Anestesia intravenosa contínua com cetamina racêmica ou dextrocetamina e detomidina em cadelas / [Continuous intravenous anesthesia with racemic ketamine or dextroketamine and detomidine in female dogs]

Objetivou-se com este estudo comparar a associação de detomidina e cetamina ou dextrocetamina, por via intravenosa contínua, em oito cadelas submetidas a dois protocolos: GCD - indução anestésica com 5mg/kg e infusão intravenosa contínua de 20mg/kg/h de cetamina; e GDD - indução com 3,5mg/kg e infusão de 14mg/kg/h de dextrocetamina. Associou-se detomidina, 30µg/kg/h, em ambos os grupos. Registraram-se frequência cardíaca (FC), pressão arterial (PA), frequência respiratória (f), temperatura (TC), miorrelaxamento, analgesia, hemogasometria e eletrocardiograma, antes e 15 minutos após a MPA (Mbasal e Mmpa); após o início da infusão (Mic); a cada 10 minutos até 90 minutos (M10, M20, M30, M40, M50, M60, M70, M80 e M90); e 30 minutos após o fim da infusão (M120). Foi observada bradicardia em Mmpa no GCD e de Mmpa a M10 no GDD. Ocorreu hipotensão em Mmpa e hipertensão a partir de Mic. A f diminuiu de M10 a M30. Foram observados: onda T de alta amplitude, bloqueios atrioventriculares e parada sinusal. Ocorreu acidose respiratória. O período de recuperação foi de 219,6±72,3 minutos no GCD e de 234,1±96,8 minutos no GDD. A cetamina e a dextrocetamina, associadas à detomidina por infusão contínua, causam efeitos cardiorrespiratórios e anestésicos similares.(AU)

The combination of detomidine and ketamine or dextrocetamine for continuous intravenous infusion was compared in eight female dogs submitted to two protocols: GCD - 5mg/kg of anesthetic induction and continuous intravenous infusion of ketamine 20mg/kg/h; and GDD - induction with 3.5mg/kg and infusion of 14mg/kg/h of dextrocetamine. Detomidine, 30µg/kg/h was associated in both groups. Heart rate (HR), blood pressure (BP), respiratory rate (RR), temperature (CT), myorelaxation, analgesia, blood gas analysis and electrocardiogram were recorded before and 15 minutes after MPA (Mbasal and Mmpa); after the start of infusion (Mic); every 10 minutes to 90 minutes (M10, M20, M30, M40, M50, M60, M70, M80 and M90); and 30 minutes after the end of infusion (M120). Bradycardia was observed in Mmpa in GCD and from Mmpa to M10 in GDD. There was hypotension in Mmpa and hypertension from Mic. The RR decreased from M10 to M30. High amplitude T wave, atrioventricular blocks and sinus arrest were observed. Respiratory acidosis occurred. The recovery period was 219.6±72.3 minutes in GCD and 234.1±96.8 minutes in GDD. Ketamine and S+ ketamine associated with detomidine for continuous infusion cause cardiorespiratory and similar anesthetic effects.(AU)

Ameliorative effect of imperatorin in chemically induced fibromyalgia: Role of NMDA/NFkB mediated downstream signaling.

Fibromyalgia (FM) is a chronic pain syndrome involving complex interplay of biogenic amines and NMDA receptor mediated hypersensitization of nociceptive pathways. Clinical management of FM is poorly addressed with only a few available therapeutic options. Coumarins are active phenolic molecules of natural origin found to have broad pharmacological activities. Current investigation explores the role of naturally occurring coumarin, imperatorin in mouse model of fibromyalgia. Administration of reserpine (0.5 mg/kg, s.c.) thrice at 24 h intervals induced behavioral and neurochemical alterations characteristic of fibromyalgia. Reserpine was found to induce allodynia quantified using electronic von Frey (e-VF) and pressure application measurement (PAM) test, depression as indicated by an increased duration of immobility in forced swim test (FST), decreased motor coordination and locomotor activity in inclined plane test (IPT) and open field test (OFT) respectively. Cognitive deficits were evident by an increased latency to locate hidden platform in Morris water maze (MWM) and passive avoidance test (PAT). Reserpine treatment was found to cause an increased anxiety as revealed by increased time spent in closed arm of the elevated plus maze (EPM). Furthermore, an up- regulation in NMDA and NFκB expression in the brain and spinal cord was observed in reserpine treated groups. Administration of imperatorin (10 mg/kg, i.p) for a period of 5 days ameliorated all behavioral deficits, biochemical changes and decreased expression of NMDA and NFκB in the brain and spinal cord of treated mice. These findings indicate an interplay of NMDA/NFκB modulation by imperatorin in the reserpine induced fibromyalgia in mice.

Simvastatin treatment reduces the cholesterol content of membrane/lipid rafts, implicating the N -methyl-D-aspartate receptor in anxiety: a literature review

ABSTRACT Membrane/lipid rafts (MLRs) are plasmalemmal microdomains that are essential for neuronal signaling and synaptic development/stabilization. Inhibitors of 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (statins) can disable the N-methyl-D-aspartate (NMDA) receptor through disruption of MLRs and, in turn, decrease NMDA-mediated anxiety. This hypothesis will contribute to understanding the critical roles of simvastatin in treating anxiety via the NMDA receptor.

Excitotoxicity triggered by Neurobasal culture medium.

Neurobasal defined culture medium has been optimized for survival of rat embryonic hippocampal neurons and is now widely used for many types of primary neuronal cell culture. Therefore, we were surprised that routine medium exchange with serum- and supplement-free Neurobasal killed as many as 50% of postnatal hippocampal neurons after a 4 h exposure at day in vitro 12-15. Minimal Essential Medium (MEM), in contrast, produced no significant toxicity. Detectable Neurobasal-induced neuronal death occurred with as little as 5 min exposure, measured 24 h later. D-2-Amino-5-phosphonovalerate (D-APV) completely prevented Neurobasal toxicity, implicating direct or indirect N-methyl-D-aspartate (NMDA) receptor-mediated neuronal excitotoxicity. Whole-cell recordings revealed that Neurobasal but not MEM directly activated D-APV-sensitive currents similar in amplitude to those gated by 1 µM glutamate. We hypothesized that L-cysteine likely mediates the excitotoxic effects of Neurobasal incubation. Although the original published formulation of Neurobasal contained only 10 µM L-cysteine, commercial recipes contain 260 µM, a concentration in the range reported to activate NMDA receptors. Consistent with our hypothesis, 260 µM L-cysteine in bicarbonate-buffered saline gated NMDA receptor currents and produced toxicity equivalent to Neurobasal. Although NMDA receptor-mediated depolarization and Ca²âº influx may support survival of young neurons, NMDA receptor agonist effects on development and survival should be considered when employing Neurobasal culture medium.

tPA contributes to impaired NMDA cerebrovasodilation after traumatic brain injury through activation of JNK MAPK.

OBJECTIVE: N-methyl-D-aspartate (NMDA)-induced pial artery dilation (PAD) is reversed to vasoconstriction after fluid percussion brain injury (FPI). Tissue type plasminogen activator (tPA) is up-regulated and the tPA antagonist, EEIIMD, prevents impaired NMDA PAD after FPI. Mitogen-activated protein kinase (MAPK), a family of at least three kinases, ERK, p38, and JNK, is also up-regulated after traumatic brain injury (TBI). We hypothesize that tPA impairs NMDA-induced cerebrovasodilation after FPI in a MAPK isoform-dependent mechanism. METHODS: Lateral FPI was induced in newborn pigs. The closed cranial window technique was used to measure pial artery diameter and to collect cerebrospinal fluid (CSF). ERK, p38, and JNK MAPK concentrations in CSF were quantified by ELISA. RESULTS: CSF JNK MAPK was increased by FPI, increased further by tPA, but blocked by JNK antagonists SP600125 and D-JNKI1. FPI modestly increased p38 and ERK isoforms of MAPK. NMDA-induced PAD was reversed to vasoconstriction after FPI, whereas dilator responses to papaverine were unchanged. tPA, in post-FPI CSF concentration, potentiated NMDA-induced vasoconstriction while papaverine dilation was unchanged. SP 600125 and D-JNKI1, blocked NMDA-induced vasoconstriction and fully restored PAD. The ERK antagonist U 0126 partially restored NMDA-induced PAD, while the p38 inhibitor SB203580 aggravated NMDA-induced vasoconstriction observed in the presence of tPA after FPI. DISCUSSION: These data indicate that tPA contributes to impairment of NMDA-mediated cerebrovasodilation after FPI through JNK, while p38 may be protective. These data suggest that inhibition of the endogenous plasminogen activator system and JNK may improve cerebral hemodynamic outcome post-TBI.

Assessment of NMDA receptor activation in vivo by Fos induction after challenge with the direct NMDA agonist (tetrazol-5-yl)glycine: effects of clozapine and haloperidol.

Induction of Fos protein by the potent and direct NMDA agonist (tetrazol-5-yl)glycine (TZG) was examined in mice. Effects of antipsychotic drugs were assessed on this in vivo index of NMDA receptor activation. TZG induced the expression of Fos in a neuroanatomically selective manner, with the hippocampal formation showing the most robust response. In mice genetically altered to express low levels of the NR1 subunit of the NMDA receptor, TZG-induced Fos was reduced markedly in comparison to the wild type controls. TZG-induced Fos was also blocked by the selective NMDA antagonist MK-801. Pretreatment of mice with clozapine (3 and 10 mg/kg) reduced TZG-induced Fos in the hippocampal formation but not in other brain regions. Haloperidol at a dose of 0.5 mg/kg did not antagonize TZG induced Fos in any region. Haloperidol at a dose of 1.0 mg/kg did attenuate the induction of Fos by TZG in the hippocampus but not in other brain regions. The relatively high dose (1 mg/kg) of haloperidol required to block effects of TZG suggests that this action may not be related to the D(2) dopamine receptor-blocking properties, since maximal D(2) receptor blockade was probably achieved by the 0.5 mg/kg dose of haloperidol. The antidepressant drug imipramine (10 or 20 mg/kg) did not antagonize TZG induced Fos in any brain region. The data suggest that clozapine can reduce excessive activation of NMDA receptors by TZG administration in vivo at doses relevant to the drugs' actions in rodent models of antipsychotic activity. Whether or not this action of clozapine contributes to its therapeutic properties will require further study.

Hipótese glutamatérgica da esquizofrenia / Glutamatergic hypothesis of schizophrenia

A esquizofrenia é um transtorno psiquiátrico devastador cuja fisiopatologia ainda está para ser esclarecida. Apesar de uma disfunção dopaminérgica estar bem estabelecida na esquizofrenia, há uma série de evidências sugerindo o envolvimento do sistema glutamatérgico na fisiopatologia do transtorno. Este artigo faz uma breve revisão de alguns aspectos básicos do funcionamento dos receptores glutamatérgicos com ênfase nos receptores N-metil-D-aspartato (NMDA). Apresenta evidências científicas sugerindo uma disfunção do sistema glutamatérgico na esquizofrenia (hipofunção de receptores NMDA). E discute as interações entre os sistemas dopaminérgico e glutamatérgico; mais especificamente como os estados hiperdopaminérgicos encontrados na esquizofrenia podem estar associados a uma alteração glutamatérgica

NMDA but not non-NMDA excitotoxicity is mediated by Poly(ADP-ribose) polymerase.

Poly(ADP-ribose) polymerase (PARP-1), a nuclear enzyme that facilitates DNA repair, may be instrumental in acute neuronal cell death in a variety of insults including, cerebral ischemia, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced parkinsonism, and CNS trauma. Excitotoxicity is thought to underlie these and other toxic models of neuronal death. Different glutamate agonists may trigger different downstream pathways toward neurotoxicity. We examine the role of PARP-1 in NMDA- and non-NMDA-mediated excitotoxicity. NMDA and non-NMDA agonists were stereotactically delivered into the striatum of mice lacking PARP-1 and control mice in acute (48 hr) and chronic (3 week) toxicity paradigms. Mice lacking PARP-1 are highly resistant to the excitoxicity induced by NMDA but are as equally susceptible to AMPA excitotoxicity as wild-type mice. Restoring PARP-1 protein in mice lacking PARP-1 by viral transfection restored susceptibility to NMDA, supporting the requirement of PARP-1 in NMDA neurotoxicity. Furthermore, Western blot analyses demonstrate that PARP-1 is activated after NMDA delivery but not after AMPA administration. Consistent with the theory that nitric oxide (NO) and peroxynitrite are prominent in NMDA-induced neurotoxicity, PARP-1 was not activated in mice lacking the gene for neuronal NO synthase after NMDA administration. These results suggest a selective role of PARP-1 in glutamate excitoxicity, and strategies of inhibiting PARP-1 in NMDA-mediated neurotoxicity may offer substantial acute and chronic neuroprotection.

Low resting potential and postnatal upregulation of NMDA receptors may cause Cajal-Retzius cell death.

Using in situ patch-clamp techniques in rat telencephalic slices, we have followed resting potential (RP) properties and the functional expression of NMDA receptors in neocortical Cajal-Retzius (CR) cells from embryonic day 18 to postnatal day 13, the time around which these cells normally disappear. We find that throughout their lives CR cells have a relatively depolarized RP (approximately -50 mV), which can be made more hyperpolarized (approximately -70 mV) by stimulation of the Na/K pump with intracellular ATP. The NMDA receptors of CR cells are subjected to intense postnatal upregulation, but their similar properties (EC50, Hill number, sensitivity to antagonists, conductance, and kinetics) throughout development suggest that their subunit composition remains relatively homogeneous. The low RP of CR cells is within a range that allows for the relief of NMDA channels from Mg2+ blockade. Our findings are consistent with the hypothesis that CR cells may degenerate and die subsequent to uncontrolled overload of intracellular Ca2+ via NMDA receptor activation by ambient glutamate. In support of this hypothesis we have obtained evidence showing the protection of CR cells via in vivo blockade of NMDA receptors with dizocilpine.