RESUMO
Objective To investigate the protective effect and its mechanism of metabotropic glutamate receptor 1 ( mGluR1) negative allosteric modulator JNJ16259685 on neuron after subarachnoid hemorrhage (SAH) in rats. Methods Ninety SPF-grade SD male rats were selected. They were randomly divided into 3 groups:sham operation group (n=18),SAH+placebo group (n=36),and SAH+JNJ16259685(JNJ) group (n=36). A SAH model was induced by intravascular puncture. SAH +placebo group received intraperitoneal injection of aseptic water containing 5% dimethyl sulfoxide (DMSO) at 2,24 and 48 h after operation. The SAH+JNJ group was intraperitoneally injected with 1 mg/kg JNJ16259685 ( dissolved in sterile water in 5% DMSO). Garcia scoring criteria were used to assess neurological deficits at 72 h after SAH. Dry and wet weight method was used to detect brain edema. Evans Blue method was used to assess blood-brain barrier permeability. A calcium assay kit was used to detect the mitochondrial calcium ion concentration. Immunofluorescence staining was used to observe neuronal apoptosis. GraphPad 7. 0 software was used to conduct one-way analysis of variance in all indicators among the 3 groups. Results Compared with the sham operation group,the Garcia score (11. 0 ± 0. 4) decreased in the SAH+placebo group. The water content in left and right hemispheres was 80. 5 ± 0. 1% and 80. 3 ± 0. 2% respectively,the Evans blue dye extravasation (2. 8 ± 0. 2),basal cortical mitochondrial calcium ion concentration (2. 5 ± 0. 3),and neuronal apoptosis in basal cortex and hippocampus CA1 region (the number of active caspase-3/NeuN positive cells was 300 ±30/mm2and 20 ± 2/mm respectively) increased (all P<0. 05);and the Garcia score (13. 0 ± 0. 5) was significantly higher in the SAH+JNJ group than in the SAH+placebo group. Water content in left and right hemispheres was 79. 8 ± 0. 2% and 79. 3 ± 0. 1% respectively,Evans blue dye extravasation (1. 8 ±0. 2),basal cortex mitochondrial calcium ion concentration (1. 7 ± 0. 1),basal cortex and the number of neuronal apoptosis in hippocampal CA1 region (the number of active caspase-3/NeuN positive cells were 180 ± 10/mm2,12 ±2/mm) reduced compared with the SAH+placebo group (all P<0. 05). Conclusion After SAH,JNJ16259685 relieves cerebral edema and reduces blood-brain barrier permeability,inhibits the increase of cortical mitochondrial calcium ion concentration,and reduces neuronal apoptosis,thereby exerting neuroprotective effects.
RESUMO
La instigación social intensifica la conducta agresiva permitiendo observar niveles más extremos de agresión. Estudios recientes indican que el receptor metabotrópico del glutamato mGlu1 está implicado en la regulación de la conducta agresiva en un modelo de agresión inducida por aislamiento. El objetivo de este trabajo fue evaluar los efectos de la administración de un antagonista del receptor mGlu1 (JNJ16259685) sobre la conducta agresiva normal e intensificada, utilizando instigación social en un modelo animal de agresión inducida por aislamiento. Varios grupos de animales aislados fueron expuestos a 5 minutos de instigación social, recibiendo la mitad de ellos JNJ16259685 (0.5 mg/kg, ip) o vehículo. Las interacciones agonísticas de 10 min de duración se realizaron en un área neutral 30 min después de la inyección. Dichos encuentros fueron grabados en vídeo para el posterior análisis etológico de diez categorías conductuales. La instigación redujo la latencia de ataque y aumentó la frecuencia y duración de los ataques frente a los animales no instigados. La administración de JNJ16259685 redujo de forma significativa la conducta agresiva en ambos casos, sugiriendo la implicación del receptor mGlu1 en la modulación de la agresión normal e intensificada.
Social instigation intensifies aggressive behavior in rodents allowing observe more extreme levels of aggression. Recent studies indicate that glutamate metabotropic receptor 1 (mGlu1) are involved in the regulation of aggressive behavior in isolation-induced aggression model. The object of this work was to examine social instigation in an animal model of isolation-induced aggression and assess the anti-aggressive effects of an mGlu1 receptor antagonist (JNJ16259685) on normal and heightened aggressive behavior. Several groups of individually housed mice were exposed to 5 minutes of social instigation, and half of them received an acute administration ofJNJ16259685 (0.5 mg/kg, ip) or vehicle. Ten minute of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area 30 min after drug or vehicle administration. The encounters were videotaped for subsequent analysis of ten ethological behavioural categories. Social instigation reduced latency of attack and increased the frequency and duration of attacks against not instigated animals. JNJ16259685 administration significantly reduced aggressive behavior in both cases, suggesting the involvement of mGlu1 receptor in the modulation of normal and heightened aggression.