RESUMEN
BACKGROUND: The neurobiological mechanisms underlying how general anesthetics render a patient's unconsciousness (hypnosis) remains elusive. The role of the cerebellum in hypnosis induced by general anesthetics is unknown. Gabra6100Q allele Sprague-Dawley (SD) rats have a naturally occurring single nucleotide polymorphism in the GABAA receptor α6 subunit gene that is expressed exclusively in cerebellum granule cells. METHODS: We examined the loss of righting reflex (LORR) induced by isoflurane, and ethanol in Gabra6100Q rats compared with those in wild type (WT) SD rats. We also examined the change of c-Fos expression induced by isoflurane exposure in cerebellum granule cells of both mutant and WT rats. RESULTS: Gabra6100Q rats are more sensitive than WT rats to the LORR induced by isoflurane and ethanol. Moreover, isoflurane exposure induced a greater reduction in c-Fos expression in cerebellum granule cells of Gabra6100Q rats than WT rats. CONCLUSIONS: Based on these data, we speculate that cerebellum may be involved in the hypnosis induced by some general anesthetics and thus may represent a novel target of general anesthetics.
Asunto(s)
Cerebelo/efectos de los fármacos , Etanol/farmacología , Isoflurano/farmacología , Receptores de GABA-A/genética , Inconsciencia/genética , Alelos , Anestésicos por Inhalación/farmacología , Animales , Depresores del Sistema Nervioso Central/farmacología , Masculino , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos , Inconsciencia/inducido químicamenteRESUMEN
BACKGROUND: Clinical and experimental studies support the therapeutic potential of Withania somnifera (WS) (L.) Dunal on anxiety disorders. This potential is attributable to components present in different plant extracts; however, the individual compound(s) endowed with specific anxiolytic effects and potential modulatory activity of the GABAA receptor complex (GABAAR) have remained unidentified until the recent isolation from a WS methanolic root extract of some GABAAR-active compounds, including the long alkyl-chain ferulic acid ester, docosanyl ferulate (DF). AIMS: This study was designed to assess whether DF (0.05, 0.25 and 2 mg/kg), similarly to diazepam (2 mg/kg), may exert anxiolytic effects, whether these effects may be significantly blocked by the benzodiazepine antagonist flumazenil (10 mg/kg) and whether DF may lack some of the benzodiazepines' typical motor, cognitive and motivational side effects. METHODS: The behavioural paradigms Elevated Plus Maze, Static Rods, Novel Object Recognition, Place Conditioning and potentiation of ethanol-induced Loss of Righting Reflex were applied on male CD-1 mice. RESULTS: Similarly to diazepam, DF exerts anxiolytic effects that are blocked by flumazenil. Moreover, at the full anxiolytic dose of 2 mg/kg, DF lacks typical benzodiazepine-like side effects on motor and cognitive performances and on place conditioning. Moreover, DF fails to potentiate ethanol's (3 g/kg) depressant activity at the ethanol-induced Loss of Righting Reflex paradigm. CONCLUSIONS: These data point to DF as an effective benzodiazepine-like anxiolytic compound that, in light of its lack of motor, mnemonic and motivational side effects, could be a suitable candidate for the treatment of anxiety disorders.
Asunto(s)
Ansiolíticos , Extractos Vegetales , Withania , Animales , Masculino , Ratones , Ansiolíticos/administración & dosificación , Ansiolíticos/farmacología , Conducta Animal/efectos de los fármacos , Diazepam/farmacología , Relación Dosis-Respuesta a Droga , Etanol/farmacología , Flumazenil/farmacología , Aprendizaje por Laberinto/efectos de los fármacos , Extractos Vegetales/administración & dosificación , Extractos Vegetales/farmacología , Reflejo de Enderezamiento/efectos de los fármacos , Withania/químicaRESUMEN
Background: Monochromatic blue light (MBL), with a wavelength between 400-490 nm, can regulate non-image-forming (NIF) functions of light in the central nervous system. The suprachiasmatic nucleus (SCN) in the brain is involved in the arousal-promoting response to blue light in mice. Animal and human studies showed that the responsiveness of the brain to visual stimuli is partly preserved under general anesthesia. Therefore, this study aimed to investigate whether MBL promotes arousal from sevoflurane anesthesia via activation of the SCN in mice. Methods: The induction and emergence time of sevoflurane anesthesia under MBL (460 nm and 800 lux) exposure was measured. Cortical electroencephalograms (EEGs) were recorded and the burst-suppression ratio (BSR) was calculated under MBL during sevoflurane anesthesia. The EEGs and local field potential (LFP) recordings with or without locally electrolytic ablated bilateral SCN were used to further explore the role of SCN in the arousal-promoting effect of MBL under sevoflurane anesthesia. Immunofluorescent staining of c-Fos was conducted to reveal the possible downstream mechanism of SCN activation. Results: Unlike the lack of effect on the induction time, MBL shortened the emergence time and the EEG recordings showed cortical arousal during the recovery period. MBL resulted in a significant decrease in BSR and a marked increase in EEG power at all frequency bands except for the spindle band during 2.5% sevoflurane anesthesia. MBL exposure under sevoflurane anesthesia enhances the neuronal activity of the SCN. These responses to MBL were abolished in SCN lesioned (SCNx) mice. MBL evoked a high level of c-Fos expression in the prefrontal cortex (PFC) and lateral hypothalamus (LH) compared to polychromatic white light (PWL) under sevoflurane anesthesia, while it exerted no effect on c-Fos expression in the ventrolateral preoptic area (VLPO) and locus coeruleus (LC) c-Fos expression. Conclusions: MBL promotes behavioral and electroencephalographic arousal from sevoflurane anesthesia via the activation of the SCN and its associated downstream wake-related nuclei. The clinical implications of this study warrant further study.
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Anestésicos por Inhalación/farmacología , Nivel de Alerta/efectos de la radiación , Hipotálamo/efectos de la radiación , Luz , Neuronas/efectos de la radiación , Corteza Prefrontal/efectos de la radiación , Sevoflurano/farmacología , Núcleo Supraquiasmático/efectos de la radiación , Anestesia , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/efectos de la radiación , Electroencefalografía , Hipotálamo/efectos de los fármacos , Hipotálamo/metabolismo , Ratones , Neuronas/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Corteza Prefrontal/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de los fármacos , Proteínas Proto-Oncogénicas c-fos/metabolismo , Proteínas Proto-Oncogénicas c-fos/efectos de la radiación , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/efectos de la radiación , Núcleo Supraquiasmático/citología , Núcleo Supraquiasmático/efectos de los fármacos , Núcleo Supraquiasmático/metabolismoRESUMEN
Cognitive impairments and poor performance on tasks needing behavioral flexibility are observable in chronic alcohol exposure. NeuroAid decreases cognitive deficits and improves functional outcomes by restoring neuronal circuits. The aim of the current study was to assess the hypothesis that ethanol exposure would induce neurobehavioral defects which may be reversed by the neuroprotective property of NeuroAid. Adult male Wistar rats were treated with saline, ethanol (0.2 g/kg), NeuroAid (0.8 g/kg) and ethanol (0.2 g/kg) + NeuroAid (0.8 g/kg). Then, behavioral tests were performed using the Y-maze apparatus, hot-plate and tail-flick apparatuses, locomotion apparatus as well as the loss of righting reflex (LORR) and hanging protocols (performance in a wire hanging test). Our results indicated that intraperitoneal (i.p.) administration of ethanol alone and administration of ethanol along with NeuroAid for one week reversed ethanol-induced spatial memory deficits in rats (P < 0.01). Interestingly, treatment with ethanol (0.2 g/kg) for one week induced nociception (P < 0.01). Moreover, one week administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) increased latency to LORR (P < 0.001) while four weeks administration of ethanol (0.2 g/kg) along with NeuroAid (0.8 g/kg) decreased sleep time (P < 0.01). In addition, a single administration of all drugs did not alter locomotor activity (P > 0.05) and hanging (P > 0.05). Improvement of behavioral tasks after one-week i.p. administration of ethanol and/or NeuroAid in comparison with a single administration of ethanol and/or NeuroAid may be due to the neuroprotective property of ethanol and/or NeuroAiD.
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Cognición/efectos de los fármacos , Medicamentos Herbarios Chinos/farmacología , Etanol/farmacología , Fármacos Neuroprotectores/farmacología , Animales , Etanol/efectos adversos , Etanol/antagonistas & inhibidores , Masculino , Actividad Motora/efectos de los fármacos , Nocicepción/efectos de los fármacos , Dimensión del Dolor , Ratas , Ratas Wistar , Reflejo de Enderezamiento/efectos de los fármacos , Memoria Espacial/efectos de los fármacosRESUMEN
Anesthetics are used to produce hypnosis and analgesic effects during surgery, but anesthesia for a long time after the operation is not conducive to the recovery of animals or patients. Therefore, finding appropriate treatments to counter the effects of anesthetics could enhance postoperative recovery. In the current study, we discovered the novel role of a GluN2A-selective positive allosteric modulator (PAM) in ketamine-induced anesthesia and investigated the effects of the PAM combined with nalmefene and flumazenil (PNF) in reversing the actions of an anesthetic combination (ketamine-fentanyl-dexmedetomidine, KFD). PAM treatment dose-dependently decreased the duration of the ketamine-induced loss of righting reflex (LORR). Compared with those in the KFD group, the duration of LORR and the analgesic effect of the KFD + PNF group were obviously decreased. Meanwhile, successive administration of PNF and KFD had no adverse effects on the cardiovascular and respiratory systems. Both the KFD group and the KFD + PNF group showed no changes in hepatic and renal function or cognitive function in rats. Moreover, the recovery of motor coordination of the KFD + PNF group was faster than that of the KFD group. In summary, our results suggest the potential application of the PNF combination as an antagonistic treatment strategy for anesthesia.
Asunto(s)
Analgesia , Anestesia , Dexmedetomidina/antagonistas & inhibidores , Fentanilo/antagonistas & inhibidores , Flumazenil/farmacología , Antagonistas de Receptores de GABA-A/farmacología , Ketamina/antagonistas & inhibidores , Naltrexona/análogos & derivados , Antagonistas de Narcóticos/farmacología , Receptores de N-Metil-D-Aspartato/agonistas , Adyuvantes Anestésicos , Regulación Alostérica , Animales , Retraso en el Despertar Posanestésico/tratamiento farmacológico , Combinación de Medicamentos , Evaluación Preclínica de Medicamentos , Femenino , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Naltrexona/farmacología , Nocicepción/efectos de los fármacos , Dimensión del Dolor , Ratas , Reflejo de Enderezamiento/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración ConstanteRESUMEN
Approaches that facilitate the recovery from coma would have enormous impacts on patient outcomes and medical economics. Orexin-producing neurons release orexins (also known as hypocretins) energy-dependently to maintain arousal. Hyperbaric oxygen (HBO) could increase ATP levels by preserving mitochondrial function. We investigated, for the first time, the arousal effects of HBO and orexins mechanisms in a rat model of unconsciousness induced by ketamine or ethanol. A total of 120 Sprague-Dawley male rats were used in this study. Unconsciousness was induced either by intraperitoneal injection of ketamine or ethanol. The HBO treatment (100% O2 at 3 ATA) was administered immediately after unconsciousness induction for 1 hr. SB334867, orexin-1 receptor (OX1R) inhibitor, or JNJ10397049, orexin-2 receptor (OX2R) inhibitor was administered 30 min intraperitoneally before unconsciousness induction. Loss of righting reflex test (LORR) and Garcia test were used to evaluate the unconsciousness duration and neurological deficits after recovering from unconsciousness, respectively. Enzyme-linked immunosorbent assay was used to measure brain tissue ATP and orexin A levels. Ketamine or ethanol injection resulted in LORR immediately and neurological deficits 6 hr after unconsciousness induction. HBO treatment significantly reduced the LORR duration, improved Garcia scores and unregulated ATP and orexin A levels in the brain tissue. Administration of OX1R inhibitor or OX2 R inhibitor abolished arousal and neurological benefits of HBO. In conclusion, HBO exerted arousal-promoting effects on unconscious rats induced by ketamine or ethanol. The underlying mechanism was via, at least in part, ATP/orexin A upregulation. HBO may be a practical clinical approach to accelerate unconsciousness recovery in patients.
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Antagonistas de los Receptores de Orexina/farmacología , Orexinas/metabolismo , Inconsciencia/metabolismo , Regulación hacia Arriba , Animales , Nivel de Alerta/efectos de los fármacos , Benzoxazoles/farmacología , Dioxanos/farmacología , Etanol , Oxigenoterapia Hiperbárica , Ketamina , Masculino , Naftiridinas/farmacología , Compuestos de Fenilurea/farmacología , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos , Inconsciencia/inducido químicamente , Urea/análogos & derivados , Urea/farmacologíaRESUMEN
Qingnaopian has been used in traditional Chinese medicine for treating central nervous system (CNS) injury and inflammatory diseases. The aim of this study was to investigate the effects of Qingnaopian in concussion mice. C57BL/6 mice were used to establish the mild Traumatic Brain Injury (mTBI)/ concussion using the weight-drop techniques. Animal behavioral experiments righting reflex response and locomotor activity were assessed. The expression of pro inflammatory cytokines, including tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), IL-1 and Glial fibrillary acidic protein (GFAP) were assessed by enzyme-linked immunosorbent assay (ELISA) and Western blot method, respectively. SPSS 19.0 software was used for statistical analysis. The results showed that righting reflex time and locomotor activity were higher in model group compared with those in control group. Qingnaopian treated mice had lower pro inflammatory cytokines, such as IL-1, IL-6 and TNF-α with alleviated GFAP. In short, Qingnaopian treatment improved GFAP induced by blow to head and inflammatory cytokines in concussion mice.
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Conmoción Encefálica/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Encefalitis/tratamiento farmacológico , Proteína Ácida Fibrilar de la Glía/metabolismo , Animales , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Conmoción Encefálica/complicaciones , Ácidos Cumáricos/análisis , Citocinas/líquido cefalorraquídeo , Medicamentos Herbarios Chinos/química , Encefalitis/líquido cefalorraquídeo , Encefalitis/metabolismo , Locomoción/efectos de los fármacos , Masculino , Ratones Endogámicos C57BL , Reflejo de Enderezamiento/efectos de los fármacosRESUMEN
Acute alcohol exposure induces unconscious condition such as coma whose main physical manifestation is the loss of righting reflex (LORR). Xingnaojing Injection (XNJI), which came from Chinese classic formula An Gong Niu Huang Pill, is widely used for consciousness disorders in China, such as coma. Although XNJI efficiently shortened the duration of LORR induced by acute ethanol, it remains unknown how XNJI acts on ethanol-induced coma (EIC). We performed experiments to examine the effects of XNJI on orexin and adenosine (AD) signaling in the lateral hypothalamic area (LHA) in EIC rats. Results showed that XNJI reduced the duration of LORR, which implied that XNJI promotes recovery form coma. Microdialysis data indicated that acute ethanol significantly increased AD release in the LHA but had no effect on orexin A levels. The qPCR results displayed a significant reduction in the Orexin-1 receptors (OX1R) expression with a concomitant increase in the A1 receptor (A1R) and equilibrative nucleoside transporter type 1 (ENT1) expression in EIC rats. In contrast, XNJI reduced the extracellular AD levels but orexin A levels remained unaffected. XNJI also counteracted the downregulation of the OX1R expression and upregulation of A1R and ENT1 expression caused by EIC. As for ADK expression, XNJI but not ethanol, displayed an upregulation in the LHA in EIC rats. Based on these results, we suggest that XNJI promotes arousal by inhibiting adenosine neurotransmission via reducing AD level and the expression of A1R and ENT1.
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Proteínas Portadoras/genética , Coma/tratamiento farmacológico , Medicamentos Herbarios Chinos/farmacología , Receptor de Adenosina A1/genética , Adenosina/genética , Adenosina/metabolismo , Animales , Coma/inducido químicamente , Coma/genética , Coma/patología , Tranportador Equilibrativo 1 de Nucleósido , Etanol/toxicidad , Regulación de la Expresión Génica/efectos de los fármacos , Humanos , Área Hipotalámica Lateral/efectos de los fármacos , Área Hipotalámica Lateral/metabolismo , Receptores de Orexina/genética , Orexinas/genética , Orexinas/metabolismo , Ratas , Reflejo de Enderezamiento/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transmisión Sináptica/efectos de los fármacos , Transmisión Sináptica/genética , Vigilia/efectos de los fármacosRESUMEN
The present study aimed to investigate the impact of perinatal potassium bromate (KBrO3) exposure on the development of sensorimotor reflexes and redox status, and on the histological architecture of the brain, liver, and kidney of newborn mice. Pregnant mice received 1-ml bottled drinking water daily by oral intubation and served as the control group. Another group of pregnant mice were supplemented orally with 200 mg/kg body weight KBrO3 dissolved in drinking water from gestation day 5 to postnatal day 21. KBrO3 induced a decrease in the postnatal body weight in the newborn mice. KBrO3-exposed newborn mice showed poor performance and delayed development of the sensorimotor reflexes. Histological changes, increased lipid peroxidation, and altered antioxidants were reported in the cerebrum, cerebellum, medulla oblongata, liver, and kidney of the KBrO3-exposed newborn mice. In conclusion, these findings demonstrated that perinatal exposure to bromate induced oxidative stress, histological and behavioral alterations, and was a potential teratogen in newborn mice.
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Bromatos/toxicidad , Efectos Tardíos de la Exposición Prenatal/inducido químicamente , Anomalías Inducidas por Medicamentos/etiología , Anomalías Inducidas por Medicamentos/patología , Animales , Animales Recién Nacidos/anomalías , Animales Recién Nacidos/crecimiento & desarrollo , Animales Recién Nacidos/metabolismo , Femenino , Glutatión/metabolismo , Peroxidación de Lípido/efectos de los fármacos , Masculino , Ratones , Estrés Oxidativo/efectos de los fármacos , Peroxidasa/metabolismo , Embarazo , Reflejo de Enderezamiento/efectos de los fármacos , Prueba de Desempeño de Rotación con Aceleración Constante , Superóxido Dismutasa/metabolismoRESUMEN
Ketamine (KET) is an antidepressant and hypnotic drug acting as an antagonist at excitatory NMDA glutamate receptors. The working hypothesis postulated that KET-induced sleep in mice results in dysregulation of mitogen-activated protein kinases (MAPK) MEK-ERK sequential phosphorylation and upregulation of survival p-FADD and other neuroplastic markers in brain. Low (5-15â¯mg/kg) and high (150â¯mg/kg) doses of KET on target proteins were assessed by Western immunoblot in mouse brain cortex. During the time course of KET (150â¯mg/kg)-induced sleep (up to 50â¯min) p-MEK was increased (up to +79%) and p-ERK decreased (up to -46%) indicating disruption of MEK to ERK signal. Subhypnotic KET (5-15â¯mg/kg) also revealed uncoupling of p-MEK (+13-81%) to p-ERK (unchanged content). KET did not alter contraregulatory MAPK mechanisms such as inactivated p-MEK1 (ERK dampening) and phosphatases MKP1/2/3 (ERK dephosphorylation). As other relevant findings, KET (5, 15 and 150â¯mg/kg) upregulated p-FADD in a dose-dependent manner, and for the hypnotic dose the effect paralleled the time course of sleep which resulted in increased p-FADD/FADD ratios. KET (150â¯mg/kg) also increased NF-κΒ and PSD-95 neuroplastic markers. Flumazenil (a neutral allosteric antagonist at GABAA receptor) prolonged KET sleep and blocked p-MEK upregulation, indicating the involvement of this receptor as a negative modulator. SL-327 (a MEK inhibitor) augmented KET sleep, further indicating the relevance of reduced p-ERK1/2 in KET-induced hypnosis. These findings suggest that hypnotic and subhypnotic doses of KET inducing uncoupling of p-MEK to p-ERK signal and regulation of p-ERK (downregulation) and p-FADD (upregulation) may participate in the expression of some of its adverse effects (e.g. amnesia, dissociative effects).
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Corteza Cerebral/efectos de los fármacos , Proteína de Dominio de Muerte Asociada a Fas/metabolismo , Pérdida de Tono Postural/efectos de los fármacos , Ketamina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Receptores de GABA-A/metabolismo , Analgésicos/farmacocinética , Animales , Corteza Cerebral/fisiología , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Flumazenil/farmacología , Moduladores del GABA/farmacología , Masculino , Ratones , Proteínas del Tejido Nervioso/metabolismo , Reflejo de Enderezamiento/efectos de los fármacos , Factores de TiempoRESUMEN
Benzodiazepine receptor agonists are widely prescribed therapeutic agents, alter gamma-aminobutyric acid (GABA)A receptor function, and have hypnotic, anxiolytic, anticonvulsant, and antispastic effects. GABAA receptor activity increases under systemic inflammatory conditions. We investigated the effect of benzodiazepine receptor agonists on pentobarbital-induced loss of righting reflex (LORR) duration using a mouse model of lipopolysaccharide (LPS)-induced inflammation. We assessed pentobarbital-induced LORR duration 24â¯h after LPS treatment in mice. Additionally, we examined the microglial response by immunohistochemistry and serum IL-6 and TNF-α concentrations in mice. LPS treatment significantly increased the duration of pentobarbital-induced LORR in mice treated with benzodiazepine receptor agonists (diazepam and brotizolam) and a GABAA receptor agonist (muscimol) compared to that of mice treated with vehicle. These effects were blocked by bicuculline, a GABAA receptor antagonist. LPS significantly increased the number of ionized calcium binding adapter molecule-1-positive hippocampal cells 2 and 24â¯h after treatment. The enhancing effect of diazepam in LPS-treated mice was significantly reduced by minocycline. These findings suggest that LPS enhances pentobarbital-induced LORR duration in mice treated with benzodiazepine via GABAA receptor activity.
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Diazepam/farmacología , Lipopolisacáridos/farmacología , Pentobarbital/farmacología , Reflejo de Enderezamiento/efectos de los fármacos , Animales , Giro Dentado/efectos de los fármacos , Giro Dentado/metabolismo , Lóbulo Frontal/efectos de los fármacos , Lóbulo Frontal/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Interleucina-6/sangre , Interleucina-6/genética , Ratones , ARN Mensajero/genética , ARN Mensajero/metabolismo , Factores de Tiempo , Factor de Necrosis Tumoral alfa/sangre , Factor de Necrosis Tumoral alfa/genéticaRESUMEN
ETHNOPHARMACOLOGICAL RELEVANCE: Pregnant women prefer herbal medicines more than pharmaceutical drugs due to the cultural belief that herbs are more suffer during pregnancy for an accurate foetus development. Artemisia herba-alba (Asteraceae) is one of the most used plants in the Mediterranean region to treat various diseases including diabetes, hypertension, spasmodic dysphonia and some bacterial infection. AIM OF THE STUDY: The present study aimed to investigate the effect of Artemisia herba-alba consumption during pregnancy on fertility, physical and behavior developments of mice offspring from birth-to-weaning days. MATERIALS AND METHODS: Female pregnant mice were divided into three groups and orally administrated with 80 and 150â¯mg/kg/day of the methanol extract of Artemisia h.a respectively, during the entire period of gestation. At birth, total fertility rate was counted. Body development; neuromotor reflex and behavior were also examined in mice offspring RESULTS: Artemisia h.a (Aha) exposure significantly decreased the fertility ratio in both Aha-treated groups and increased the weight and length of mice offspring in 80â¯mg/kg/day Aha-exposed group. Moreover, Aha administration prolonged the time of completing the reflex response of surface righting, negative geotaxis, cliff avoidance and jumping test of mice offspring in Aha-exposed groups. CONCLUSION: The present study provides strong evidence that discourage the use of Artemisia h.a during gestation period.
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Artemisia , Reacción de Prevención/efectos de los fármacos , Peso Corporal/efectos de los fármacos , Fertilidad/efectos de los fármacos , Extractos Vegetales/farmacología , Efectos Tardíos de la Exposición Prenatal , Animales , Conducta Animal/efectos de los fármacos , Femenino , Masculino , Intercambio Materno-Fetal , Ratones , Embarazo , Reflejo de Enderezamiento/efectos de los fármacosRESUMEN
BACKGROUND: Current concepts suggest that impaired representation of information in cortical networks contributes to loss of consciousness under anaesthesia. We tested this idea in rat auditory cortex using information theory analysis of multiunit responses recorded under three anaesthetic agents with different molecular targets: isoflurane, propofol, and dexmedetomidine. We reasoned that if changes in the representation of sensory stimuli are causal for loss of consciousness, they should occur regardless of the specific anaesthetic agent. METHODS: Spiking responses were recorded with chronically implanted microwire arrays in response to acoustic stimuli incorporating varied temporal and spectral dynamics. Experiments consisted of four drug conditions: awake (pre-drug), sedation (i.e. intact righting reflex), loss of consciousness (a dose just sufficient to cause loss of righting reflex), and recovery. Measures of firing rate, spike timing, and mutual information were analysed as a function of drug condition. RESULTS: All three drugs decreased spontaneous and evoked spiking activity and modulated spike timing. However, changes in mutual information were inconsistent with altered stimulus representation being causal for loss of consciousness. First, direction of change in mutual information was agent-specific, increasing under dexmedetomidine and decreasing under isoflurane and propofol. Second, mutual information did not decrease at the transition between sedation and LOC for any agent. Changes in mutual information under anaesthesia correlated strongly with changes in precision and reliability of spike timing, consistent with the importance of temporal stimulus features in driving auditory cortical activity. CONCLUSIONS: The primary sensory cortex is not the locus for changes in representation of information causal for loss of consciousness under anaesthesia.
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Anestesia General/métodos , Anestésicos Generales/farmacología , Corteza Auditiva/efectos de los fármacos , Estado de Conciencia/efectos de los fármacos , Estimulación Acústica/métodos , Anestésicos por Inhalación/farmacología , Anestésicos Intravenosos/farmacología , Animales , Corteza Auditiva/fisiología , Estado de Conciencia/fisiología , Dexmedetomidina/farmacología , Electroencefalografía/efectos de los fármacos , Femenino , Hipnóticos y Sedantes/farmacología , Isoflurano/farmacología , Propofol/farmacología , Ratas Endogámicas ACI , Tiempo de Reacción/efectos de los fármacos , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/fisiologíaRESUMEN
WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Many general anesthetics were discovered empirically, but primary screens to find new sedative-hypnotics in drug libraries have not used animals, limiting the types of drugs discovered. The authors hypothesized that a sedative-hypnotic screening approach using zebrafish larvae responses to sensory stimuli would perform comparably to standard assays, and efficiently identify new active compounds. METHODS: The authors developed a binary outcome photomotor response assay for zebrafish larvae using a computerized system that tracked individual motions of up to 96 animals simultaneously. The assay was validated against tadpole loss of righting reflexes, using sedative-hypnotics of widely varying potencies that affect various molecular targets. A total of 374 representative compounds from a larger library were screened in zebrafish larvae for hypnotic activity at 10 µM. Molecular mechanisms of hits were explored in anesthetic-sensitive ion channels using electrophysiology, or in zebrafish using a specific reversal agent. RESULTS: Zebrafish larvae assays required far less drug, time, and effort than tadpoles. In validation experiments, zebrafish and tadpole screening for hypnotic activity agreed 100% (n = 11; P = 0.002), and potencies were very similar (Pearson correlation, r > 0.999). Two reversible and potent sedative-hypnotics were discovered in the library subset. CMLD003237 (EC50, ~11 µM) weakly modulated γ-aminobutyric acid type A receptors and inhibited neuronal nicotinic receptors. CMLD006025 (EC50, ~13 µM) inhibited both N-methyl-D-aspartate and neuronal nicotinic receptors. CONCLUSIONS: Photomotor response assays in zebrafish larvae are a mechanism-independent platform for high-throughput screening to identify novel sedative-hypnotics. The variety of chemotypes producing hypnosis is likely much larger than currently known.
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Ensayos Analíticos de Alto Rendimiento/métodos , Hipnóticos y Sedantes/farmacología , Larva/efectos de los fármacos , Locomoción/efectos de los fármacos , Reflejo de Enderezamiento/efectos de los fármacos , Animales , Relación Dosis-Respuesta a Droga , Evaluación Preclínica de Medicamentos/métodos , Femenino , Larva/fisiología , Locomoción/fisiología , Masculino , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/fisiología , Xenopus , Pez CebraRESUMEN
Maternal folate status during pregnancy may influence central nervous system (CNS) development in offspring. However, the recommended intakes of folic acid for women of childbearing age differ among countries and there is still no consensus about whether folic acid should be supplemented continuously throughout pregnancy. We hypothesized that folic acid supplementation may be more beneficial for offspring's neurobehavioral development if prolonged throughout pregnancy instead of being limited to the periconceptional period. In this study, three groups of the female rats were fed folate-normal, folate-deficient, or folate-supplemented diets throughout pregnancy. In another group, the female rats were fed folate-supplemented diet from mating for 10 consecutive days and then fed folate-normal diet for remainder days of pregnancy. The results showed that maternal folate deficiency increased plasma homocysteine (Hcy) concentration in dams, delayed early sensory-motor reflex development, impaired spatial learning and memory ability, and caused ultrastructural damages in the hippocampus of offspring. Maternal folic acid supplementation would be more effective on improving early sensory-motor reflex development and spatial learning and memory ability in offspring if prolonged throughout pregnancy instead of being limited to the periconceptional period. In conclusion, prolonged maternal folic acid supplementation throughout pregnancy would be more effective in neurobehavioral development of offspring in rats.
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Suplementos Dietéticos , Ácido Fólico/administración & dosificación , Aprendizaje/efectos de los fármacos , Embarazo/efectos de los fármacos , Desempeño Psicomotor/efectos de los fármacos , Reflejo de Enderezamiento/efectos de los fármacos , Factores de Edad , Animales , Animales Recién Nacidos , Femenino , Hipocampo/efectos de los fármacos , Hipocampo/fisiología , Hipocampo/ultraestructura , Aprendizaje/fisiología , Masculino , Salud Materna , Embarazo/fisiología , Desempeño Psicomotor/fisiología , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/fisiologíaRESUMEN
Although general anesthetics are routinely administered to surgical patients to induce loss of consciousness, the mechanisms underlying anesthetic-induced unconsciousness are not fully understood. In rats, we characterized changes in the extradural EEG and intracranial local field potentials (LFPs) within the prefrontal cortex (PFC), parietal cortex (PC), and central thalamus (CT) in response to progressively higher doses of the inhaled anesthetic sevoflurane. During induction with a low dose of sevoflurane, beta/low gamma (12-40 Hz) power increased in the frontal EEG and PFC, PC and CT LFPs, and PFC-CT and PFC-PFC LFP beta/low gamma coherence increased. Loss of movement (LOM) coincided with an abrupt decrease in beta/low gamma PFC-CT LFP coherence. Following LOM, cortically coherent slow-delta (0.1-4 Hz) oscillations were observed in the frontal EEG and PFC, PC and CT LFPs. At higher doses of sevoflurane sufficient to induce loss of the righting reflex, coherent slow-delta oscillations were dominant in the frontal EEG and PFC, PC and CT LFPs. Dynamics similar to those observed during induction were observed as animals emerged from sevoflurane anesthesia. We conclude that the rat is a useful animal model for sevoflurane-induced EEG oscillations in humans, and that coherent slow-delta oscillations are a correlate of sevoflurane-induced behavioral arrest and loss of righting in rats.
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Anestésicos por Inhalación/farmacología , Ritmo Delta/efectos de los fármacos , Éteres Metílicos/farmacología , Lóbulo Parietal/efectos de los fármacos , Corteza Prefrontal/efectos de los fármacos , Tálamo/efectos de los fármacos , Animales , Ritmo beta/efectos de los fármacos , Sincronización Cortical/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Electrodos Implantados , Ritmo Gamma/efectos de los fármacos , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Músculo Esquelético/efectos de los fármacos , Músculo Esquelético/fisiología , Lóbulo Parietal/fisiología , Corteza Prefrontal/fisiología , Ratas Sprague-Dawley , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/fisiología , Sevoflurano , Tálamo/fisiologíaRESUMEN
BACKGROUND: Thalamocortical electroencephalographic rhythms in gamma (30-80 Hz) and high-gamma (80-200 Hz) ranges have been linked to arousal and conscious processes. We have recently shown that propofol causes a concentration-dependent attenuation of the power of thalamocortical rhythms in the 50 to 200 Hz range and that this effect is far more pronounced for the thalamus. To determine whether similar attenuation occurs with other anesthetics, we characterized the concentration-effect relationship of the inhaled anesthetic isoflurane on the spectral power of these rhythms. METHODS: Local field potentials were recorded from the barrel cortex and ventroposteromedial thalamic nucleus in 9 chronically instrumented rats to measure spectral power in the gamma/high-gamma range (30-200 Hz). Rats were placed in an airtight chamber and isoflurane was administered at 0.75%, 1.1%, and 1.5% concentrations. Spectral power was assessed during baseline, at the 3 isoflurane concentrations after 30 minutes for equilibration, and during recovery over 4 frequency bands (30-50, 51-75, 76-125, and 126-200 Hz). Unconsciousness was defined as sustained loss of righting reflex. Multiple linear regression was used to model the change in power (after logarithmic transformation) as a function of concentration and recording site. P values were corrected for multiple comparisons. RESULTS: Unconsciousness occurred at the 1.1% concentration in all animals. Isoflurane caused a robust (P ≤ 0.008) linear concentration-dependent attenuation of cortical and thalamic power in the 30 to 200 Hz range. The concentration-effect slope for the thalamus was steeper than for the cortex in the 51 to 75 Hz (P = 0.029) and 76 to 200 Hz (P < 0.001) ranges but not for the 30 to 50 Hz range (P = 0.320). Comparison with our previously published propofol data showed that slope for cortical power was steeper with isoflurane than with propofol for all frequency bands (P = 0.033). For thalamic power, the slope differences between isoflurane and propofol were not statistically significant (0.087 ≤ P ≤ 0.599). CONCLUSIONS: Isoflurane causes a concentration-dependent attenuation of the power of thalamocortical rhythms in the 30 to 200 Hz range, and this effect is more pronounced for the thalamus than for the cortex for frequencies >50 Hz. In comparison with propofol, isoflurane caused a greater attenuation in the cortex, but the effects on the thalamus were similar. Isoflurane and propofol cause common alterations of fast thalamocortical rhythms that may constitute an electrophysiologic signature of the anesthetized state.
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Anestésicos por Inhalación/administración & dosificación , Corteza Cerebral/efectos de los fármacos , Electroencefalografía , Ritmo Gamma/efectos de los fármacos , Isoflurano/administración & dosificación , Tálamo/efectos de los fármacos , Potenciales de Acción/efectos de los fármacos , Animales , Conducta Animal/efectos de los fármacos , Corteza Cerebral/fisiología , Estado de Conciencia/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Masculino , Ratas Long-Evans , Reflejo de Enderezamiento/efectos de los fármacos , Procesamiento de Señales Asistido por Computador , Tálamo/fisiología , Factores de TiempoRESUMEN
This study investigated the hypnotic, anti-convulsant and anxiolytic effects of 1-nitro-2-phenylethane (BPNE) obtained from the oil of Dennettia tripetala G. Baker (Annonaceae) and established its mechanism of action. The essential oil (EO) from the leaf, fruit and seed was obtained by hydrodistillation, followed by isolation of BPNE purified to 99.2% by accelerated gradient chromatography on silica, and identified by NMR and GC-MS. The pure BPNE and EO of the dried seed (93.6%) were comparatively evaluated for hypnotic, anticonvulsant and anxiolytic effects in mice. The acute toxicity of BPNE was determined and the LD50 was 490 mg/kg, intrapritonealy. The hypnotic activities of the EO and BPNE (50-400 mg/kg, i.p.) were assessed by loss of righting reflex, while sodium pentobarbitone (PBS) and diazepam (DZM) were used as positive controls. The anticonvulsant and anxiolytic effects of the EO and BPNE were evaluated in mice. Both BPNE and EO at doses ≥100 mg/kg induced spontaneous hypnosis with loss of righting reflex, significantly decreased sleep latency (SL) and also increased total sleeping time (TST) dose-dependently. They had comparable activity with NAP in TST. The BPNE exhibited higher hypnotic potency than EO at the same dose levels. The EO and BPNE offered comparable dose-related protections against PTZ- and strychnine-induced convulsions. Flumazenil (2 mg/kg) blocked the hypnotic and anticonvulsant (PTZ-convulsions) effects of both EO and BPNE. The essential oil at 5-20 mg/kg dose levels significantly (p<0.05) increased the percentage time spent and number of entries into the open arms. While at the same dose range BPNE significantly (p<0.05) increased the percentage time spent and the number of entries into the open arms respectively. The study concluded that 1-nitro-2-phenylethane exhibited dose dependent significant hypnotic, anticonvulsant and anxiolytic effects and it is the compound largely responsible for the neuropharmacological effects of the oil.
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Annonaceae/química , Ansiolíticos/uso terapéutico , Anticonvulsivantes/uso terapéutico , Derivados del Benceno/uso terapéutico , Hipnóticos y Sedantes/uso terapéutico , Aceites Volátiles/uso terapéutico , Fitoterapia , Animales , Ansiolíticos/aislamiento & purificación , Ansiolíticos/farmacología , Anticonvulsivantes/aislamiento & purificación , Anticonvulsivantes/farmacología , Ansiedad/tratamiento farmacológico , Reacción de Prevención , Derivados del Benceno/aislamiento & purificación , Derivados del Benceno/farmacología , Relación Dosis-Respuesta a Droga , Femenino , Flumazenil/farmacología , Moduladores del GABA/farmacología , Hipnóticos y Sedantes/aislamiento & purificación , Hipnóticos y Sedantes/farmacología , Masculino , Ratones , Aceites Volátiles/química , Aceites Volátiles/farmacología , Extractos Vegetales/farmacología , Extractos Vegetales/uso terapéutico , Estructuras de las Plantas , Reflejo de Enderezamiento/efectos de los fármacos , Convulsiones/inducido químicamente , Convulsiones/prevención & control , Sueño/efectos de los fármacos , Trastornos del Inicio y del Mantenimiento del Sueño/tratamiento farmacológico , EstricninaRESUMEN
Ethanol is a widely used drug, yet an understanding of its sites and mechanisms of action remains incomplete. Among the protein targets of ethanol are glycine receptors (GlyRs), which are potentiated by millimolar concentrations of ethanol. In addition, zinc ions also modulate GlyR function, and recent evidence suggests that physiologic concentrations of zinc enhance ethanol potentiation of GlyRs. Here, we first built a homology model of a zinc-bound GlyR using the D80 position as a coordination site for a zinc ion. Next, we investigated in vitro the effects of zinc on ethanol action at recombinant wild-type (WT) and mutant α1 GlyRs containing the D80A substitution, which eliminates zinc potentiation. At D80A GlyRs, the effects of 50 and 200 mM ethanol were reduced as compared with WT receptors. Also, in contrast to what was seen with WT GlyRs, neither adding nor chelating zinc changed the magnitude of ethanol enhancement of mutant D80A receptors. Next, we evaluated the in vivo effects of the D80A substitution by using heterozygous Glra1(D80A) knock-in (KI) mice. The KI mice showed decreased ethanol consumption and preference, and they displayed increased startle responses compared with their WT littermates. Other behavioral tests, including ethanol-induced motor incoordination and strychnine-induced convulsions, revealed no differences between the KI and WT mice. Together, our findings indicate that zinc is critical in determining the effects of ethanol at GlyRs and suggest that zinc binding at the D80 position may be important for mediating some of the behavioral effects of ethanol action at GlyRs.
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Consumo de Bebidas Alcohólicas , Conducta Animal/efectos de los fármacos , Etanol/farmacología , Mutación Puntual , Receptores de Glicina/genética , Zinc/metabolismo , Estimulación Acústica , Consumo de Bebidas Alcohólicas/genética , Sustitución de Aminoácidos , Animales , Sitios de Unión , Fenómenos Electrofisiológicos , Etanol/administración & dosificación , Femenino , Técnicas de Sustitución del Gen , Homocigoto , Masculino , Ratones , Ratones Mutantes , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Oocitos/metabolismo , Reflejo de Enderezamiento/efectos de los fármacos , Reflejo de Enderezamiento/genética , Reflejo de Sobresalto/efectos de los fármacos , Reflejo de Sobresalto/genética , Prueba de Desempeño de Rotación con Aceleración Constante , Estricnina/farmacología , Transfección , Xenopus laevis , Zinc/farmacologíaRESUMEN
OBJECTIVE: To comparative study the acute toxicity of four extracts from Xanthii Fructus in mice. METHOD: Observed the toxic manifestations in mice which were given the four extracts by intragastric administration and calculated the LD50 of the four extracts from Xanthii Fructus. RESULT: The toxic manifestations of the mice given water extract by intragastric administration were repose, pilo-erection, cyanosis, intention tremor, respiratory inhibition, loss of righting reflex and convulsion . The toxic manifestations of the mice given ethanol extract by intragastric administration were repose, abdominal respiration, intention tremor, intermittent convulsions, incontinence. The LD50 of Xanthii Fructus processed water extract, processed ethanol extract, crude water extract, crude ethanol extract were material drug 155.93, 317.80, 167.6, 275.41 g x kg(-1), respectively. CONCLUSION: The acute toxicity of water extract is distinctly stronger than that of ethanol extract, but there is no marked distinguish between crude and processed extract.