RESUMEN
Compartment syndrome is a rare but devastating condition that can result in permanent neuromuscular or soft tissue injuries. Extravasation injuries, among the iatrogenic causes of compartment syndrome, occur under a wide variety of circumstances in the inpatient setting. Total parenteral nutrition via a peripheral route is an effective alternative for the management of critically ill children who do not obtain adequate nutrition via the oral route. However, there is an inherent risk of extravasation, which can cause compartment syndrome, especially when detected at a later stage. Herein, we report a rare case of compartment syndrome and skin necrosis due to extravasation, requiring emergency fasciotomy and skin graft in a 7-month-old boy who was treated with peripheral parenteral nutrition via a pressurized infusion pump. Although we cannot estimate the exact time at which extravasation occurred, the extent and degree of the wound suggest that the ischemic insult was prolonged, lasting for several hours. Pediatric clinicians and medical teams should carefully examine the site of insertion of the intravenous catheter, especially in patients receiving parenteral nutrition via a peripheral intravenous catheter with a pressurized infusion pump.
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The telecare medical information systems (TMISs) support convenient and rapid health-care services. A secure and efficient authentication scheme for TMIS provides safeguarding patients' electronic patient records (EPRs) and helps health care workers and medical personnel to rapidly making correct clinical decisions. Recently, Kumari et al. proposed a password based user authentication scheme using smart cards for TMIS, and claimed that the proposed scheme could resist various malicious attacks. However, we point out that their scheme is still vulnerable to lost smart card and cannot provide forward secrecy. Subsequently, Das and Goswami proposed a secure and efficient uniqueness-and-anonymity-preserving remote user authentication scheme for connected health care. They simulated their scheme for the formal security verification using the widely-accepted automated validation of Internet security protocols and applications (AVISPA) tool to ensure that their scheme is secure against passive and active attacks. However, we show that their scheme is still vulnerable to smart card loss attacks and cannot provide forward secrecy property. The proposed cryptanalysis discourages any use of the two schemes under investigation in practice and reveals some subtleties and challenges in designing this type of schemes.
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Seguridad Computacional/instrumentación , Confidencialidad , Registros Electrónicos de Salud/organización & administración , Telemedicina/organización & administración , Interfaz Usuario-Computador , Acceso a la Información , Humanos , Diseño de SoftwareRESUMEN
Sheldon-Hall syndrome (SHS) is a rare autosomal dominant, inherited arthrogryposis syndrome characterized by multiple congenital contractures of the distal limbs. To date, four genes that encode the skeletal muscle fiber complex have been confirmed as the causative genes. Mutations in MYH3 have been identified most frequently and few cases of SHS caused by TPM2 mutations have been reported worldwide. This report describes, for the first time, a Korean family with two generations of SHS resulting from a rare TPM2 mutation, p.R133W. The affected mother and daughter manifested typical facial features of SHS including a triangular face with downslanting palpebral fissures, small mouth, high arched palate, and prominent nasolabial folds, and showed camptodactyly of fingers and deformities of feet with congenital vertical tali. Generalized myopathy with relative sparing of the slow-twitch muscle fibers was also revealed by electromyography in the affected mother.
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Artrogriposis/genética , Pueblo Asiatico/genética , Tropomiosina/genética , Alelos , Exones , Femenino , Falanges de los Dedos de la Mano/diagnóstico por imagen , Huesos del Pie/diagnóstico por imagen , Humanos , Recién Nacido , Mutación , Linaje , Fenotipo , Radiografía , República de Corea , Análisis de Secuencia de ADNRESUMEN
Dextromethorphan (DM) is a well-known antitussive dextrorotatory morphinan. We and others have demonstrated that sigma (σ) receptors may be important for DM-mediated neuromodulation. Because an earlier report suggested that DM might affect sexual function and that σ receptor ligands affect signaling pathways in the periphery, we examined whether DM-induced psychotoxic burden affected male reproductive function. We observed that DM had a high affinity at σ-1 receptors in the brain and testis but relatively low affinity at σ-2 receptors. Prolonged treatment with DM resulted in conditioned place preference and hyperlocomotion, followed by an increase in Fos-related antigen expression in the nucleus accumbens in male mice. Simultaneously, DM induced significant reductions in gonadotropin-releasing-hormone immunoreactivity in the hypothalamus. Moreover, we observed that DM induced increased sperm abnormalities and decreased sperm viability and sexual behavior. These phenomena were significantly attenuated by combined treatment with BD1047, a σ-1 receptor antagonist, but not by SM-21, a σ-2 receptor antagonist. Thus, these results suggest that DM psychotoxicity might lead to reproductive stress in male mice by activating σ-1 receptors.
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Dextrometorfano/efectos adversos , Receptores sigma/agonistas , Conducta Sexual Animal/efectos de los fármacos , Animales , Inmunohistoquímica , Locomoción , Masculino , Ratones , Ratones Endogámicos ICR , Ensayo de Unión Radioligante , Motilidad Espermática/efectos de los fármacos , Receptor Sigma-1RESUMEN
Previously, we demonstrated acupuncture at acupoint HT7 (Shen-Men) attenuated ethanol withdrawal syndrome by normalizing the dopamine release in nucleus accumbens shell. In the present study, we investigated the effect of acupuncture on anxiety-like behavior in rats and its relevant mechanism by studying neuro-endocrine parameters during ethanol withdrawal. Rats were treated with 3 g kg(-1)day(-1) of ethanol (20%, w/v) or saline by intraperitoneal injections for 28 days. The rats undergoing ethanol withdrawal exhibited anxiety-like behavior 72 h after the last dose of ethanol characterized by the decrease of time spent in the open arms of the elevated plus maze compared with the saline-treated rats (P < .05). Radioimmunoassay exhibited there were notably increased concentrations of plasma corticosterone in ethanol-withdrawn rats compared with saline-treated rats (P < .05). Additionally, high performance liquid chromatography analysis also showed the levels of norepinephrine and 3-methoxy-4-hydroxy-phenylglycol were markedly increased while the levels of dopamine and 3,4-dihydroxyphenylacetic acid were significantly decreased in the central nucleus of the amygdala of ethanol-withdrawn rats compared with saline-treated rats (P < .01). Acupuncture groups were treated with acupuncture at acupoint HT7 or PC6 (Nei-Guan). Acupuncture at HT7 but not PC6 greatly attenuated the anxiety-like behavior during ethanol withdrawal as evidenced by significant increases in the percentage of time spent in open arms (P < .05). In the meantime, acupuncture at HT7 also markedly inhibited the alterations of neuro-endocrine parameters induced by ethanol withdrawal (P < .05). These results suggest that acupuncture may attenuate anxiety-like behavior during ethanol withdrawal through regulation of neuro-endocrine system.
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This study was designed to investigate the mechanisms that are associated with manganese (Mn) toxicity. In addition, the association between Mn toxicity and 3, 4, 5 amino salicylic acid (ASA), anti-oxidants, including N-acetyl cysteine (NAC), was examined by dopaminergic cell line, SK-M-NC. Our studies showed that Mn influenced the mitochondria dysfunction and endoplasmic reticulum stress (ER stress). It reduced the mitochondria complex I activity but did not affect the complex II, III, or IV activities. The presence of 3, 4, 5 ASA protected against Mn-induced-apoptosis, as did NAC. However, the salicylate analogues and the antioxidants did not mediate ER stress in this model. The salicylate analogues reduced reactive oxygen species (ROS) and reversed the deficient mitochondrial membrane potential that was induced by Mn. Taken together, the 3, 4, 5 ASA worked in a similar way, regulating the Mn-induced mitochondrial dysfunction and protecting cells.
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Ácidos Aminosalicílicos/farmacología , Flavoproteínas Transportadoras de Electrones/metabolismo , Estrés del Retículo Endoplásmico/efectos de los fármacos , Manganeso/toxicidad , Neuronas/efectos de los fármacos , Acetilcisteína/farmacología , Antioxidantes/farmacología , Muerte Celular/efectos de los fármacos , Línea Celular Tumoral , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Mitocondrias/efectos de los fármacosRESUMEN
Acupuncture has been used to treat drug addiction by nicotine, alcohol, cocaine and morphine. This study was designed to investigate the effect of bee venom (BV) acupuncture on hyperactivity and hyperthermia induced by acute exposure to methamphetamine (METH, 1mg/kg, s.c.) in mice. Diluted BV (20µl of 0.01, 0.1, 1 and 10mg/ml in saline, s.c.) was administered bilaterally into the Zusanli acupoint (ST36) or control points (SP9 or GB39 or tail base). BV injection into ST36 dose dependently reduced METH-induced hyperactivity and hyperthermia, while BV injection (1mg/ml) into control points did not produce these suppressive effects. METH injection significantly increased Fos expression in several brain regions including nucleus accumbens (NA), caudate putamen (CPU), ventral tegmental area (VTA), substantia nigra (SN) and locus coeruleus (LC). Interestingly, BV (1mg/ml) injection into ST36 further increased METH-induced Fos expression in NA (core and shell), SN and LC. When we performed sciatic denervation or combination treatment of BV and lidocaine (BV diluted in 5% lidocaine solution), the enhancement of Fos elevation by BV was completely blocked in the NA, SN and LC in METH-injected mice, indicating that BV-induced peripheral nerve stimulation played an important role in the BV effect. Furthermore, the effects of BV were completely blocked by the α2-adrenoceptor antagonist, idazoxan (3mg/kg, i.p.), but not by ß-adrenoceptor antagonist, propranolol (10mg/kg, i.p.). Taken together, these findings suggest that BV acupuncture into ST36 may modulate METH-induced hyperactivity, hyperthermia and Fos expression through activation of the peripheral nerve and the central α2-adrenergic activation.
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Terapia por Acupuntura/métodos , Venenos de Abeja , Estimulantes del Sistema Nervioso Central/efectos adversos , Fiebre , Metanfetamina/efectos adversos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Agitación Psicomotora/tratamiento farmacológico , Antagonistas de Receptores Adrenérgicos alfa 2/farmacología , Anestésicos Locales/farmacología , Animales , Venenos de Abeja/administración & dosificación , Venenos de Abeja/uso terapéutico , Encéfalo/anatomía & histología , Encéfalo/metabolismo , Fiebre/inducido químicamente , Fiebre/tratamiento farmacológico , Humanos , Idazoxan/farmacología , Lidocaína/farmacología , Masculino , Ratones , Neuronas Aferentes/efectos de los fármacos , Neuronas Aferentes/metabolismo , Proteínas Proto-Oncogénicas c-fos/genética , Trastornos Relacionados con Sustancias/terapiaRESUMEN
OBJECTIVES: Manganese chloride (MnCl(2)) is one of heavy metals for causing neurogenerative dysfunction like Manganism. The purpose of this study was to determine the acute toxicity of MnCl(2) using different times and various concentrations including whether manganese toxicity may involve in two intrinsic pathways, endoplasmic reticulum (ER) stress and mitochondria dysfunction and lead to neuronal apoptosis mediated by organelle disorders in neuroblastoma cell line SK-N-MC. METHODS: In the acute toxicity test, five concentrations (200, 400, 600, 800, 1,000 uM) of MnCl(2) with 3, 6, 12, 24, 48 hours exposure were selected to analyze cell viability. In addition, to better understand their toxicity, acute toxicity was examined with 1,000 uM MnCl(2) for 24 hours exposure via reactive oxygen species (ROS), mitochondria membrane potential, western blotting and mitochondrial complex activities. RESULTS: Our results showed that both increments of dose and time prompt the increments in the number of dead cells. Cells treated by 1,000 µM MnCl(2) activated 265% (±8.1) caspase-3 compared to control cell. MnCl(2) induced intracellular ROS produced 168% (±2.3%) compared to that of the control cells and MnCl(2) induced neurotoxicity significantly dissipated 48.9% of mitochondria membrane potential compared to the control cells. CONCLUSIONS: This study indicated that MnCl(2) induced apoptosis via ER stress and mitochondria dysfunction. In addition, MnCl(2) affected only complex I except complex II, III or IV activities.
RESUMEN
BACKGROUND AND AIMS: Several studies have provided convincing evidence that psychosocial factors, chronic stress and emotional factors are all independent predictors of atherosclerosis and cardiovascular events as well. However, psychosocial factors have received little attention in the medical setting. The purpose of this study is to evaluate the influence of stress on photothrombotic ischemic cortical injury in an animal model. METHODS: Sprague-Dawley rats were assigned to the four groups and cortical photothrombosis was induced in the sensorimotor cortex. The stress groups were subjected to restraint stress for five days. We evaluate the behavioral function, infarct volume, apoptotic cell death and the activations of mitogen-activated protein kinases (MAPK: Erk1/Erk2, and p38MAPK) for the evaluation of stress effects on stroke. RESULTS: There was a significant increase in cortical infarct volume and apoptotic cell death at the stroke group subjected to restraint stress (p<0.05, and p<0.01, respectively). The functional recovery was worst in restraint stress group during five days (p<0.05). The activation of Erk1 and Erk2 were increased by restraint stress in sham operation group but decreased in stroke-stress group than stroke control group (p<0.01). The activation of p38MAPK was increased by stroke but this effect was decreased by restraint stress (p<0.05, and p<0.01, respectively). Our data demonstrates that restraint stress increases infarction volume and decreases functional recovery in rat stroke models by modulation of the MAPK pathway.
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Trombosis Intracraneal/metabolismo , Sistema de Señalización de MAP Quinasas/fisiología , Recuperación de la Función/fisiología , Estrés Psicológico/metabolismo , Accidente Cerebrovascular/metabolismo , Animales , Apoptosis/fisiología , Infarto Cerebral/metabolismo , Infarto Cerebral/patología , Modelos Animales de Enfermedad , Trombosis Intracraneal/patología , Masculino , Proteína Quinasa 1 Activada por Mitógenos/metabolismo , Proteína Quinasa 3 Activada por Mitógenos/metabolismo , Actividad Motora/fisiología , Ratas , Ratas Sprague-Dawley , Restricción Física , Estrés Psicológico/patología , Accidente Cerebrovascular/patología , Proteínas Quinasas p38 Activadas por Mitógenos/metabolismoRESUMEN
As adolescence is a critical period when dopaminergic neuronal maturation peaks, we hypothesized that 6-hydroxydopamine (OHDA) lesions of the medial prefrontal cortex (mPFC) in adolescent rats would have more negative effects than lesions in adult rats. Therefore, we investigated the effects of 6-OHDA lesions of the mPFC in adolescent and adult rats on stress-induced c-fos expression in the brain. Adolescent and adult Sprague-Dawley rats, aged 4 and 7 weeks on arrival, respectively, were studied. 6-OHDA (8.0 microg) for the lesion groups and ascorbic acid for the sham groups were injected bilaterally into the mPFC. All animals were pretreated with desipramine 30 min before being anesthetized. The control group did not undergo any surgery-related procedure except the desipramine injection. After recovery for 1 week, the rats were subjected to restraint stress for 1 h. Immediately after the stress, the rats were killed and c-fos immunohistochemistry was examined. The c-fos expression in the nucleus accumbens core (AcbC), nucleus accumbens shell (AcbSh), CA1, CA3, dentate gyrus (DG), central amygdaloid (Ce), basolateral amygdaloid (BL), and temporal cortex (Tc) was compared. Adolescent rats with 6-OHDA lesions subjected to restraint stress had greater c-fos expression in the AcbC, AcbSh, DG, Ce, BL, and Tc, compared to the sham and control groups, whereas these differences were not observed among the adult groups. These results suggest that a hypodopaminergic state in the mPFC of adolescent rats, but not adult rats, is related to increased sensitivity to stress, suggesting that damage to or maldevelopment of dopaminergic neurons during adolescence has an age-specific effect. Further research is warranted to investigate the mechanism of the age-specific effect of 6-OHDA lesions of the mPFC.
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Amígdala del Cerebelo/metabolismo , Hipocampo/metabolismo , Núcleo Accumbens/metabolismo , Oxidopamina/farmacología , Corteza Prefrontal/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Estrés Fisiológico , Ácido 3,4-Dihidroxifenilacético/metabolismo , Factores de Edad , Amígdala del Cerebelo/efectos de los fármacos , Análisis de Varianza , Animales , Cromatografía Líquida de Alta Presión , Dopamina/metabolismo , Hipocampo/efectos de los fármacos , Inmunohistoquímica , Masculino , Neuronas/efectos de los fármacos , Neuronas/metabolismo , Norepinefrina/metabolismo , Núcleo Accumbens/efectos de los fármacos , Corteza Prefrontal/metabolismo , Ratas , Ratas Sprague-Dawley , Restricción FísicaRESUMEN
OBJECTIVES: Although acupuncture is most commonly used for its analgesic effect, it has also been used to treat various drug addictions including cocaine and morphine in humans. This study was designed to investigate the effect of bee venom injection on methamphetamine-induced addictive behaviors including conditioned place preference and hyperlocomotion in mice. METHODS: Methamphetamine (1 mg/kg) was subcutaneously treated on days 1, 3 and 5 and the acquisition of addictive behaviors was assessed on day 7. After confirming extinction of addictive behaviors on day 17, addictive behaviors reinstated by priming dose of methamphetamine (0.1 mg/kg) was evaluated on day 18. Bee venom (20 microl of 1 mg/ml in saline) was injected to the acupuncture point ST36 on days 1, 3 and 5. RESULTS: Repeated bee venom injections completely blocked development of methamphetamine-induced acquisition and subsequent reinstatement. Single bee venom acupuncture 30 minutes before acquisition and reinstatement test completely inhibited methamphetamine-induced acquisition and reinstatement. Repeated bee venom acupunctures from day 8 to day 12 after methamphetamine-induced acquisition partially but significantly suppressed reinstatement. DISCUSSION: These findings suggest that bee venom acupuncture has a preventive and therapeutic effect on methamphetamine-induced addiction.
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Venenos de Abeja/farmacología , Fármacos del Sistema Nervioso Central/farmacología , Estimulantes del Sistema Nervioso Central/farmacología , Condicionamiento Clásico/efectos de los fármacos , Metanfetamina/farmacología , Percepción Espacial/efectos de los fármacos , Animales , Venenos de Abeja/administración & dosificación , Conducta Adictiva/tratamiento farmacológico , Fármacos del Sistema Nervioso Central/administración & dosificación , Estimulantes del Sistema Nervioso Central/administración & dosificación , Masculino , Metanfetamina/administración & dosificación , Ratones , Ratones Endogámicos ICR , Factores de TiempoRESUMEN
OBJECTIVE: Clozapine causes few extrapyramidal symptoms and is recommended as a treatment drug for severe tardive dyskinesia (TD). However, several case reports have suggested that clozapine could also cause TD. We investigated whether clozapine used as a first-line antipsychotic drug can cause TD. METHOD: We identified 101 patients at Yanbian Socio-Mental Hospital and Yanbian Brain Hospital in China who had received clozapine as a primary antipsychotic drug since their first episode of illness and evaluated the prevalence rate, type, and severity of TD using the Extrapyramidal Symptoms Rating Scale (ESRS). The criterion for TD was a score of > or = 3 on one item or 2 on two or more items of the ESRS. RESULTS: The mean age and duration of illness of the patients were 38.93+/-8.36 and 12.88+/-6.90 years, respectively. The mean duration of clozapine treatment was 12.10+/-6.26 years. The prevalence of TD was 3.96% (4/101). Compared to patients without TD, patients with TD had a long duration of illness and clozapine treatment; all had the orolingual type of TD. TD was relatively mild, with a mean score of 4.75, and tended to accentuate with an activation procedure of rapid pronation and supination of the hands. CONCLUSIONS: These results suggest that clozapine may cause TD; however, the prevalence is low and the severity is relatively mild, with no or mild self-reported discomfort. Therefore, we recommend that regular examination for TD using the activation procedure should be performed in patients who use clozapine on a long-term basis.
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Antipsicóticos/efectos adversos , Clozapina/efectos adversos , Discinesia Inducida por Medicamentos/etiología , Esquizofrenia/tratamiento farmacológico , Adulto , Antipsicóticos/uso terapéutico , Enfermedades de los Ganglios Basales/inducido químicamente , Enfermedades de los Ganglios Basales/diagnóstico , Enfermedades de los Ganglios Basales/epidemiología , China/epidemiología , Clozapina/uso terapéutico , Esquema de Medicación , Discinesia Inducida por Medicamentos/diagnóstico , Discinesia Inducida por Medicamentos/epidemiología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Prevalencia , Especies Reactivas de Oxígeno/metabolismo , Índice de Severidad de la Enfermedad , Encuestas y CuestionariosRESUMEN
OBJECTIVES: This study tested whether sodium para-amino salicylic dihydrate, an antibacterial drug for tuberculosis, could block manganese-induced apoptosis in SK-N-MC neurons. METHODS: Cell viability, Hoechst staining, dichlorofluorescin diacetate analysis for reactive oxygen species measurement, and immunoblotting were performed. KEY FINDINGS: In vitro, manganese chloride significantly decreased the viability of SK-N-MC cells, accompanied by apoptotic features such as changes in nuclear morphology. Sodium para-amino salicylic dihydrate inhibited these apoptotic characteristics through reducing intracellular reactive oxygen species generation, protecting mitochondrial membrane potential and caspase-3 activation. CONCLUSIONS: Sodium para-amino salicylic dihydrate inhibits manganese-induced apoptosis in neurons and may reduce manganese-mediated neurodegeneration.
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Antioxidantes/farmacología , Apoptosis/efectos de los fármacos , Manganeso/efectos adversos , Neuronas/efectos de los fármacos , Especies Reactivas de Oxígeno/metabolismo , Salicilato de Sodio/farmacología , Caspasa 3/metabolismo , Línea Celular , Supervivencia Celular/efectos de los fármacos , Humanos , Potencial de la Membrana Mitocondrial/efectos de los fármacos , Neuronas/metabolismoRESUMEN
Intracranial headaches, including migraines, are mediated by nociceptive activation of the trigeminal nucleus caudalis (TNC), but the precise mechanisms are poorly understood. We previously demonstrated that selective blockage of spinal sigma-1 receptors (Sig-1R) produces a prominent antinociceptive effect in several types of pain models. This study evaluates whether the Sig-1R antagonist (BD1047) has an antinociceptive effect on capsaicin (a potent C-fiber activator) induced headache models in rats. Intracisternal infusion of capsaicin evoked pain behavior (face grooming), which was significantly attenuated by BD1047 pretreatment. BD1047 consistently reduced capsaicin-induced Fos-like immunoreactivity (Fos-LI), a neuronal activator, in the TNC in a dose-dependent manner. Moreover, capsaicin-induced phosphorylation of N-methyl-D-aspartate receptor subunit 1 was reversed by BD1047 pretreatment in the TNC. These results indicate that the Sig-1R antagonist has an inhibitory effect on nociceptive activation of the TNC in the capsaicin-induced headache animal model.
RESUMEN
BACKGROUND: Selective blockade of spinal sigma(1) receptors (Sig-1R) suppresses nociceptive behaviors in the mouse formalin test. The current study was designed to verify whether intrathecal Sig-1R antagonists can also suppress chronic neuropathic pain. METHODS: Neuropathic pain was produced by chronic constriction injury (CCI) of the right sciatic nerve in rats. The Sig-1R antagonist BD1047 was administered intrathecally twice daily from postoperative days 0 to 5 (induction phase of neuropathic pain) or from days 15 to 20 (maintenance phase). Western blot and immunohistochemistry were performed to determine changes in Sig-1R expression and to examine the effect of BD1047 on N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation in spinal cord dorsal horn from neuropathic rats. RESULTS: BD1047 administered on postoperative days 0-5 significantly attenuated CCI-induced mechanical allodynia, but not thermal hyperalgesia, and this suppression was blocked by intrathecal administration of the Sig-1R agonist PRE084. In contrast, BD1047 treatment during the maintenance phase of neuropathic pain had no effect on mechanical allodynia. Sig-1R expression significantly increased in the ipsilateral spinal cord dorsal horn from days 1 to 3 after CCI. Importantly, BD1047 (30 nmol) administered intrathecally during the induction, but not the maintenance phase, blocked the CCI-induced increase in N-methyl-D-aspartate receptor subunit 1 expression and phosphorylation. CONCLUSIONS: These results demonstrate that spinal Sig-1Rs play a critical role in both the induction of mechanical allodynia and the activation of spinal N-methyl-d-aspartate receptors in CCI rats and suggest a potential therapeutic role for the use of Sig-1R antagonists in the clinical management of neuropathic pain.
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Etilenodiaminas/administración & dosificación , Neuralgia/metabolismo , Neuralgia/prevención & control , Receptores de N-Metil-D-Aspartato/biosíntesis , Receptores sigma/biosíntesis , Médula Espinal/metabolismo , Animales , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/fisiología , Inyecciones Espinales , Masculino , Estimulación Física/métodos , Ratas , Ratas Sprague-Dawley , Receptores de N-Metil-D-Aspartato/antagonistas & inhibidores , Receptores sigma/antagonistas & inhibidores , Médula Espinal/efectos de los fármacosRESUMEN
Sigma sites, originally proposed as opioid receptor subtypes, are currently thought to represent unique receptors with a specific pattern of drug selectivity, a well-established anatomical distribution and broad range of functional roles including potential involvement in nociceptive mechanisms. We have recently demonstrated that intrathecal (i.t.) treatment with a sigma-1 receptor antagonist reduced formalin-induced pain behavior. In the present study, we investigated the potential role of spinal sigma-1 receptor agonists in peripherally initiated nociception and attempted to elucidate intracellular signaling mechanisms associated with spinal cord sigma-1 receptor activation in mice. The i.t. injection of the sigma-1 receptor agonists PRE-084 (PRE) or carbetapentane (CAR) significantly decreased tail-flick latency (TFL) and increased the frequency of paw withdrawal responses to mechanical stimulation (von Frey filament, 0.6 g) as well as the amount of Fos expression in the spinal cord dorsal horn induced by noxious paw-pinch stimulation. These PRE- or CAR-induced facilitatory effects on nociception were significantly blocked by i.t. pretreatment with the sigma-1 receptor antagonist, BD-1047, the phospholipase C (PLC) inhibitor, U-73,122, the Ca(2+)-ATPase inhibitor, thapsigargin, and the protein kinase C (PKC) inhibitor, chelerythrine. Western blot analysis further revealed that i.t. PRE or CAR injection significantly increased pan-PKC as well as the PKCalpha, epsilon, and zeta isoforms in the dorsal horn. Collectively, these findings demonstrate that calcium-dependent second messenger cascades including PKC are involved in the facilitation of nociception associated with spinal sigma-1 receptor activation.
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Morfolinas/farmacología , Nociceptores/efectos de los fármacos , Dolor/inducido químicamente , Proteína Quinasa C/efectos de los fármacos , Receptores sigma/agonistas , Médula Espinal/efectos de los fármacos , Animales , Antitusígenos/farmacología , Señalización del Calcio/efectos de los fármacos , Señalización del Calcio/fisiología , Ciclopentanos/farmacología , Modelos Animales de Enfermedad , Inhibidores Enzimáticos/farmacología , Etilenodiaminas/farmacología , Mediadores de Inflamación/metabolismo , Mediadores de Inflamación/farmacología , Inyecciones Espinales , Masculino , Ratones , Ratones Endogámicos ICR , Nociceptores/metabolismo , Dolor/metabolismo , Dolor/fisiopatología , Dimensión del Dolor/efectos de los fármacos , Umbral del Dolor/efectos de los fármacos , Umbral del Dolor/fisiología , Células del Asta Posterior/efectos de los fármacos , Células del Asta Posterior/metabolismo , Proteína Quinasa C/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Receptores sigma/antagonistas & inhibidores , Receptores sigma/metabolismo , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiología , Médula Espinal/metabolismo , Médula Espinal/fisiopatología , Receptor Sigma-1RESUMEN
Methamphetamine, a commonly used addictive drug, is a powerful addictive stimulant that dramatically affects the CNS. Repeated METH administration leads to a rewarding effect in a state of addiction that includes sensitization, dependence, and other phenomena. It is well known that susceptibility to the development of addiction is influenced by sources of reinforcement, variable neuroadaptive mechanisms, and neurochemical changes that together lead to altered homeostasis of the brain reward system. These behavioral abnormalities reflect neuroadaptive changes in signal transduction function and cellular gene expression produced by repeated drug exposure. To provide a better understanding of addiction and the mechanism of the rewarding effect, it is important to identify related genes. In the present study, we performed gene expression profiling using microarray analysis in a reward effect animal model. We also investigated gene expression in four important regions of the brain, the nucleus accumbens, striatum, hippocampus, and cingulated cortex, and analyzed the data by two clustering methods. Genes related to signaling pathways including G-protein-coupled receptor-related pathways predominated among the identified genes. The genes identified in our study may contribute to the development of a gene modeling network for methamphetamine addiction.
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Trastornos Relacionados con Anfetaminas/fisiopatología , Condicionamiento Operante/fisiología , Dopamina/fisiología , Perfilación de la Expresión Génica , Sistema Límbico/fisiología , Metanfetamina/farmacología , Recompensa , Animales , Cuerpo Estriado/fisiología , Giro del Cíngulo/fisiología , Hipocampo/fisiología , Núcleo Accumbens/fisiología , Análisis de Secuencia por Matrices de Oligonucleótidos , Ratas , Ratas Sprague-Dawley , Área Tegmental Ventral/fisiologíaRESUMEN
ABSTRACT Methamphetamine (MAP) is a commonly used, addictive drug, and a powerful stimulant that dramatically affects the central nervous system. In this study, we used the conditioned place preference (CPP) paradigm in order to study the reinforcing properties of MAP and the herewith associated changes in proteins within the mesolimbic dopamine system. A CPP was induced by MAP after three intermittent intraperitoneal injections (1 mg/kg) in rats and protein profiles in the nucleus accumbens, striatum, prefrontal cortex, cingulate cortex and hippocampus were compared with a saline-treated control group. In addition, a group of animals was run through extinction and protein profiles were compared with a non-extinguished group. Protein screening was conducted using two-dimensional electrophoresis analysis which identified 27 proteins in the group that showed MAP-induced CPP. Some of the proteins were confirmed by Western lot analysis. Identified proteins had functions related to the cytoskeleton, transport/endocytosis or exocytosis (e.g. profilin-2 and syntaxin-binding protein), and signal transduction, among others.
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Estimulantes del Sistema Nervioso Central/farmacología , Dopamina/metabolismo , Sistema Límbico/efectos de los fármacos , Metanfetamina/farmacología , Proteómica/métodos , Refuerzo en Psicología , Animales , Estimulantes del Sistema Nervioso Central/administración & dosificación , Electroforesis en Gel Bidimensional , Masculino , Metanfetamina/administración & dosificación , Plasticidad Neuronal/efectos de los fármacos , Ratas , Ratas Sprague-DawleyRESUMEN
Methamphetamine is an illicit drug that is often abused and can cause neuropsychiatric and neurotoxic damage. Repeated administration of psychostimulants such as methamphetamine induces a behavioral sensitization. According to a previous study, Bax was involved in neurotoxicity by methamphetamine, but the function of Bax in rewarding effect has not yet been elucidated. Therefore, we have studied the function of Bax in a rewarding effect model. In the present study, we treated chronic methamphetamine exposure in a Bax-deficient mouse model and examined behavioral change using a conditioned place preference (CPP) test. The CPP score in Bax knockout mice was decreased compared to that of wild-type mice. Therefore, we screened for Bax-related genes that are involved in rewarding effect using microarray technology. In order to confirm microarray data, we applied the RT-PCR method to observe relative changes of Bcl2, a pro-apoptotic family gene. As a result, using our experiment microarray, we selected genes that were associated with Bax in microarray data, and eventually selected the Tgfbr2 gene. Expression of the Tgfbr2 gene was decreased by methamphetamine in Bax knockout mice, and the gene was overexpressed in Bax wild-type mice. Additionally, we confirmed that Creb, FosB, and c-Fos were related to rewarding effect and Bax using immunohistochemistry.
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Perfilación de la Expresión Génica , Metanfetamina/farmacología , Recompensa , Proteína X Asociada a bcl-2/deficiencia , Animales , Regulación hacia Abajo/efectos de los fármacos , Femenino , Masculino , Ratones , Análisis por Micromatrices , Ratas , Receptores de Factores de Crecimiento Transformadores beta/genética , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Regulación hacia Arriba/efectos de los fármacos , Proteína X Asociada a bcl-2/genética , Proteína X Asociada a bcl-2/metabolismoRESUMEN
The Fas pathway and oxidative stress mediate neuronal death in stroke and may contribute to neurodegenerative disease. We tested the hypothesis that these two factors synergistically produce spinal motor neuron degeneration in amyotrophic lateral sclerosis (ALS). Levels of reactive oxygen species were increased in motor neurons from ALS mice compared with wild-type mice at age 10 weeks, before symptom onset. The proapoptotic proteins Fas, Fas-associated death domain, caspase 8, and caspase 3 were also elevated. Oral administration of 2-hydroxy-5-(2,3,5,6-tetrafluoro-4-trifluoromethyl-benzylamino)-benzoic acid (Neu2000), a potent antioxidant, blocked the increase in reactive oxygen species but only slightly reduced activation of proapoptotic proteins. Administration of lithium carbonate (Li(+)), a mood stabilizer that prevents apoptosis, blocked the apoptosis machinery without preventing oxidative stress. Neu2000 or Li(+) alone significantly enhanced survival time and motor function and together had an additive effect. These findings provide evidence that jointly targeting oxidative stress and Fas-mediated apoptosis can prevent neuronal loss and motor dysfunction in ALS.