Secuelas cognitivas en encefalitis inmunomediadas: cohorte de pacientes en Argentina / Cognitive sequelae in immunomediated encephalitis: cohort of patients in Argentina

Resumen Introducción: Las encefalitis inmunomediadas son un desorden neurológico de origen autoinmune. Actual mente es escasa la descripción de las secuelas cognitivas crónicas. El objetivo del presente trabajo fue caracterizar la secuela cognitiva de diferentes tipos de encefalitis inmunomediadas en una cohorte de un centro único de Argentina. Métodos: Estudio prospectivo, observacional, trans versal, de pacientes en seguimiento en un hospital de la Ciudad de Buenos Aires, con diagnóstico de encefalitis inmunomediada probable y definitiva. Se evaluaron variables epidemiológicas, clínicas, paraclínicas y tra tamiento. Se determinó la secuela cognitiva a través de una evaluación neurocognitiva realizada a partir del año de la presentación clínica. Resultados: Fueron incluidos 15 pacientes, todos con resultado disminuido en al menos un test. La memoria fue el dominio más afectado. Aquellos que se encon traban bajo tratamiento inmunosupresor al momento de evaluarse presentaron menores resultados en el aprendizaje seriado (media -2.94; desvío estándar 1.54) versus los que se encontraban sin tratamiento (media -1.18; desvío estándar 1.40; p = 0.05) y en la prueba de reconocimiento (media -10.34; desvío estándar 8.02) ver sus sin tratamiento (media -1.39; desvío estándar 2.21; p = 0.003). Los pacientes con estatus epiléptico tuvieron resultados deficitarios en la prueba de reconocimiento (media -7.2; desvío estándar 7.91) en comparación a los que no lo tenían (media -1.47; desvío estándar 2.34; p = 0.05). Conclusión: Nuestros resultados demuestran que, a pesar del curso monofásico de la enfermedad, todos los pacientes presentan daño cognitivo persistente más allá del año del inicio del cuadro. Estudios prospectivos de mayor envergadura serían necesarios para confirmar nuestros hallazgos.

Abstract Introduction: Autoimmune encephalitis represents a group of immune-mediated neurological disorders. At present, the description of the chronic cognitive sequela is scarce. The objective of this study was to characterize the cognitive after effects of different types of autoimmune encephalitis in a cohort from a single center in Argentina. Methods: Prospective, observational, cross-sectional study of patients under follow-up at a hospital in Buenos Aires city, with a diagnosis of probable and definitive immune-mediated encephalitis. Epidemiological, clini cal, paraclinical and treatment related variables were evaluated. Cognitive sequela was determined through a neurocognitive evaluation performed at least a year after the clinical presentation. Results: Fifteen patients were included. All had di minished results in at least one test. Memory was the most affected domain. Patients who were under im munosuppressive treatment at the time of evaluation presented lower results in serial learning (mean -2.94; standard deviation 1.54) versus those who weren't under treatment (mean -1.18; standard deviation 1.40; p = 0.05). The same pattern was observed on the recognition test of treatment group (mean -10.34; standard deviation 8.02) versus treatment-free group (mean -1.39; standard deviation 2.21; p =0.003). Patients with status epilepticus had poorer results in the recognition test (mean -7.2; standard deviation 7.91) compared to those without it (mean -1.47; standard deviation 2.34; p = 0.05). Conclusion: Our results show that, despite the mo nophasic course of this disease, all patients had persis tent cognitive damage beyond the year of onset. Larger prospective studies are required to confirm our findings.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. Δ9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

Action of ketamine and endocannabinoid system in rapid anti-depression therapy / 上海交通大学学报（医学版）

Major depression disorder (MDD) is a common but serious affective disorder in modern society. Suicide idea and suicide behaviour induced by MDD during its later stage put a heavy burden on society and family. Anti-depression drugs lack efficiency in treating a portion of MDD patients. This is referred to as treatment resistant depression (TRD). A study reported the rapid onset and long lasting anti-depression effect of ketamine, which also come into effect in TRD patients. △9-Tetrahydrocannabinol is the active substance of marijuana, which also exerts rapid anti-depression effect via targeting at brain cannabinoid receptors. The two central nerve system stimulants belonging to the tightly controlled psychoactive substances have obvious adverse effects. This article summarizes the action of ketamine and endocannabinoid system in rapid anti-depression therapy in recent researches.

Role of Sigma Receptor and Neurosteroids in Pain Sensation / 한양의대학술지

The sigma-1 receptor has recently been implicated in a myriad of cellular functions and biological processes. Previous studies have demonstrated that the spinal sigma-1 receptor plays a pro-nociceptive role in acute pain and that the direct activation of sigma-1 receptor enhances the nociceptive response to peripheral stimuli, which is closely associated with calcium-dependent second messenger cascades including protein kinase C (PKC). In addition, the activation of sigma-1 receptor increases PKC- and protein kinase alpha (PKA)-dependent phosphorylation of the N-Methyl- D-aspartate (NMDA) receptor in the spinal cord, which results in the potentiation of intrathecal NMDA-evoked spontaneous pain behavior. Moreover, the blockade of spinal sigma-1 receptor suppresses the development of neuropathic pain and blocks the increase of phosphorylation of extracellular signal-regulated kinase (ERK) as well as pNR1 in the spinal cord. Recently, it was also reported that spinal neurosteroids such as pregnenolone and dehydroepiandrosterone sulfate, which are recognized as endogenous ligands for sigma-1 receptor, could produce mechanical hypersensitivity via sigma-1 receptor-mediated increase of pNR1. Collectively, these findings demonstrate that the activation of spinal sigma-1 receptor or the increase of neurosteroids is closely associated with the acute pain sensation or the development of chronic pain, and imply that sigma-1 receptor can be a new potential target for the development of analgesics.

Peripheral N-methyl-D-aspartate Receptors Involved in Long-term Hyperalgesia Induced by Peripheral Injection of Formalin in Rats / 中国康复理论与实践

@#Objective To investigate the role of peripheral N-methyl-D-aspartate (NMDA) receptors in the long-term hyperalgesia induced by peripheral injection of formalin in rats. Methods Formalin was injected in the paws of the SD rats with or without the MK-801 pre-injection. OX-42 expressions in the dorsal horn were observed, and the paw withdrawal thermal latency was measured. Results The OX-42 expression decreased and the paw withdrawal thermal latency prolonged in rats with MK-801 pre-injection. Conclusion Peripheral NMDA receptors may be involved in the long-term hyperalgesia.

Ketamina, una antigua droga que renace ante el dolor: parte I / Ketamine, and old drug coming back for pain management: part I

La Ketamina es una antigua droga usada como inductor anestésico, que debido a sus efectos adversos alucinatorios se subutilizó en las últimas décadas, pero debido al avance de las neurociencias y al conocimiento del dolor, renace como un potente medicamento analgésico (antihiperalgésico). Es un bloqueador no competitivo de los receptores NMDA, que son los receptores que se activan cuando el dolor es intenso, se postula que se podría utilizar para disminuir la percepción del dolor. es un neuromodulador del dolor y potenciador de la acción analgésica de los opioides. Los estudios clínicos han evidenciado su uso en el manejo del dolor postoperatorio dentro de una modalidad multimodal, con menor incidencia de náuseas y vómitos que al usar opioides solos y con reacciones adversas de tipo alucinatorias escasas. Las dosis ideales para los distintos tipos de cirugía, actualmente se basan en opiniones de expertos y se requieren mayores estudios. En dolor neuropático y en dolor por cáncer existe evidencia tipo IV, basadas en serie de casos que muestra ser útil. En tolerancia por opioides y en cronificación del dolor postoperatorio existen buenos estudios, pero aún no concluyentes. En conclusión, la ketamina es un fármaco útil, pero se debe conocer muy bien su farmacología para poder usarlo de manera segura y con un buen criterio clínico para el manejo del dolor moderado y/o intenso.

Ketamine is an old drug used in the induction of anesthesia that due to adverse hallucinatory effects has been under utilized during the past decades. However, the advances in neuroscience and a deeper knowledge of pain, ketamine is reborn as a strong analgesic (antihyperalgesic) aid. Ketamine is a non competitive blocker of NMDA receptors that are activated by severe pain and it could be used in pain reduction. Ketamine is a pain neuromodulator and enhancer of the opioids analgesic action. Clinicals trials showed it can be used in post surgery pain management in a number of ways with lessened side effects sunch as nausea and vomiting and scare hallucinatory effects compared to those caused by opioid treatment alone. the ideal dosage for different types of surgery now relies on the opinion of experts, however, further research is required. In neuropathic and cancer pain there is type IV evidence based on a number of cases that proves to be useful. Good trials, but not yet conclusive have been made in matters of tolerance to opioids and post surgery chronic pain. In conclusion, Ketamine is a useful drug, however, a deep knowledge of the same as well as good judgement are required for using it in moderate and/or severe pain management.

NMDA receptor channel / 한양의대학술지

Glutamate receptor channels have been classified into three major subtypes, the alpha-amino-3 - hydroxy-5-methyl-4-isoxazole propionic acid (AMPA), kainite and N-Methyl-D-aspartate (NMDA) receptor channels. The NMDA receptor channel differs in fundamental ways from the non-NMDA receptor channels, and these properties relate directly to its physiological roles. NMDA ion channels play important roles in various physiological or pathologic functions in neuroprotection, neurodegeneration, long-term potentiation, memory, cognition, neurological disorders, psychiatric disorders, and neuropathic pain syndromes. The NMDA receptor channel is gated in a unique manner both by ligands and by voltage. The voltage dependence is caused by Mg2+ block within the ion channel. The NMDA receptor is highly permeable to Ca2+ unlike most other ions. In addition, it can be modulated at a number of sites other than glutamate recognition site. Among these sites, an allosteric site through glycine modulates the NMDA response. The molecular cloning and diversity of the NMDA receptor channel have been identified. The mechanisms that control the opening and closing, or gating, of the channel of NMDA receptors are among the most basic determinants of receptor function, and yet are not well understood. This review summarizes from a molecular perspective the recent advances in our understanding of the pharmacological properties of NMDA receptor channels.

The Expression of Isoforms of Nitric Oxide Synthase (NOS) and Subunits of N-methyl-D-aspartate (NMDA) Receptor according to Administration of Mycophenolic Acid before or after Perinatal Hypoxic Ischemic Brain Injury

PURPOSE: Mycophenolic acid (MPA), a potent inhibitor of inosine-monophosphate dehydrogenase (IMPDH), was used as a new immunosuppressive drug since 1990s. It was reported that MPA increased neuronal survival after excitotoxic injury, induced apoptosis in microglial cells, inhibited the induction of inducible nitric oxide synthase (iNOS) in astrocytes. and inhibited microglial cell proliferation in N-methyl-D-aspartate (NMDA) induced hippocampal cells. However, the effects of MPA on the perinatal hypoxic-ischemic (HI) brain injury had not been yet evaluated. Therefore, we examined whether MPA could be neuroprotective in the HI brain injury. METHODS: Cortical cells were cultured using a 18-day-pregnant Sprague-Dawley (SD) rats and incubated in 1% O2 incubator for hypoxia. MPA (10 ug/mL) before or after a HI insult were treated. Seven-day-old SD rat pups were subjected to left carotid occlusion followed by 2.5 hours of hypoxic exposure (8% O2). MPA (10 mg/kg) were administrated intraperitoneally before or after a HI insult. Nitric oxide (NO) activity and expression of N-methyl-D-aspartate (NMDA) receptors also measured using Real-time PCR with primer pairs of isoforms of NOS; iNOS, endothelial NOS (eNOS), neuronal NOS (nNOS), and subunits of NMDA receptors; NR1, NR2A, NR2B, NR2C, NR2D. RESULTS: The expression of iNOS was decreased in the hypoxia group but increased in the MPA-treated group. However express or that eNOS and nNOS were inversed. The expression of all NMDA receptor subunits except NR2B was decreased in the hypoxia group but increased in the MPA-treated group. CONCLUSION: This study indicates that the administration of MPA before a HI insult could significantly protect against perinatal HI brain injury via some parts of NO-mediated or excitotoxic mechanisms.

Effect of behavior training on the expression of NR2B around the infarcted focus and in the cortex of temporal lobe in rats with bilateral hippocampal infarction / 中国康复理论与实践

@#ObjectiveTo study the effect of behavior training on the expression of NR2B around the infarcted focus and in the cortex of temporal lobe in rats with bilateral hippocampal infarction.Methods54 SD rats were randomized into pre-training, 7 d, 14 d, 21 d after training groups, pre-immobilization, 7 d, 14 d, 21 d immobilization groups and control group. Behavior training and immobilization were performed on the 3rd day after the infarction. Immunohistochemistry was used to detect the expression of NR2B around the infarcted focus and in the cortex of temporal lobe at different points of time.ResultsThe expression of NR2B was abundant in the normal hippocampus and cortex of temporal lobe of rats. The expression of NR2B decreased after infarction and increased after behavior training. However, the expression of NR2B had little increased in immobilization groups, and showed significant difference compared with that in behavior training groups (P<0.01).ConclusionBehavior training can accelerate the expression of NR2B around the infarcted focus and in the cortex of temporal lobe in rats with bilateral hippocampal infarction.

Effect of Etomidate on N-methyl-D-aspartate Induced Neurotoxicity in Rat Cortical Neurons / 대한마취과학회지

BACKGROUND: The present investigation was undertaken to evaluate the neuroprotective effect of etomidate against N-methyl-D- aspartate (NMDA) induced neurotoxicity in rat cortical neurons by measuring lactate dehydrogenase (LDH). METHODS: The cerebral cortical neurons of fetal rat were grown for 12 days in dissociated cell culture. They were divided into four groups: first group acted as control with no drug administration and other groups treated with either NMDA 100microM or Etomidate (ET) 10microM + NMDA 100microM or ET 100microM + NMDA 100microM After 24 hrs, cell death was assessed by morphology under the light microscope and quantified by measuring the LDH in the culture media. RESULTS: In the light microscopic findings, the intact cortical neurons were increased in the ET groups. NMDA-induced LDH production also significantly suppressed in ET group (P<0.05). There were no significant difference between the ET 10microM and 100microM groups. CONCLUSIONS: These results suggest that the etomidate has protective effect on the cultured rat cortical neurons against NMDA-induced neurotoxicity.

Protective effect of pyrroloquinoline quinone on damage of hippocampal neurons induced by NMDA in rats / 中国康复理论与实践

@# ObjectiveTo investigate the protective effect of pyrroloquinoline quinone (PQQ) on damage of hippocampal neurons induced by NMDA.MethodsHippocampal neurons were cultured in vitro and NMDA was used to induce neurotoxicity 8 d after, while PQQ were used or not before. The metamorphosis of hippocampal neurons was observed under the microscope. Intracellular calcium levels was measured by confocal laser microscopy. ResultsThe intracellular Ca2+ level increased rapidly after exposure to 0.1 mmol/L NMDA and resulted in neuronal necrosis and apoptosis. Otherwise, pretreatment of the cultured neurons with PQQ reduced the increase of the intracellular Ca2+ level and the neuronal necrosis or apoptosis induced by NMDA.ConclusionPQQ can protect hippocampal neurons from damage induced by NMDA.

Relation between modulation of the N-methyl-D-aspartate receptor and cyanide-induced neurotoxicity / 中国临床药理学与治疗学

Cyanide can activate the N-methyl-D-aspartate (NMDA) receptor by two approaches directly and indirectly. Firstly cyanide-induced depletion of energy is associated with the activation of NMDA receptors indirectly by increasing extracellular glutamate (Glu) and affecting cytosolic Ca 2+ homeostatic mechanisms. Secondly most likely as a conditioner of the NMDA receptor, cyanide enhances NMDA receptors responses by modulating redox sites of cysteine residue located in the subunit NR 1 or NR 2 of the NMDA receptor. NMDA receptor-induced neurotoxicity, initiated by the direct or indirect activation of NMDA receptor, leads to neuronal injury, apoptosis or necrosis finally. Therefore, it is believed that the activation of the NMDA receptor is presumably the key event in the mechanism of cyanide-induced neuronal injures.

Differential effect of homocysteic acid and cysteic acid on changes of inositol phosphates and (Ca2+)i in rat cerebellar granule cells

The present study was undertaken to characterize homocysteic acid (HCA)-and cysteic acid (CA)mediated formation of inositol phosphates (InsP) in primary culture of rat cerebellar granule cells. HCA and CA stimulated InsP formation in a dose-dependent manner, which was prevented by the N-methyl-D-aspartate (NMDA) receptor antagonist D,L-2-amino-5-phosphopentanoic acid (APV). CA-, but not HCA-, mediated InsP formation was in part prevented by the metabotropic glutamate receptor antagonist alpha-methyl-4-carboxyphenylglycine ((+/-)-MCPG). Both HCA- and CA-mediated increases in intracellular calcium concentration were completely blocked by APV, but were not altered by (+/-)-MCPG. CA-mediated InsP formation was in part prevented by removal of endogenous glutamate. In contrast, the glutamate transport blocker L-aspartic acid-beta-hydroxamate synergistically increased CA responses. These data indicate that in cerebellar granule cells HCA mediates InsP formation wholly by activating NMDA receptor. In contrast, CA stimulates InsP formation by activating both NMDA receptor and metabotropic glutamate receptor, and in part by releasing endogenous glutamate into extracellular milieu.