RESUMO
The astrocytic glutamate transporter GLT-1 performs glutamate uptake thereby mediating NMDAr responses in neurons. Ceftriaxone (CEF) upregulates astrocytic GLT-1 expression/activity, which could counteract excessive glutamate levels and aggressive behavior induced by anabolic synthetic steroids such as nandrolone decanoate (ND). Here, adult male CF-1 mice were allocated to oil (VEH), ND, CEF, and ND/CEF groups. Mice were subcutaneously (s.c.) injected with ND (15 mg/kg) or VEH for 19 days, and received intraperitoneal (i.p.) injections of CEF (200 mg/kg) or saline for 5 days. The ND/CEF group received ND for 19 days plus coadministration of CEF in the last 5 days. On the 19th day, the aggressive phenotypes were evaluated through the resident-intruder test. After 24 h, cerebrospinal fluid was collected to measure glutamate levels, and the pre-frontal cortex was used to assess GLT-1, pGluN2BTyr1472, and pGluN2ATyr1246 by Western blot. Synaptosomes from the left brain hemisphere was used to evaluate mitochondrial function including complex II-succinate dehydrogenase (SDH), Ca2+ handling, membrane potential (ΔÑ°m), and H2O2 production. ND decreased the latency for the first attack and increased the number of attacks by the resident mice against the intruder, mechanistically associated with an increase in glutamate levels and pGluN2BTyr1472 but not pGluN2ATyr1244, and GLT-1 downregulation. The abnormalities in mitochondrial Ca2+ influx, SDH, ΔÑ°m, and H2O2 implies in deficient energy support to the synaptic machinery. The ND/CEF group displayed a decreased aggressive behavior, normalization of glutamate and pGluN2BTyr1472levels, and mitochondrial function at synaptic terminals. In conclusion, the pharmacological modulation of GLT-1 highlights its relevance as an astrocytic target against highly impulsive and aggressive phenotypes.
Assuntos
Agressão/efeitos dos fármacos , Astrócitos/fisiologia , Transportador de Glucose Tipo 1/fisiologia , Psicoses Induzidas por Substâncias/psicologia , Congêneres da Testosterona/efeitos adversos , Agressão/fisiologia , Animais , Astrócitos/efeitos dos fármacos , Astrócitos/metabolismo , Transportador de Glucose Tipo 1/metabolismo , Ácido Glutâmico/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Nandrolona/efeitos adversos , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Psicoses Induzidas por Substâncias/metabolismo , Psicoses Induzidas por Substâncias/fisiopatologia , Receptores de N-Metil-D-Aspartato/metabolismo , Transtornos Relacionados ao Uso de Substâncias/complicações , Transtornos Relacionados ao Uso de Substâncias/metabolismo , Transtornos Relacionados ao Uso de Substâncias/psicologia , Regulação para Cima/efeitos dos fármacosRESUMO
Traumatic brain injury (TBI) increases Ca2+ influx into neurons and desynchronizes mitochondrial function leading to energy depletion and apoptosis. This process may be influenced by brain testosterone (TS) levels, which are known to decrease after TBI. We hypothesized that a TS-based therapy could preserve mitochondrial neuroenergetics after TBI, thereby reducing neurodegeneration. C57BL/6J mice were submitted to sham treatment or severe parasagittal controlled cortical impact (CCI) and were subcutaneously injected with either vehicle (VEH-SHAM and VEH-CCI) or testosterone cypionate (15 mg/kg, TS-CCI) for 10 days. Cortical tissue homogenates ipsilateral to injury were used for neurochemical analysis. The VEH-CCI group displayed an increased Ca2+-induced mitochondrial swelling after the addition of metabolic substrates (pyruvate, malate, glutamate, succinate, and adenosine diphosphate [PMGSA]). The addition of Na+ stimulated mitochondrial Ca2+ extrusion through Na+/Ca2+/Li+ exchanger (NCLX) in VEH-SHAM and TS-CCI, but not in the VEH-CCI group. Reduction in Ca2+ efflux post-injury was associated with impaired mitochondrial membrane potential formation/dissipation, and decreased mitochondrial adenosine triphosphate (ATP)-synthase coupling efficiency. Corroborating evidence of mitochondrial uncoupling was observed with an increase in H2O2 production post-injury, but not in superoxide dismutase (SOD2) protein levels. TS administration significantly reduced these neuroenergetic alterations. At molecular level, TS prevented the increase in pTauSer396 and alpha-Spectrin fragmentation by the Ca2+dependent calpain-2 activation, and decreased both caspase-3 activation and Bax/BCL-2 ratio, which suggests a downregulation of mitochondrial apoptotic signals. Search Tool for the Retrieval of Interacting Genes/Proteins database provided two distinct gene/protein clusters, "upregulated and downregulated," interconnected through SOD2. Therefore, TS administration after a severe CCI improves the mitochondrial Ca2+extrusion through NCLX exchanger and ATP synthesis efficiency, ultimately downregulating the overexpression of molecular drivers of neurodegeneration.
Assuntos
Androgênios/farmacologia , Lesões Encefálicas Traumáticas/patologia , Mitocôndrias/efeitos dos fármacos , Degeneração Neural/patologia , Testosterona/análogos & derivados , Animais , Masculino , Camundongos Endogâmicos C57BL , Mitocôndrias/patologia , Distribuição Aleatória , Testosterona/farmacologiaRESUMO
ABSTRACT Objective To compare resting metabolic rate values determined by indirect calorimetry with values estimated using different predictive equations in lean and overweight postmenopausal women. Methods Twenty-four women, who had stopped menstruating for at least two years, were subjected to anthropometric measurements and indirect calorimetry after 12-hour overnight fasting to determine, mathematically and experimentally, resting metabolic rate values. Results There was no difference in the indirect calorimetry values between the groups evaluated. Difference values of resting metabolic rate were obtained with all equations used. For the lean women, there was no difference between the values obtained by indirect calorimetry and those estimated using the equations proposed by Food and Agricultural Organization, Fredix, Lazzer, and Schofield. However, in the overweight group, the resting metabolic rate values estimated using the Institute of Medicine, Berstein and Owen equations were different from those obtained by indirect calorimetry. Conclusion This study suggests that differences in body composition in postmenopausal women influence the accuracy of predictive equations, demonstrating the need for more accurate estimation methods for resting metabolic rate in postmenopausal women with different body compositions.
RESUMO Objetivo Comparar os valores de taxa metabólica de repouso determinados por calorimetria indireta com os valores obtidos utilizando diferentes equações preditivas em mulheres pós-menopausicas eutróficas e com sobrepeso. Métodos Vinte e quatro mulheres com pelo menos dois anos de menopausa foram submetidas à avaliações antropométricas e à calorimetria indireta após 12 horas de jejum para determinar, matematicamente e experimentalmente, a taxa metabólica de repouso. Resultados Os valores para calorimetria indireta não diferiram entre os grupos e a taxa metabólica de repouso predita por equações foi diferente para todas as equações usadas. Para o grupo de eutróficas, as equações que não foram estatisticamente diferentes da calorimetria indireta foram Food and Agricultural Organization, Fredix, Lazzer e Schofield. No entanto, apenas as equações Berstein e Owen foram significativamente diferentes comparadas com calorimetria indireta para o grupo sobrepeso. Conclusão O presente estudo sugere que diferenças na composição corporal em mulheres na pós-menopausa modificam a precisão de equações que predizem a taxa metabólica de repouso, demonstrando a necessidade de aprimorar métodos de estimação de taxa metabólica de repouso em mulheres pós-menopáusicas com diferentes composições corporais.