhibiting accumulated glutamate-induced ROS and decreasing PC12 cell apoptosis rate within the range from 50 micromol x L(-1) to 200 micromol x L(-1).</p><p><b>CONCLUSION</b>The study proves that Sal B prevented against glutamate-induced cell injury via inhibiting ROS formation and Caspase-3 pathway-dependent apoptosis in PC12 cells.</p>

Microinjection of NMDA-type glutamate receptor agonist NMDA and antagonist D-AP-5 into the central nucleus of the amygdale alters water intake rather than food intake / 南方医科大学学报

<p><b>OBJECTIVE</b>To investigate the role of N-Methyl-D-aspartic acid (NMDA)-type glutamate receptors in the central nucleus of the amygdale (CeA) in food and water intake.</p><p><b>METHODS</b>Male Sprague-Dawley rats with stainless steel cannulae implanted unilaterally into the CeA were used. The prototypic NMDA receptor agonist NMDA, or the selective NMDA receptor antagonist D(-)-2-amino-5-phosphonopentanoic acid (D-AP-5) was microinjected into the CeA of satiated and euhydrated rats.</p><p><b>RESULTS</b>Intra-CeA injection of 8.50, 17.00, or 34.00 nmol NMDA did not alter food intake but significantly increased water intake 0-1 h after the injection (F(3,32)=3.191, P=0.037) independent of food intake. Without affecting the food intake, injection of 6.34, 12.70, or 25.40 nmol D-AP-5 into the CeA significantly decreased water intake 0-1 h after the injection (F(3,28)=3.118, P=0.042) independent of food intake.</p><p><b>CONCLUSION</b>NMDA receptors in the CeA may participate in the control of water intake rather than food intake.</p>

Neurotrasmisores en niños con meningitis bacteriana / Neurotransmitters in children with bacterial meningitis

La meningitis bacteriana continúa siendo una enfermedad potencialmente fatal, especialmente en países en vías de desarrollo. Los aminoácidos excitatorios están fuertemente implicados en la patogénesis del daño neuronal en meningitis bacteriana. El objetivo fue medir niveles de glutamato, GABA, glicina y taurina en liquido cefalorraquídeo y correlacionarlos con el grado de severidad, complicaciones y secuelas. Estudio prospectivo en 31 pacientes con meningitis bacteriana y 10 pacientes con líquido cefalorraquídeo normal (control), con edades de 1 mes - 13 años de edad. El análisis de aminoácidos se realizó al ingreso y al tercer día mediante cromatografía líquida de alta presión. De los 31 pacientes que ingresaron al estudio 64,5 % fueron de género femenino, 13 lactantes, 8 preescolares y 10 escolares. El promedio de aminoácidos en los niños con meningitis fue más alto que en el grupo control (P<0,01). El glutamato disminuyó significativamente en pacientes con hidrocefalia. El GABA está disminuido en pacientes con parálisis cerebral y la taurina está disminuida en higroma y aumentada en lesión de pares craneales, trastornos de la conducta e hipoacusia. Los cambios en los niveles de aminoácidos en líquido cefalorraquídeo refleja el estado patológico y severidad del daño cerebral. Este estudio provee información del eventual papel de la inmunomodulación y posible uso de antagonistas de aminoácidos excitatorios, con efecto neuroprotector, en el tratamiento de meninigitis bacteriana e indica que esta clase de molécula neurotóxica puede represetar un importante blanco en la terapia adyuvante para meningitis bacteriana.

Bacterial meningitis rmains a potentially fatal disease, especially in developing countries. Exitatory amino acids are strongly implicated in the pathogenesis of neuronal damage in bacterial meningitis. To measure levels of glutamate, GABA, glycine and taurine in cerebroespinal fluid and correlate with the degree of severity, complications and sequelae. Prospective study in 31 patients with bacterial meningitis and 10 patients with normal cerebrospinal fluid (control), aged 1 month - 13 years old. Amino acid analysis was performed on admission and on the third day using high pressure liquid chromatography. Of the 31 patients entering the study 64.5 % were females, 13 infants, 8 preschoolers and 10 elementary school students. The average number of amino acids in children with meningitis was higher than in the control group (P<0.01). Glutamate levels significantly decreased in patients with hydrocephalus. GABA levels decreased in patients with cerebral pasly, and taurine diminished in hygroma, and increased in cranial nerve injury, eating disorders and hearing loss. Changes in amino acid levels in cerebrospinal fluid reflect pathological state and severity of brain damage. This study provides information on the possible role of immunomudulation and possible use of excitatory amino acid antogonists with neuroprotective effects in the treatment of bacterial meningitis, indicating that this class of neurotoxic molecules may represent important target in adjuvant therapy for bacterial meningitis.

Activation of hippocampal D1 dopamine receptor inhibits glutamate-mediated depression induced by chronic unpredictable mild stress in rats / 生理学报

The present study was to investigate the role of dopamine D1 receptors and its relationship with glutamate, N-methyl-D-aspartic acid (NMDA) receptor and α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor in depression induced by chronic unpredictable mild stress (CUMS). CUMS-induced depression model was established in Sprague-Dawley rats, and intrahippocampal microinjections of D1 dopamine receptor agonist SKF38393, non-competitive NMDA receptor antagonist MK-801 and AMPA receptor antagonist NBQX were respectively adopted by rat brain stereotaxic coordinates. The behavioral observations were conducted by measurement of weight changes, sucrose preference test, open-field test and tail suspension test. The concentration of glutamic acid and the expression of its receptors' subunits were detected by HPLC and Western blot, respectively. The results showed that, compared with control group, CUMS rats showed depression-like behavioral changes, higher concentration of glutamic acid, lower expressions of NMDA receptor (NR1) and AMPA receptor (GluR2/3) in hippocampus. Pretreatment with injection of SKF38393 could rescue such depression effect of CUMS, decrease the concentration of glutamic acid, and increase the expressions of NMDA receptor (NR1), AMPA receptor (GluR2/3) in hippocampus. Pretreatment with MK-801 could enhance the antidepressant effect of SKF38393, while NBQX weakened. These results suggest that agonists of D1 dopamine receptor could reduce the concentration of glutamic acid in hippocampus, and its antidepressant effect may be mediated by AMPA receptor partially.

Effects of glial cell line-derived neurotrophic factor and memantine on long-term prognosis in neonatal rats with periventricular leukomalacia / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To evaluate the effects of glial cell line-derived neurotrophic factor (GDNF) and memantine on the long-term prognosis in neonatal rats with ischemia-induced periventricular leukomalacia (PVL).</p><p><b>METHODS</b>Thirty-two 5-day-old neonatal rats were randomly divided into 4 groups: sham-operated, PVL, GDNF-treated and memantine-treated. PVL was induced by right carotid artery ligation and hypoxia in the PVL, GDNF-treated and memantine-treated groups. GDNF (100 μg/kg) or memantine (20 mg/kg) was injected in the two treatment groups immediately after PVL inducement. The weight of the rats was measured immediately before and after hypoxia ischemia (HI). Both of Morris water maze test and Rivlin inclined plane test were performed at 26 days old (21 days after HI). The values of the escape latency (EL) and swimming distance, and the maximum inclined plane degree which the rats could stand at least 5 seconds were compared among the four groups.</p><p><b>RESULTS</b>The lower weight, the prolonged mean values of EL and swimming distance and the reduced maximum inclined plane degree were observed in the PVL group compared to those in the sham-operated, GDNF-treated and memantine-treated groups. There were no significant differences in the weight, the values of EI and swimming distance and the maximum inclined plane degree between the two treatment groups and the sham-operated group.</p><p><b>CONCLUSIONS</b>The administration of either GDNF or memantine can markedly increase the abilities of spatial discrimination,learning and memory, and motor coordination, promote weight gain, and improve long-term prognosis in rats with PVL.</p>

Effect of ketamine combined with penehyclidine hydrochloride on the expression of synaptophysin in the brain of neonatal rats / 中国当代儿科杂志

<p><b>OBJECTIVE</b>To study the effects of ketamine combined with penehyclidine hydrochloride on the learning and memory abilities and the expression of synaptophysin in the hippocampus CA3 region in the brain of neonatal rats.</p><p><b>METHODS</b>Eighty seven-day-old Sprague-Dawly rats were randomly intraperitoneally injected with 50 mg/kg of ketamine (K group), 2 mg/kg of penehyclidine hydrochloride (P group), 50 mg/kg of ketamine plus 2 mg/kg penehyclidine hydrochloride (PK group) or normal saline (control group). The rats were trained and tested in a Morris water maze 14 days after administration. The immunhistochemical method was used to ascertain the expression of synaptophysin in the hippocampus CA3 region 24 hrs, 14 days and 28 days after administration.</p><p><b>RESULTS</b>In the Morris water maze training, the rats in the PK group performed worst, followed by the K group. The rats from the P and NS groups performed well. Compared with the NS group, the expression of synaptophysin in the K and the PK groups decreased significantly 24 hrs and 14 days after administration (p<0.05). The PK group had lower synaptophysin expression than the K group 24 hrs and 14 days after administration (p<0.05). Up to 28 days after administration, the synaptophysin expression increased in all of the four groups and there were no significant differences between groups.</p><p><b>CONCLUSIONS</b>Ketamine combined with penehyclidine hydrochloride may inhibit more significantly learning and memory abilities and the synaptophysin expression in the hippocampus CA3 region than ketamine alone in neonatal rats. Penehyclidine hydrochloride alone has no effect on learning and memory abilities and the synaptophysin expression. The synaptophysin expression may increase to a normal level by training and with increasing age.</p>

Effect of acute administration of ketamine and imipramine on creatine kinase activity in the brain of rats / Efeito da administração aguda da cetamina e imipramina sobre a atividade da creatina quinase no encéfalo de ratos

OBJECTIVE: Clinical findings suggest that ketamine may be used for the treatment of major depression. The present study aimed to compare behavioral effects and brain Creatine kinase activity in specific brain regions after administration of ketamine and imipramine in rats. METHOD: Rats were acutely given ketamine or imipramine and antidepressant-like activity was assessed by the forced swimming test; Creatine kinase activity was measured in different regions of the brain. RESULTS: The results showed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) reduced immobility time when compared to saline group. We also observed that ketamine (10 and 15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in striatum and cerebral cortex. Ketamine at the highest dose (15mg/kg) and imipramine (20 and 30mg/kg) increased Creatine kinase activity in cerebellum and prefrontal cortex. On the other hand, hippocampus was not affected. CONCLUSION: Considering that metabolism impairment is probably involved in the pathophysiology of depressive disorders, the modulation of energy metabolism (like increase in Creatine kinase activity) by antidepressants could be an important mechanism of action of these drugs.

OBJETIVO: Vários achados clínicos sugerem que a cetamina apresenta efeito antidepressivo. O presente estudo tem como objetivo comparar efeitos comportamentais e a atividade da creatina quinase em regiões específicas do encéfalo após a administração de cetamina e imipramina em ratos. MÉTODO: Ratos Wistar receberam uma administração aguda de cetamina ou imipramina e a atividade antidepressiva foi avaliada pelo teste de nado forçado; a atividade da creatina quinase foi medida em diferentes regiões encefálicas. RESULTADOS: Os resultados mostraram que a cetamina (10 e 15mg/kg) e a imipramina (20 e 30mg/kg) diminuíram o tempo de imobilidade quando comparados ao grupo salina. Também foi observado que a cetamina (10 e 15mg/kg) e a imipramina (20 e 30mg/kg) aumentaram a atividade da creatina quinase no estriado e córtex cerebral. A dose mais alta de cetamina (15mg/kg) e a imipramina (20 e 30mg/kg) aumentaram a atividade da creatina quinase no cerebelo e córtex pré-frontal. Por outro lado, o hipocampo não foi alterado. CONCLUSÃO: Considerando que a diminuição no metabolismo provavelmente está envolvida na fisiopatologia da depressão, a modulação do metabolismo energético (como um aumento na atividade da creatina quinase) por antidepressivos pode ser um importante mecanismo de ação destes fármacos.