Allopregnanolone protecting cell line SH-SY5Y against 6-hydroxydopamine-induced lesion / 解剖学报

Objective To clarify the protective effect of allopregnanolone (APα) on cell line SH-SY5Y damaged by 6-hydroxydopamine (6-OHDA) and its possible molecular mechanism. Methods 6-OHDA, APα, γ-aminobutyric acid A receptor (GABAAR) antagonist, voltage-gated L-type Ca2

Mutación de protocadherina 19 (PC-DH19), en paciente con epilepsia refractaria / Mutation of protocadherin 19 (PCDH19), in patients with refractory epilepsy

Paciente de 4 años de edad, con epilepsia de difícil manejo, cuya etiología se atribuye a patología autoinmune y que finalmente se diagnostica una mutación de protocadherina (PCDH19). Se discute la fisiopatología, características clínicas, exámenes y los posibles tratamientos.

Four-year-old patient with intractable epilepsy, whose etiology is attributed to autoimmune pathology and who is eventually diagnosed with a protocadherin mutation (PCDH19). Pathophysiology, clinical characteristics, examinations and possible treatments are discussed.

Allopregnanolone restores dopaminergic neurons and motor performance in Parkinson’s disease mice and its molecular mechanisms / 解剖学报

[ Abstract] Objective To investigate the effects of allopregnanolone (APα) on the dopaminergic neurons in substantia nigra, striatal dopaminergic neural fibers and behavioral performance in Parkinson’ s disease (PD) model mice, as well as its possible molecular mechanisms. Methods C57BL / 6 adult male mice with 20-25 g at 3-month old (n = 90) were successively injected with 6-hydroxydopamine (6-OHDA) to generate a PD animal model. APα and its receptor γ-aminobutyric acid A receptor (GABAAR) antagonist—bicuculline (Bic) were successively injected. ELISA was used to detect the APα or dopamine concentration in the serum, cerebral cortex and striatum. The number of tyrosine hydroxylase (TH) in the substantia nigra (SN) and striatal dopaminergic neural projections were examined by immunohistochemical staining. The expression levels of GABAAR in membrane fractions and Ca

Allopregnanolone suppresses mechanical allodynia and internalization of neurokinin-1 receptors at the spinal dorsal horn in a rat postoperative pain model

BACKGROUND: To identify a new strategy for postoperative pain management, we investigated the analgesic effects of allopregnanolone (Allo) in an incisional pain model, and also assessed its effects on the activities of the primary afferent fibers at the dorsal horn. METHODS: In experiment 1, 45 rats were assigned to Control, Allo small-dose (0.16 mg/kg), and Allo large-dose (1.6 mg/kg) groups (n = 15 in each). The weight bearing and mechanical withdrawal thresholds of the hind limb were measured before and at 2, 24, 48, and 168 h after Brennan's surgery. In experiment 2, 16 rats were assigned to Control and Allo (0.16 mg/kg) groups (n = 8 in each). The degree of spontaneous pain was measured using the grimace scale after the surgery. Activities of the primary afferent fibers in the spinal cord (L6) were evaluated using immunohistochemical staining. RESULTS: In experiment 1, the withdrawal threshold of the Allo small-dose group was significantly higher than that of the Control group at 2 h after surgery. Intergroup differences in weight bearing were not significant. In experiment 2, intergroup differences in the grimace scale scores were not significant. Substance P release in the Allo (0.16 mg/kg) group was significantly lower than that in the Control group. CONCLUSIONS: Systemic administration of Allo inhibited mechanical allodynia and activities of the primary afferent fibers at the dorsal horn in a rat postoperative pain model. Allo was proposed as a candidate for postoperative pain management.

Overexpression of 18 ku translocator protein in mouse hippocampal dentate gyrus mediates anxiety and depressive behavior / 中国药理学与毒理学杂志

OBJECTIVE To investigate the effect of overexpession of 18 ku translocator protein (TSPO) on the hippocampal dentate gyrus. METHODS Lentiviral (LV) vectors containing TSPO or the lentiviral sequence were infused into the hippocampus bilateral dentate gyri (2 × 108 TU · mL-1,1 μL per side)of mice. Behavioral tests were carried out. The anxiolytic-like behavior of mice was examined by such means as the elevated plus maze test , the staircase test , light dark box test for 12, 14 and 16 d, two behavioral despair models, tail suspension test and the forced swimming test for 16 and 18 d,respec?tively. Western blotting and ELISA were used to evaluate the TSPO expression and the concentration of allopregnanolone in hippocampal tissue (3 mm in diameter around the injection site on both sides) at the end of tests. RESULTS The results of behavioral experiments showed that TSPO overexpression group deneloped anxiolytic and antidepression-like behavior. LV-TSPO significantly increased the retention time in the central area〔14 ± 4 vs (25 ± 12)s,P<0.05〕. LV-TSPO significantly increased the percentage of entry into open arms entries percentage and the percentage of time spent in open arms time without changing total entries and total time in the elevated plus-maze test〔(13±8)%vs (26±18)%, P<0.05;(6 ± 6)%vs (27 ± 6)%, P<0.05)〕. LV-TSPO significantly decreased the number of rearings without changing the number of steps in staircase test (21±7 vs 12±5,P<0.05). LV-TSPO increased entries into the light area and retention time in light-dark transition test〔(18 ± 8)% vs (26 ± 7)%, P<0.05;72 ± 36 vs (191 ± 90)s, P<0.05)〕but significantly decreased immobility time in the tail suspension test and forced swimming test〔94±33 vs (36±20)s, P<0.01;137±36 vs (90±37)s, P<0.05)〕, without excitatory or inhibitory actions on the central nervous system. At the same time, the level of TSPO expression in hippocampal tissues (3 mm in diameter around the injection site on both sides) was significantly increased, so did the concentration of allopregnanolone (P<0.05). CONCLUSION Overexpression of TSPO in the hippocamus dentate gyrus of mice can induce anxiolytic and antidepressant-like behavior, and the downstream allo?pregnanolone biosynthesis at least partially mediates the behavioral effects.

Anti-post-traumatic-stress-disorder effects of YL-IPA08, a selective 18kDa translocator protein ligand / 国际药学研究杂志

Objective To explore the anti-post-traumatic-stress-disorder(anti-PTSD)effects of YL-IPA08,a selective 18kDa translocator protein(TSPO)ligand.Methods The time-dependent stress sensitization(TDS)method was used to establish a rat mod?el of PTSD.The open field test(OFT)was used to evaluate the locomotor activity in rats.The contextual freezing(CF)measurement, elevated plus maze(EPM)test and novel objective recognition(NOR)test were used to evaluate the PTSD-like behaviors in rats.The concentration of allopregnanolone in rat hippocampus was detected by ELISA. Results Compared with the control group,neither TDS nor drug treatment affected the locomotor activity in rats(P>0.05).However,PTSD rats showed significant PTSD-like behaviors with enhanced CF time in CF mearsurement,decreased open arm time and open arm entries in EPM test,and dropped object recogni?tion index in NOR test(P<0.05 or 0.01).Moreover,the concentration of hippocampus allopregnanolone was decreased in PTSD rats (P<0.05).YL-IPA08(0.05-0.1mg/kg)or positive drug sertraline(15 mg/kg),administered intragastrically after establishment of PTSD model,significantly reversed the above PTSD-like behavioral changes(P<0.05 or 0.01)and increased the concentration of hip?pocampus allopregnanolone in PTSD rats.Conclusion YL-IPA08 could improve the PTSD-like behavior in rats,and the mechanism may be related to the increased allopregnanolone level in hippocampus.

Protective effect of selective 18 ku translocator protein ligand YL-IPA08 on BV-2 apoptosis induced by corticosterone / 中国药理学与毒理学杂志

OBJECTIVE To investigate the protective effect of selective 18 ku translocator protein (TSPO) ligand YL-IPA08 on corticosterone(CORT)-induced apoptosis of BV-2 cells and its potential mecha?nisms. METHODS BV-2 Cells were pretreated with selective TSPO ligand YL-IPA08 1-100 nmol · L-1 and(or) TSPO antagonist PK11195 100 nmol · L-1 for 2 h,and then co-incubated with CORT for another 24 h. The apoptosis rate was measured by flow cytometry. CCK-8 kit was used to test BV-2 cell viability. The protein expression of TSPO was determined by Western blotting. The level of allopreg?nanolone was detected by ELISA kit. RESULTS In line with positive drug-AC-5216, the cell apoptosis rate decreased in YL-IPA08 1-100 nmol · L-1 and CORT co-treatment groups(P<0.01), which was antago?nized by PK11195 100 nmol · L-1 treatment(P<0.05). Cell viability increased in YL-IPA08 100 nmol · L-1and CORT co-treatment groups (P<0.01), which was blocked by PK11195 100 nmol·L-1 treatment(P<0.01). The expression of TSPO and the level of allopregnanolone(P<0.01) were enhanced by YL-IPA08 100 nmol · L-1 pretreatment followed by CORT treatment. The enhancement of allopregnanolone level was blocked by PK11195 100 nmol·L-1 treatment(P<0.05). CONCLUSION YL-IPA08 can protect BV-2 cells from CORT induced apoptosis. The protective effect of YL-IPA08 may be conferred by the increasing level of TSPO expression and allopregnanolone.

Efecto de la alopregnanolona sobre la ansiedad en ratas con separación materna durante la lactancia / The effect of allopregnanolone on anxiety induced in rats separated from their young during breastfeeding

Antecedentes. La relación madre-hijo y el cuidado parental al recién nacido son fundamentales en el desarrollo fisiológico y emocional de los individuos. Evidencias asocian el estrés temprano con el desarrollo de enfermedades mentales. El modelo de separación materna durante la lactancia (SMDL) se ha utilizado para inducir estrés temprano en ratas y estudiar efectos a largo plazo. Diversos estudios han encontrado que, en ratas separadas de sus madres, disminuyen los niveles del receptor GABA-A y esos bajos niveles están asociados a comportamientos ansiosos. Objetivo. Evaluar el efecto de la alopregnanolona, un neuroesteroide agonista del receptor GABA-A, sobre la ansiedad inducida por SMDL. Materiales y métodos. Se utilizaron 30 ratas Wistar dividas en dos grupos, uno control y uno experimental (SMDL). La SMDL se realizó desde el día postnatal 1 hasta el día postnatal 21, durante 180 minutos en la mañana y 180 minutos en la tarde. Desde el día 22 los sujetos se alojaron en cajas por sexo y tratamiento y continuaron su desarrollo normal hasta el día 60, en el que se hizo la inyección con alopregnanolona y la prueba comportamental en el laberinto en cruz elevado. Resultados. El estrés crónico causado por la SMDL afecta el comportamiento de los individuos, perfil comportamental que varía dependiendo del sexo. Se encontró que los machos presentan comportamientos más ansiosos que las hembras, las cuales a su vez muestran más actividad locomotora y exploración Conclusiones. Al aplicar alopregnanolona el repertorio comportamental varía en los animales con SMDL; estos resultados sugieren que la alopregnanolona, a través de su unión al receptor GABA-A, puede llegar a revertir los efectos de la separación materna, sobre los comportamientos relacionados con ansiedad.

Background. The mother-child relationship and parental care for the newborn are fundamental in individuals' physiological and emotional development. Evidence-based research associates early stress with the development of mental illnesses. Maternal separation during lactation (MSDL) models have been used to induce early stress in rats and for studying the long-term effects of such intervention. Several studies have found decreased GABA-A receptor levels in separated rats from their mothers and such low levels have been associated with anxious behaviour. Objective. Assessing the effect of allopregnanolone (a GABA-A receptor neurosteroid agonist) on MSDL-induced anxiety. Materials and methods. Thirty Wistar rats were divided into two groups: control and experimental (MSDL). SMDL occurred for 180 minutes in the morning and 180 minutes in the afternoon. Subjects were housed in boxes by gender and treatment following day 22 and their normal development was allowed to continue until day 60 when they were injected with allopregnanolone and underwent a behavioural test in an elevated plus maze (EPM). Results. Chronic stress induced by MSDL affected individuals' behaviour, their behavioural profile varying according to their gender. Males exhibited more anxious behaviour than females who engaged in more locomotive and exploratory activity. Conclusions. MSDL animals' behavioural repertoire varied due to the allopregnanolone injection, suggesting that the effect of allopregnanolone due to GABA-A receptor interaction could reverse the effects of maternal separation on anxiety-related behaviour.

Neuroactive steroids and their role in epilepsy.

Neuroactive steroids are the certain steroids that alter neuronal excitability via the cell surface through interaction with certain neurotransmitter receptors. Neuroactive steroids regulate physiological functions of the central nervous system and have possible therapeutic potential in neurological diseases. They have been shown to affect neuronal excitability via their interaction with the ligand-gated ion channel family, such as the GABAA receptor by acting genomically as well as nongenomically. Positive modulators of GABAA receptor have anticonvulsant action as they enhance GABAergic transmission thereby increasing the seizure threshold. By virtue of these properties, neurosteroids appear to be relevant to pathophysiology and pharmacological treatment of many neurological diseases including catamenial epilepsy, stress induced epilepsy, temporal lobe epilepsy, alcohol withdrawal seizures, infantile spasm and status epilepticus. So far, only synthetic neurosteroid, ganaxolone has been tried in treatment of epilepsy and has shown good efficacy and tolerability. But, human data of trials are limited and hence, large double-blinded, placebo-controlled, randomized clinical trials are required before their use. The paper reviews the biosynthesis and GABAA receptor modulation of neurosteroids and their potential role in epilepsy.

Timing of progesterone and allopregnanolone effects in a serial forced swim test / Duración del efecto de progesterona y alopregnanolona en la prueba de nado forzado seriada

The forced swim test (FST) is commonly employed to test the potency of drugs to reduce immobility as an indicator of anti-despair. Certainly, antidepressant drugs reduce the total time of immobility and enlarge the latency to the first immobility period. FST is preceded by the open field test (OFT) to discard any influence of changes in general motor activity that could interfere with immobility in the FST. Albeit progesterone and its a-reduced metabolite allopregnanolone produce antidepressant-like effects in the FST, the timing of actions is unknown. We hypothesized that the latency and duration of effects produced by progesterone and allopregnanolone may be characterized by repeated FST sessions; we therefore devised a serial-FST experimental design to evaluate the timing effects of these steroids on immobility, locomotion in the open field test, and grooming in the later as an indicator of response to stress. We included fifty-one ovariectomized adult Wistar rats weighing 200-250 g at the beginning of the experiments. They were ovariectomized by abdominal approach under anesthesia. Rats were housed six per cage, at room temperature (25 ± 1°C) under a 12 h/12 h light/dark cycle (lights ON at 7:00 a.m.) with ad libitum access to purified water and food. All of the experimental procedures followed National Institutes of Health Guidelines. The local Ethics Committee (Biomedical Research Institute, Universidad Nacional Autónoma de México) approved the experimental protocol. A first group received vehicle (2-hidroxypropyl-γ-cyclodextrin dissolved in injectable sterilized water to obtain a 35% solution, control group n=17), the second group progesterone (1.0 mg/kg, n=17), and the third group allopregnanolone (1.0 mg/kg, n=17). All single injections were applied by intraperitoneal route at a volume of 0.8 ml/kg. The effects of treatments were evaluated in the serial-FST at 0.25, 0.5, 1, 2, 4, 6, and 24 h after injection, in a rectangular pool (height, 60 cm; length, 30 cm; width, 50 cm), with 24 cm deep water (25 ± 1°C). We evaluated the total time of immobility, during 5 min, considered as the principal indicator of an anti-despair effect. Before each session of serial-FST, locomotion was evaluated in the OFT during 5 minutes. The apparatus consisted on an acrylic box (height, 20 cm; length, 44 cm; width, 33 cm), with twelve squares delineated on the floor (11x11 cm). In the same OFT sessions, grooming was evaluated as an indicator of response to stress. Statistical analysis consisted in two-way analysis of variance (ANOVA) and Student-Newman-Keuls as post hoc test. Total time in immobility was the highest and remained at similar levels only in the control group throughout the seven sessions of the serial-FST. In the allopregnanolone group a reduction in immobility was observed beginning 0.5 h after injection and lasted approximately 1.5 h. Similarly, progesterone reduced immobility beginning 1.0 h after injection, and the reduction lasted for approximately 5.0 h. In all groups, locomotion in the OFT was reduced after the first serial-FST session and remained at similar low levels during the serial-FST. In the control group, grooming was reduced after the first serial-FST session and lasted 24 h, but grooming did not change in the progesterone-or allopregnanolone-treated rats. From a serial-FST design, we conclude that progesterone and allopregnanolone exert short time-dependent reductions in immobility and anti-stress-like effects no longer than 24 hrs, and seemingly a reduction in the response to stress, which may have some clinical applications.

Introducción La progesterona y su metabolito activo alopregnanolona se han estudiado ampliamente en modelos experimentales de ansiedad y depresión, y por su propiedad de ser sintetizadas en el cerebro se les considera como neuroesteroides. Entre las pruebas que permiten determinar la potencia antidepresiva de ciertos fármacos se encuentra la prueba de nado forzado, la cual se diseñó originalmente para detectar la potencia de sustancias con propiedades antidepresivas. Estas sustancias reducen el tiempo de inmovilidad y alargan la latencia al primer periodo de inmovilidad, lo cual es considerado como un efecto antidepresivo. Usualmente, la prueba de nado forzado se aplica dos veces, una sesión de preprueba que dura 15 minutos, en la cual la rata o ratón desarrolla el estado de desesperanza. La preprueba es seguida de la sesión de prueba que se realiza 24 horas después durante 5 minutos. En ella se evalúa el efecto de las sustancias con propiedades antidepresivas. Además, la prueba de nado forzado es precedida por la prueba de campo abierto con la finalidad de identificar cambios en la actividad motora general (hipoactividad o hiperactividad) que pudiera interferir con la interpretación de las variables evaluadas en la prueba de nado forzado. Algunos esteroides, como la progesterona y alopregnanolona, reducen la inmovilidad y alargan la latencia a la primera inmovilidad en la prueba de nado forzado, lo que indica su efecto tipo-antidepresivo. Sin embargo, la latencia y la duración de los efectos farmacológicos son desconocidas. La hipótesis de este trabajo fue que, si utilizábamos la prueba de nado forzado de forma repetida, podríamos identificar el tiempo de duración de los efectos de estos esteroides. Por lo tanto, diseñamos un experimento con la prueba de nado forzado seriada para evaluar el tiempo de permanencia de los efectos de progesterona y alopregnanolona en esta prueba conductual. Materiales y métodos Sujetos: En este estudio se incluyeron 51 ratas adultas ovariectomizadas de la cepa Wistar, con peso entre 200 y 250 g al inicio de los experimentos. Las ratas fueron anestesiadas y ovariectomizadas por aproximación ventral y fueron alojadas en cajas de acrílico trasparente (n=6), con una temperatura ambiente de 25 ± 1°C y con un ciclo de luz-oscuridad de 12 ×12 h (la luz se encendió a las 7:00 am). Las ratas tuvieron libre acceso al agua purificada y al alimento (Purina). Todos los procedimientos realizados en este estudio fueron de acuerdo con las normas éticas en el uso de animales de experimentación, basándonos en la Guía del National Institute of Health, y el protocolo fue aprobado por el Comité de Ética del Instituto de Investigaciones Biomédicas de la Universidad Nacional Autónoma de México. Grupos y tratamientos: Las ratas del grupo control recibieron el vehículo (solución al 35% de 2-hidroxipropil-g-ciclodextrina), el segundo grupo recibió progesterona (1.0 mg/kg) y el tercero recibió alopregnanolona (1.0 mg/kg) por vía intraperitoneal, en un volumen de 0.8 ml/kg. Pruebas conductuales: El efecto de los tratamientos fue evaluado en la prueba de nado forzado a las 0.25, 0.5, 1, 2, 4, 6 y 24 horas después de la administración. Utilizamos un estanque rectangular (base 50 × 34 cm, altura 60 cm), con agua a 25°C y una altura de 24 cm. Sólo se evaluó el tiempo total de inmovilidad, considerando que es el principal indicador de un efecto antidesesperanza. Antes de cada sesión de nado forzado se evaluó la actividad motora (cuadros deambulados) y el acicalamiento en campo abierto. Esta prueba consistió en colocar a la rata en una caja de acrílico (base 33 × 44 cm, altura 20 cm) con el piso dividido en 12 cuadros de 11 × 11 cm. Los resultados obtenidos de ambas pruebas fueron evaluados por medio de una ANOVA de dos vías y como prueba post hoc se aplicó Student-Newman-Keuls. Resultados La prueba de nado forzado aplicada de forma repetida resultó ser útil para evaluar los efectos temporales producidos por dos esteroides con potencia antidepresiva. Las ratas del grupo control mostraron los valores más altos de inmovilidad en la prueba de nado forzado, los cuales se mantuvieron así durante las sesiones de prueba. En los grupos tratados con progesterona o alopregnanolona hubo una reducción de la inmovilidad, gradual y temporal. Los animales tratados con alopregnanolona redujeron la inmovilidad a partir de las 0.5 horas después de la administración, efecto que se mantuvo por un periodo de 1.5 h. Los animales tratados con progesterona redujeron la inmovilidad a partir de 1.0 hora después de la administración, efecto que se mantuvo por un periodo de 5.0h. En campo abierto, independientemente del tratamiento, hubo una reducción del número de cuadros cruzados después de la primera sesión de nado forzado, efecto que permaneció hasta las 24h. En el acicalamiento, se observó que sólo los animales del grupo control redujeron significativamente el tiempo empleado en esta conducta, mientras que los animales inyectados con progesterona o alopregnanolona no modificaron esta variable. Es decir, mantuvieron niveles semejantes durante todas las sesiones de prueba y estuvieron por arriba de los valores encontrados en los animales control. Conclusión La progesterona y la alopregnanolona ejercen un efecto antidesesperanza de breve latencia, no mayor a 24 horas. Este hallazgo podría tener implicaciones clínicas en pacientes con depresión refractaria al tratamiento convencional.

The synthesis and metabolism of neurosteroids and the effects on the nervous system / 中国临床药理学与治疗学

Neurosteroids exist in central and peripheral nervous system, independence of peripheral glands, including pregnenolone, progesterone, allopregnanolone, and dehydroepiandrosterone, etc. They can be synthesized in the nervous system from sterol or sterol precursors catalyzed by certain enzymes. They play roles by interacting with GABAA, NMDA or?receptors, and have effects on memory, sleep, convulsion, cellular excitability, etc.

Anticonvulsant activity of allopregnanolone against pentylenetetrazol- induced seizures in rodents / 中国组织工程研究

Objective To examine the protective effects of allopregnanolone against pentylenetetrazol- induced seizures. Methods The protective effects of allopregnanolone against pentylenetetrazol- induced seizures were studied in C57 mice and SD rats 15 minutes after vehicle or drug intraperitoneal (ip) administration. Results The pretreatment with the allopregnanolone produced a dose- dependent protective effect against pentylenetetrazol- induced seizures. The potencies (ED50 values) were 4.7 mg/kg and 9.8 mg/kg for mice and rats, respectively. Conclusion Allopregnanolone has anticonvulsant activity against pentylenetetrazol- induced seizures in rodents.

Protective effects of allopregnanolone against different seizure models in mice / 中国临床药理学与治疗学

Aim To examine the protective effects of allopregnanolone against seizure on different animal models.Methods　The protective effects of allopregnanolone against maximal electrical seizure (MES) and picrotoxin-induced seizure were studied in C57 mice 15 minutes after vehicle or drug intraperitoneal administration.Results　In the MES test, we found that pretreatment with the phenobarbital or allopregnanolone produced a dose-dependent protective effect against seizure. The potency (ED50 value) of phenobarbital in the MES test was 2.40 mg·kg-1, with 95% confidence interval range from 1.22 to 4.72 mg·kg-1. The potency (ED50 value) of allopregnanolone in the MES test was 0.086 mg·kg-1, with 95%confidence interval range from 0.037 to 0.201 mg·kg-1, which was significantly higher than that of phenobarbital (P<0.01). The combination study of half ED50 values of phenobarbital and allopregnanolone resulted in a 80% of protective effect in MES test, which was higher than 50% produced by either phenobarbital or allopregnanolone at their ED50 values respectively. This result indicated that there was a synergism between phenobarbital and allopregnanolone in their anticonvulsant activities. In the picrotoxin test, we found that pretreatment with the allopregnanolone also produced a dose-dependent protective effect against picrotoxin-induced seizure. The potency of allopregnanolone in the picrotoxin seizure test was 0.123 mg·kg-1, with 95% confidence interval range from 0.058 to 0.263 mg·kg-1.Conclusion　Allopregnanolone(ip) could protect different seizures in a dose-dependent manner,had a higher potency than phenobarbital,and had synergism with phenobarbital in the MES test.

Comparison of anxiolytic effects of allopregnanolone and diazepam on the elevated plus-maze in mice / 中国临床药理学与治疗学

To compare the anxiolytic effects of reduced metabolite of progesterone and benzodiazepine.Methods　The effects of allopregnanolone and diazepam on spontaneous locomotor activity and on exploration in the elevated plus-maze were studied in C57 mice 20 min after vehicle or drug intraperitoneal administration.Results Allopregnanolone (0.1 mg.kg-1,ip) elicited marked anxiolytic effects in terms of significantly reducing the latency to enter the open arm from (31.30±8.39)s to (8.80±6.00)s,(P<0.001),and significantly increasing both the number of open arm entries from 1.20 ± 0.42 to 4.80 ±1.75,(P<0.001) and the proportion of total time spent on the open arm from 7.13％ to 32.50％,(P<0.001).Meanwhile,the diazepam (0.25 mg·kg-1) produced a lower anxiolytic effect comparing to that of the allopregnanolone.Analysis of spontaneous locomotor activity showed while 0.5 mg·kg-1 of diazepam decreased the locomotor activity (P<0.01),neither 0.1 mg·kg-1 of allopregnanolone nor 0.25 mg·kg-1 of diazepam affect the locomotor activity score.Conclusion Together,these results provide evidence for differential behavioral actions of the neurosteroids and benzodiazepines.Since the allopregnanolone produce a selective anxiolytic effect without affecting the spontaneous locomotor activity,the allopregnanolone may be a better alternative for diazepam in treating anxiety.

Protective effects of allopregnanoloneagainst different seizure models in mice / 中国临床药理学与治疗学

Aim To examine the protective effects of allopregnanolone against seizure on different animal models.Methods The protective effects of allopregnanolone against maximal electrical seizure (MES) and picrotoxin-induced seizure were studied in C57 mice 15 minutes after vehicle or drug intraperitoneal administration.Results In the MES test, we found that pretreatment with the phenobarbital or allopregnanolone produced a dose-dependent protective effect against seizure. The potency (ED50 value) of phenobarbital in the MES test was 2.40 mg?kg-1, with 95% confidence interval range from 1.22 to 4.72 mg?kg-1. The potency (ED50 value) of allopregnanolone in the MES test was 0.086 mg?kg-1, with 95% confidence interval range from 0.037 to 0.201 mg?kg-1, which was significantly higher than that of phenobarbital (P

Comparison of anxiolytic effects of allopregnanolone anddiazepam on the elevated plus-maze in mice / 中国临床药理学与治疗学

Aim To compare the anxiolytic effects of reduced metabolite of progesterone and benzodiazepine.Methods The effects of allopregnanolone and diazepam on spontaneous locomotor activity and on exploration in the elevated plus_maze were studied in C57 mice 20 min after vehicle or drug intraperitoneal administration. Results Allopregnanolone (0.1 mg?kg-1, ip) elicited marked anxiolytic effects in terms of significantly reducing the latency to enter the open arm from (31.30?8.39)s to (8.80?6.00)s, (P