Encefalitis autoinmune y síndrome paraneoplásico por teratoma maduro ovárico / Autoimmune encephalitis and paraneoplasic syndrome due to ovarian mature teratoma

Antecedentes: La encefalitis por anticuerpos contra el receptor de N-metil-D- aspartato (NMDAr), fue descrita por primera vez en 2005, y en 2007 Dalmau et al identificaron los anticuerpos contra el receptor NMDA. Se estima que anualmente hay 1.5 casos por cada millón de habitantes con mayor frecuencia en mujeres jóvenes entre 15 a 25 años, puede presentarse como un síndrome paraneoplásico asociado a teratoma ovárico en un 37%. Descripción del caso clínico: Femenina de 17 años con antecedente de teratoma de ovario izquierdo de recién diagnóstico, una semana posterior a la resección quirúrgica presenta: alucinaciones auditivas, ideación de persecución, insomnio, anhedonia, agitación psicomotriz, alteraciones del habla, discinesias orofaciales y alteraciones en la marcha, de un mes de evolución. El electroencefalograma (EEG) reportó hallazgos de disfunción cortico-subcortical severa según reporte por clínica privada sin acceso al estudio. La Resonancia Magnética (IRM) cerebral y citoquímica de líquido cefalorraquídeo (LCR) sin anormalidades. Ante sospecha clínica se inició tratamiento inmunosupresor con corticosteroides intravenosos y manejo sintomático antipsicótico, para agitación y ansiedad; inicialmente con midazolam en infusión y luego con olanzapina, risperidona y clonazepam; obteniendo una evolución clínica satisfactoria. Finalmente, se confirmó el diagnóstico al obtener un resultado positivo para IgG contra la subunidad N1 de glutamato (GluN1) del NMDAr. Conclusión: La encefalitis anti NMDAr es una condición rara y subdiagnosticada, puede confundirse con una enfermedad psiquiátrica primaria. Ante un primer episodio psicótico se debe hacer un interrogatorio y evaluación extensa, con la finalidad de descartar causas secundarias, como los trastornos autoinmunes con repercusiones neurológicas...(AU)

Glutamate and its ionotropic receptor agonists inhibit the response to acute hypoxia in carotid body of rats / 生理学报

The purpose of this study was to investigate the effect of glutamate and its ionotropic receptor agonists on the response to acute hypoxia in rat carotid body in vitro. Briefly, after SD rats were anesthetized and decapitated, the bilateral carotid bifurcations were rapidly isolated. Then bifurcation was placed into a recording chamber perfused with 95% O2-5% CO2 saturated Kreb's solution. The carotid body-sinus nerve complex was dissected, and the carotid sinus nerve discharge was recorded using a suction electrode. To detect the response of carotid body to acute hypoxia, the chamber was perfused with 5% O2-5% CO2-90% N2 saturated Kreb's solution for a period of 100 s at an interval of 15 min. To observe the effect of glutamate, ionotropic α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor agonist AMPA or N-methyl-D-aspartate (NMDA) receptor agonist NMDA on the response to acute hypoxia in rat carotid body, the chamber was perfused with 5% O2-5% CO2-90% N2 saturated Kreb's solution containing the corresponding reagent. The results showed that glutamate (20 μmol/L), AMPA (5 μmol/L) or NMDA (10 μmol/L) inhibited the acute hypoxia-induced enhancement of carotid sinus nerve activity, and these inhibitory effects were dose-dependent. In summary, the activation of glutamate ionotropic receptors appears to exert an inhibitory effect on the response to acute hypoxia in carotid body of rats.

Prostate-derived IL-1β upregulates expression of NMDA receptor in the paraventricular nucleus and shortens ejaculation latency in rats with experimental autoimmune prostatitis / 亚洲男科学杂志(英文版)

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.

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)

A diagnostic dilemma: Laparoscopic approach in treating ovarian Teratoma-associated anti-N-methyl-D-aspartate receptor Encephalitis / Philippine Journal of Obstetrics and Gynecology

@#A 24-year-old nulligravida who presented with seizures and behavioral changes with prodrome of flu-like symptoms was initially treated as a case of viral encephalitis. Neurologic diagnostic tests including electroencephalogram, cerebrospinal fluid analysis (CSF), and cranial magnetic resonance imaging were done and inconclusive. Patient's seizure attacks persisted and her neurologic status was deteriorating despite giving appropriate anti-epileptic medications, hence an autoimmune disease was highly considered. The CSF was positive for N-methyl-D-aspartate receptor antibodies. This prompted a search for an associated teratoma and revealed a diagnostic dilemma between presence of an ovarian new growth versus a normal enlarged ovary. Laparoscopy which is both diagnostic and therapeutic was utilized. This report highlights prompt recognition of a rare case and prevented its progression to a potentially fatal condition as resection of the tumor dramatically relieved the symptoms. The significance of minimally invasive surgery in managing this case, effect in fertility, and possible association with pelvic inflammatory disease are also discussed.

Banderas rojas para sospechar encefalitis anti-NMDAr en un primer episodio psicótico: reporte de dos casos / Red flags for suspecting anti-NMDAr encephalitis in a first psychotic episode: report of two cases

RESUMEN La encefalitis asociada a anticuerpos contra el receptor de N-metil-D-Aspartato (NMDAr) es una entidad clínica recientemente descrita con un número creciente de casos reporta dos. Los síntomas psiquiátricos en etapas tempranas de la enfermedad conforman un reto diagnóstico para el médico tratante. Presentamos dos casos clínicos: el caso clínico 1, un hombre de 26 arios y el caso clínico 2, un joven de 18 arios, ambos abordados como primer episodio de psicosis y hospitalizados en instituciones psiquiátricas. Posteriormente, ambos casos fueron diagnosticados como encefalitis anti-NMDAr. La alta prevalencia de síntomas psiquiátricos en la encefalis anti-NMDAr demanda a los médicos psiquiatras y neurólogos a tener un alto índice de sospecha en presencia de síntomas atípicos en pacientes evaluados por primer episodio de psicosis.

ABSTRACT Anti-N-methyl-D-Aspartate receptor (NMDAr) encephalitis is a recently described clinical entity with an increasing number of reported cases. Psychiatric symptoms in the early stages of the disease constitute a diagnostic challenge for the treating physician. We present two clinical cases: clinical case 1, a 26-year-old man, and clinical case 2, an 18-year-old man; both presented with a first episode of psychosis and were hospitalized as psychiatric disorders. Subsequently, both cases were diagnosed as anti-NMDAr encephalitis. The high prevalence of psychiatric symptoms in anti-NMDAr encephalitis forces psychiatrists and neurologists to have a high degree of suspicion in the presence of atypical symptoms in patients evaluated for the first episode of psychosis.

Increased Nociceptive Responses in Streptozotocin-Induced Diabetic Rats and the Related Expression of Spinal NR2B Subunit of N-Methyl-D-Aspartate Receptors

BACKGROUND: This study investigated the role of NR2B in a modulated pain process in the painful diabetic neuropathy (PDN) rat using various pain stimuli. METHODS: Thirty-two Sprague-Dawley male rats were randomly allocated into four groups (n=8): control, diabetes mellitus (DM) rats and diabetic rats treated with ifenprodil at a lower dose (0.5 µg/day) (I 0.5) or higher dose (1.0 µg/day) (I 1.0). DM was induced by a single injection of streptozotocin at 60 mg/kg on day 0 of experimentation. Diabetic status was assessed on day 3 of the experimentation. The responses on both tactile and thermal stimuli were assessed on day 0 (baseline), day 14 (pre-intervention), and day 22 (post-intervention). Ifenprodil was given intrathecally for 7 days from day 15 until day 21. On day 23, 5% formalin was injected into the rats' hind paw and the nociceptive responses were recorded for 1 hour. The rats were sacrificed 72 hours post-formalin injection and an analysis of the spinal NR2B expression was performed. RESULTS: DM rats showed a significant reduction in pain threshold in response to the tactile and thermal stimuli and higher nociceptive response during the formalin test accompanied by the higher expression of phosphorylated spinal NR2B in both sides of the spinal cord. Ifenprodil treatment for both doses showed anti-allodynic and anti-nociceptive effects with lower expression of phosphorylated and total spinal NR2B. CONCLUSION: We suggest that the pain process in the streptozotocin-induced diabetic rat that has been modulated is associated with the higher phosphorylation of the spinal NR2B expression in the development of PDN, which is similar to other models of neuropathic rats.

Hepatoprotective effect of sodium hydrosulfide on hepatic encephalopathy in rats

Hydrogen sulfide is well-known to exhibit anti-inflammatory and cytoprotective activities, and also has protective effects in the liver. This study aimed to examine the protective effect of hydrogen sulfide in rats with hepatic encephalopathy, which was induced by mild bile duct ligation. In this rat model, bile ducts were mildly ligated for 26 days. Rats were treated for the final 5 days with sodium hydrosulfide (NaHS). NaHS (25 µmol/kg), 0.5% sodium carboxymethyl cellulose, or silymarin (100 mg/kg) was administered intraperitoneally once per day for 5 consecutive days. Mild bile duct ligation caused hepatotoxicity and inflammation in rats. Intraperitoneal NaHS administration reduced levels of aspartate aminotransferase and alanine aminotransferase, which are indicators of liver disease, compared to levels in the control mild bile duct ligation group. Levels of ammonia, a major causative factor of hepatic encephalopathy, were also significantly decreased. Malondialdehyde, myeloperoxidase, catalase, and tumor necrosis factor-α levels were measured to confirm antioxidative and anti-inflammatory effects. N-Methyl-D-aspartic acid (NMDA) receptors with neurotoxic activity were assessed for subunit NMDA receptor subtype 2B. Based on these data, NaHS is suggested to exhibit hepatoprotective effects and guard against neurotoxicity through antioxidant and anti-inflammatory actions.

Effects of Intraperitoneal N-methyl-D-aspartate (NMDA) Administration on Nociceptive/Repetitive Behaviors in Juvenile Mice

Dysregulation of excitatory neurotransmission has been implicated in the pathogenesis of neuropsychiatric disorders. Pharmacological inhibition of N-methyl-D-aspartate (NMDA) receptors is widely used to model neurobehavioral pathologies and underlying mechanisms. There is ample evidence that overstimulation of NMDA-dependent neurotransmission may induce neurobehavioral abnormalities, such as repetitive behaviors and hypersensitization to nociception and cognitive disruption, pharmacological modeling using NMDA has been limited due to the induction of neurotoxicity and blood brain barrier breakdown, especially in young animals. In this study, we examined the effects of intraperitoneal NMDA-administration on nociceptive and repetitive behaviors in ICR mice. Intraperitoneal injection of NMDA induced repetitive grooming and tail biting/licking behaviors in a dose- and age-dependent manner. Nociceptive and repetitive behaviors were more prominent in juvenile mice than adult mice. We did not observe extensive blood brain barrier breakdown or neuronal cell death after peritoneal injection of NMDA, indicating limited neurotoxic effects despite a significant increase in NMDA concentration in the cerebrospinal fluid. These findings suggest that the observed behavioral changes were not mediated by general NMDA toxicity. In the hot plate test, we found that the latency of paw licking and jumping decreased in the NMDA-exposed mice especially in the 75 mg/kg group, suggesting increased nociceptive sensitivity in NMDA-treated animals. Repetitive behaviors and increased pain sensitivity are often comorbid in psychiatric disorders (e.g., autism spectrum disorder). Therefore, the behavioral characteristics of intraperitoneal NMDA-administered mice described herein may be valuable for studying the mechanisms underlying relevant disorders and screening candidate therapeutic molecules.

Memantine Attenuates Salicylate-induced Tinnitus Possibly by Reducing NR2B Expression in Auditory Cortex of Rat

Memantine, a noncompetitive antagonist of the N-methyl-d-aspartate (NMDA) receptor, suppresses the release of excessive levels of glutamate that may induce neuronal excitation. Here we investigated the effects of memantine on salicylate-induced tinnitus model. The expressions of the activity-regulated cytoskeleton-associated protein (ARC) and tumor necrosis factor-alpha (TNF α)genes; as well as the NMDA receptor subunit 2B (NR2B) gene and protein, were examined in the SH-SY5Y cells and the animal model. We also used gap-prepulse inhibition of the acoustic startle reflex (GPIAS) and noise burst prepulse inhibition of acoustic startle, and the auditory brainstem level (electrophysiological recordings of auditory brainstem responses, ABR) and NR2B expression level in the auditory cortex to evaluate whether memantine could reduce salicylate-mediated behavioral disturbances. NR2B was significantly upregulated in salicylate-treated cells, but downregulated after memantine treatment. Similarly, expression of the inflammatory cytokine genes TNFα and immediate-early gene ARC was significantly increased in the salicylate-treated cells, and decreased when the cells were treated with memantine. These results were confirmed by NR2B immunocytochemistry. GPIAS was attenuated to a significantly lesser extent in rats treated with a combination of salicylate and memantine than in those treated with salicylate only. The mean ABR threshold in both groups was not significant different before and 1 day after the end of treatment. Additionally, NR2B protein expression in the auditory cortex was markedly increased in the salicylate-treated group, whereas it was reduced in the memantine-treated group. These results indicate that memantine is useful for the treatment of salicylate-induced tinnitus.

Spinal Nitric Oxide Synthase Type II Increases Neurosteroid-metabolizing Cytochrome P450c17 Expression in a Rodent Model of Neuropathic Pain

We have previously demonstrated that the neurosteroid dehydroepiandrosterone sulfate (DHEAS) induces functional potentiation of N-methyl-D-aspartate (NMDA) receptors via increases in phosphorylation of NMDA receptor GluN1 subunit (pGluN1). However, the modulatory mechanisms responsible for the expression of the DHEA-synthesizing enzyme, cytochrome P450c17 following peripheral nerve injury have yet to be examined. Here we determined whether oxidative stress induced by the spinal activation of nitric oxide synthase type II (NOS-II) modulates the expression of P450c17 and whether this process contributes to the development of neuropathic pain in rats. Chronic constriction injury (CCI) of the sciatic nerve induced a significant increase in the expression of NOS-II in microglial cells and NO levels in the lumbar spinal cord dorsal horn at postoperative day 5. Intrathecal administration of the NOS-II inhibitor, L-NIL during the induction phase of neuropathic pain (postoperative days 0~5) significantly reduced the CCI-induced development of mechanical allodynia and thermal hyperalgesia. Sciatic nerve injury increased the expression of PKC- and PKA-dependent pGluN1 as well as the mRNA and protein levels of P450c17 in the spinal cord at postoperative day 5, and these increases were suppressed by repeated administration of L-NIL. Co-administration of DHEAS together with L-NIL restored the development of neuropathic pain and pGluN1 that were originally inhibited by L-NIL administration alone. Collectively these results provide strong support for the hypothesis that activation of NOS-II increases the mRNA and protein levels of P450c17 in the spinal cord, ultimately leading to the development of central sensitization and neuropathic pain induced by peripheral nerve injury.

Calpain-2 as a Treatment Target in Prenatal Stress-induced Epileptic Spasms in Infant Rats

Stress can induce a serious epileptic encephalopathy that occurs during early infancy. Recent studies have revealed that prenatal stress exposure is a risk factor for the development of infantile spasms. Our previous work demonstrates that prenatal stress with betamethasone-induced alterations to the expression of the K⁺/Cl⁻ co-transporter (KCC2) in gamma-aminobutyric acid (GABA) interneurons lowers the seizure threshold in exposed animals. Here, we further investigated the mechanisms involved in this KCC2 dysfunction and explored possible treatment options. We stressed Sprague-Dawley rats prenatally and further treated dams with betamethasone on gestational day 15, which increases seizure susceptibility and NMDA (N-Methyl-D-aspartate)-triggered spasms on postnatal day 15. In this animal model, first, we evaluated baseline calpain activity. Second, we examined the cleavage and dephosphorylation of KCC2. Finally, we checked the effect of a calpain inhibitor on seizure occurrence. The phosphorylated-N-methyl-D-aspartate Receptor 2B (NR2B):non-phosphorylated NR2B ratio was found to be higher in the cortex of the prenatally stressed beta-methasone model. We further found that the betamethasone model exhibited increased phosphorylation of calpain-2 and decreased phosphorylation of KCC2 and Glutamic acid decarboxylase 67 (GAD67). After using a calpain inhibitor in prenatal-stress rats, the seizure frequency decreased, while latency increased. GABAergic depolarization was further normalized in prenatal-stress rats treated with the calpain inhibitor. Our study suggests that calpain-dependent cleavage and dephosphorylation of KCC2 decreased the seizure threshold of rats under prenatal stress. Calpain-2 functions might, thus, be targeted in the future for the development of treatments for epileptic spasms.

Memantine Improves Cognitive Function and Alters Hippocampal and Cortical Proteome in Triple Transgenic Mouse Model of Alzheimer's Disease

Memantine is a non-competitive N-methyl-D-aspartate receptor (NMDAR) antagonist clinically approved for moderate-to-severe Alzheimer's disease (AD) to improve cognitive functions. There is no report about the proteomic alterations induced by memantine in AD mouse model yet. In this study, we investigated the protein profiles in the hippocampus and the cerebral cortex of AD-related transgenic mouse model (3×Tg-AD) treated with memantine. Mice (8-month) were treated with memantine (5 mg/kg/bid) for 4 months followed by behavioral and molecular evaluation. Using step-down passive avoidance (SDA) test, novel object recognition (NOR) test and Morris water maze (MWM) test, it was observed that memantine significantly improved learning and memory retention in 3xTg-AD mice. By using quantitative proteomic analysis, 3301 and 3140 proteins in the hippocampus and the cerebral cortex respectively were identified to be associated with AD abnormalities. In the hippocampus, memantine significantly altered the expression levels of 233 proteins, among which PCNT, ATAXIN2, TNIK, and NOL3 were up-regulated, and FLNA, MARK 2 and BRAF were down-regulated. In the cerebral cortex, memantine significantly altered the expression levels of 342 proteins, among which PCNT, PMPCB, CRK, and MBP were up-regulated, and DNM2, BRAF, TAGLN 2 and FRY1 were down-regulated. Further analysis with bioinformatics showed that memantine modulated biological pathways associated with cytoskeleton and ErbB signaling in the hippocampus, and modulated biological pathways associated with axon guidance, ribosome, cytoskeleton, calcium and MAPK signaling in the cerebral cortex. Our data indicate that memantine induces higher levels of proteomic alterations in the cerebral cortex than in the hippocampus, suggesting memantine affects various brain regions in different manners. Our study provides a novel view on the complexity of protein responses induced by memantine in the brain of AD.

Effect of Ginkgo Biloba Extract on N-Methyl-D-Aspartic Acid Receptor Subunit 2B Expression in a Salicylate-Induced Ototoxicity Model

OBJECTIVES.: Sodium salicylate (SS) is well known for its ototoxic properties that induce functional and morphological changes in the cochlea and brain. Ginkgo biloba extract (GBE) has been widely used for treatment of various neurodegenerative diseases; however, its effects on salicylate-induced ototoxicity remain unclear. Herein, we examined the effects of EGb 761 (EGb), a standard form of GBE, on the plasticity of the N-methyl-D-aspartate receptor subunit 2B (GluN2B) in the inferior colliculus (IC) following SS administration. METHODS.: Seven-week-old Sprague Dawley rats (n=24) were randomly allocated to control, SS, EGb, and EGb+SS groups. The SS group received a single intraperitoneal SS injection (350 mg/kg), the EGb group received EGb orally for 5 consecutive days (40 mg/kg), and the EGb+SS group received EGb for 5 consecutive days, followed by an SS injection. The auditory brainstem responses (ABRs) were assessed at baseline and 2 hours after SS administration. GluN2B expression was examined by Western blot and immunohistochemistry. RESULTS.: There were no significant differences in ABR threshold shifts among the groups. The expression of the GluN2B protein normalized by which of glyceraldehyde 3-phosphate dehydrogenase (GAPDH) was significantly lower in the EGb+SS group, as compared to the SS group (P=0.012). Weak and diffused GluN2B immunoreactivity was detected in the IC neural cells of the EGb+SS group, while those of the SS group exhibited strong and diffused GluN2B positivity. CONCLUSION.: EGb may play a role in regulating the GluN2B expression in the IC of salicylate-induced ototoxicity model.

Two Cases of Opioid-Induced Hyperalgesia in Cancer Patients Treated with Opioids for Pain Management / 한국호스피스완화의료학회지

Opioids are important drugs for the management of severe cancer pain without a ceiling effect. However, opioid administration leads to dose-limiting complications including drowsiness, hallucinations, delirium, respiratory depression, cognitive impairment, seizure, myoclonus, and hyperalgesia. Opioid-induced hyperalgesia (OIH) is a paradoxical phenomenon as opioid exposure increases pain sensitivity. Reducing or stopping opioids, opioid rotation, or co-administration of N-methyl-D-aspartate (NMDA) antagonists have been suggested for the management of OIH. In this study, we report two clinical cases of successful management of OIH in cancer pain patients that were treated with opioids.

Dexmedetomidine and propofol sedation requirements in an autistic rat model / 대한마취과학회지

BACKGROUND: Autism is a challenging neurodevelopmental disorder. Previous clinical observations have suggested altered sedation requirements for children with autism. Our study aimed to test this observation experimentally in an animal model and to explore its possible mechanisms. METHODS: Eight adult pregnant female Sprague-Dawley rats were randomly divided into two groups. Four were injected with intraperitoneal sodium valproate on gestational day 12 and four were injected with normal saline. On postnatal day 28, the newborn male rats were subjected to the open-field test to confirm autistic features. Each rat was injected intraperitoneally with a single dose of propofol (50 mg/kg) or dexmedetomidine (0.2 mg/kg). The times to loss of righting reflex (LORR) and to return of righting reflex (RORR) were recorded. On the following day, all rats were re-sedated and underwent electroencephalography (EEG). Thereafter, the rats were euthanized and their hippocampal gamma-aminobutyric acid type A (GABA(A)) and glutamate N-methyl-D-aspartate (NMDA) receptor gene expressions were assessed. RESULTS: Autistic rats showed significantly longer LORR times and shorter RORR times than did the controls (median LORR times: 12.0 versus 5.0 min for dexmedetomidine and 22.0 versus 8.0 min for propofol; P < 0.05). EEG showed a low-frequency, high-amplitude wave pattern 2 min after LORR in the control rats. Autistic rats showed a high-frequency, low-amplitude awake pattern. Hippocampal GABA(A) receptor gene expression was significantly lower and NMDA gene expression was greater in autistic rats. CONCLUSIONS: This study supports the clinical observations of increased anesthetic sedative requirements in children with autism and our biochemical analyses using and glutamate receptor gene expression highlight possible underlying mechanisms.

Recapitulation of Neuropsychiatric Behavioral Features in Mice Using Acute Low-dose MK-801 Administration

Despite some innate limitations, animal models are a potent investigative tool when used to model specific symptoms of a disorder. For example, MK-801, an N-methyl-D-aspartate receptor antagonist, is used as a pharmacological tool to induce symptoms found in some neuropsychiatric disorders. However, a close examination of literature suggests that the application window of MK-801 doses is relatively narrow between individual behavioral paradigms, necessitating careful characterization of the evoked behavioral aberrations and the doses used to induce them. Moreover, variation in behaviors depending on the animal strain, gender of the subject, and the timing of administration is observed, making it difficult to compare the behavioral characteristics reported in different studies. We aim to characterize the behavioral aberrations induced by different doses of MK-801 in CD-1 mice and create a ready reference for future studies. We used CD-1 mice to recapitulate behavioral impairments resulting from acute administration of MK-801. In 0.1 mg kg⁻¹, we observed diminished spontaneous alteration during the Y-maze test, while 0.12 mg kg⁻¹ resulted in hyperlocomotion and social deficit. Mice treated with 0.2 and 0.3 mg kg⁻¹ of MK-801 demonstrated a decreased self-grooming. Finally, all doses significantly impaired cliff avoidance behaviors suggesting increased impulsivity. These results affirm that MK-801 can effectively model various symptoms of different neuropsychiatric disorders in a dose-dependent manner. The observed sensitivity against spatial-memory impairment and impulsive behaviors at low concentration of MK-801 suggest that MK801 may modulate cognitive function and impulsivity in even lower concentration before it can modulate other behavioral domains.

Association of Low Serum Ionized Magnesium Level with Fever-Triggered Seizures in Epileptic Children / 대한소아신경학회지

PURPOSE: Several studies have shown that magnesium plays an important role in modulating N-methyl-D-aspartate (NMDA)-related seizures by blocking NMDA ion channel receptors. Clinicians usually measure total serum magnesium levels instead of biologically active ionized magnesium levels. We compared the serum ionized magnesium (iMg2+) level between epileptic children with and without a history of fever-triggered seizure (FTS). METHODS: All epileptic children who visited the outpatient clinic or pediatric emergency department at Korea University Guro Hospital between January 2015 and July 2017 were included. Only epileptic children aged 1–8 years who were newly diagnosed within 2 years were included. RESULTS: There were 12 children with FTS and 16 without FTS. Median serum iMg2+ level was 0.93 (0.85–1.14, quartile) mEq/L. Serum iMg2+ level was significantly lower in epileptic children with FTS (0.86 mEq/L) compared to those without FTS (1.10 mEq/L) (P=0.005). No difference was noted in clinical variables between the two groups. Lower serum iMg2+ level significantly increased the risk of having FTS in epileptic children based on multivariable logistic regression analysis (odds ratio [OR]=0.028). CONCLUSION: Serum iMg2+ level was significantly lower in epileptic children with FTS than in those without FTS. Measurement of biologically active serum iMg2+ level could be considered in epileptic children with recurrent FTS. A large-scale prospective study is warranted.

The antidepressant action of 3-(2-carboxypiperazin-4-yl)propyl-1-phosphonic acid is mediated by phosphorylation of histone deacetylase 5

3-(2-Carboxypiperazin-4-yl)propyl-1-phosphonic acid (CPP), a competitive N-methyl-D-aspartate (NMDA) receptor antagonist, produces rapid antidepressant-like effects in animal models of depression. However, the molecular mechanisms underlying these behavioral actions remain unknown. Here, we demonstrate that CPP rapidly stimulates histone deacetylase (HDAC) 5 phosphorylation and nuclear export in rat hippocampal neurons. These effects are accompanied by calcium/calmodulin kinase II (CaMKII) and protein kinase D (PKD) phosphorylation. Behavioral experiments revealed that viral-mediated hippocampal knockdown of HDAC5 blocked the antidepressant effects of CPP in stressed animals. Taken together, our results imply that CPP acts via HDAC5 and suggest that HDAC5 is a common regulator contributing to the antidepressant actions of NMDA receptor antagonists such as CPP.

Striatal Inhibition of MeCP2 or TSC1 Produces Sociability Deficits and Repetitive Behaviors

Autism spectrum disorder (ASD) is a heterogeneous group of neurobehavioral disorders characterized by the two core domains of behavioral deficits, including sociability deficits and stereotyped repetitive behaviors. It is not clear whether the core symptoms of ASD are produced by dysfunction of the overall neural network of the brain or that of a limited brain region. Recent studies reported that excessive glutamatergic or dopaminergic inputs in the dorsal striatum induced sociability deficits and repetitive behaviors. These findings suggest that the dorsal striatum plays a crucial role in autistic-like behaviors. The present study addresses whether functional deficits of well-known ASD-related genes in the dorsal striatum also produce ASD core symptoms. This study also examines whether these behavioral changes can be modulated by rebalancing glutamate and/or dopamine receptor activity in the dorsal striatum. First, we found that the siRNA-mediated inhibition of Shank3, Nlgn3, Fmr1, Mecp2, or Tsc1 in the dorsal striatum produced mild to severe behavioral changes in sociability, cognition, and/or repetitive behaviors. The knockdown effects of Mecp2 and Tsc1 on behavioral changes were the most prominent. Next, we demonstrated that behavioral changes induced by striatal inhibition of MeCP2 and TSC1 were rescued by D-cycloserine (an NMDA agonist), fenobam (an mGluR5 antagonist), SCH23390 (a D1 antagonist), and/or ecopipam (a D1 partial antagonist), pharmacological drugs that are known to regulate ASD-like symptoms in animal models. Collectively, these results suggest that the dorsal striatum is a critical brain region that, when dysfunctional, produces the core symptoms of ASD.