RESUMO
Estradiol and some selective estrogen receptor modulators (SERMs) are neuroprotective in a variety of experimental models of neurodegeneration, reduce the inflammatory response of glial cells, reduce anxiety and depression, promote cognition and modulate synaptic plasticity in the hippocampus of rodents. In this study we have assessed whether estradiol and two SERMs currently used in clinics, tamoxifen and raloxifene, affect medial prefrontal cortex function and morphology. Rats were ovariectomized and six days later some animals received a subcutaneous injection of the estrogenic compounds. In a first experiment animals were treated with estradiol benzoate or sesame oil vehicle. In a second experiment animals received raloxifene, tamoxifen or dimethyl sulfoxide as vehicle. Twenty four hours after the pharmacological treatment, animals were challenged to solve an allocentric working memory paradigm in a "Y" maze. Twenty trials consisting of a study phase and a test phase were conducted according to a delayed match-to-sample procedure in a single one-day session. Animals that were not submitted to behavioral test were used for Golgi analysis of the prefrontal cortex. Rats treated with estradiol benzoate, tamoxifen or raloxifene performed better in the Y maze and showed a significant increase in the numerical density of dendritic spines in secondary apical dendrites of layer III pyramidal neurons from the prelimbic/infralimbic prefrontal cortex, compared to their respective control groups. These findings suggest that estradiol, tamoxifen and raloxifene improve prefrontal cortex-related cognitive performance and modulate prefrontal cortex morphology in ovariectomized rats.
Assuntos
Espinhas Dendríticas/efeitos dos fármacos , Memória de Curto Prazo/efeitos dos fármacos , Ovariectomia , Córtex Pré-Frontal/efeitos dos fármacos , Células Piramidais/efeitos dos fármacos , Moduladores Seletivos de Receptor Estrogênico/farmacologia , Animais , Comportamento Animal/efeitos dos fármacos , Estradiol/análogos & derivados , Estradiol/farmacologia , Feminino , Aprendizagem em Labirinto/efeitos dos fármacos , Córtex Pré-Frontal/citologia , Desempenho Psicomotor/efeitos dos fármacos , Cloridrato de Raloxifeno/farmacologia , Ratos , Ratos Sprague-Dawley , Sinapses/efeitos dos fármacos , Tamoxifeno/farmacologiaRESUMO
BACKGROUND AND PURPOSE: Contrast curve truncation in CTP protocols may introduce errors. We sought to identify risk factors and design a protocol to avoid truncation while limiting radiation. MATERIALS AND METHODS: In an initial fixed-timing cohort, patients underwent a 65-second CTP with 2-second delay postcontrast injection. Multivariable analysis identified factors associated with truncation. A later case-specific cohort underwent either the original protocol or a low cardiac output protocol with a 7-second delay and 75-second scanning window, with selection determined by CTA test-dose enhancement upswing delay. Time-density curves were assessed for truncation and compared between the 2 groups, and the radiation dose was evaluated. RESULTS: From September 2017 through May 2018, one hundred fifty-three patients underwent the standard fixed-timing protocol. Age (OR, 1.82/10-year increase; P = .019), reduced left ventricle ejection fraction (OR, 9.23; P = .001), and hypertension (OR, 0.32; P = .06) were independently associated with truncation in an exploratory multivariable model. From May 2018 through April 2019, one hundred fifty-seven patients underwent either the standard (72 patients) or low cardiac output protocol (85 patients). The fixed-timing cohort had 15 truncations (9.8%) versus 4 in the case-specific cohort (2.5%; P = .009). If the low cardiac output protocol were applied to those with >10.6% predicted risk of truncation based on age, left ventricle ejection fraction, and hypertension, the number of truncations would have decreased from 15 to 4 in the fixed-timing cohort. CONCLUSIONS: Older age, left ventricle ejection fraction, and the absence of hypertension increase the risk of time-density curve truncation. However, a CTA test-dose-directed case-specific protocol can reduce truncation to ensure accurate data while mitigating radiation dose increases.
Assuntos
Hipertensão , Acidente Vascular Cerebral , Humanos , Baixo Débito Cardíaco , Angiografia Cerebral/métodos , Software , Acidente Vascular Cerebral/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodosRESUMO
Assessments of ecosystem service and function losses of wetlandscapes (i.e., wetlands and their hydrological catchments) suffer from knowledge gaps regarding impacts of ongoing hydro-climatic change. This study investigates hydro-climatic changes during 1976-2015 in 25 wetlandscapes distributed across the world's tropical, arid, temperate and cold climate zones. Results show that the wetlandscapes were subject to precipitation (P) and temperature (T) changes consistent with mean changes over the world's land area. However, arid and cold wetlandscapes experienced higher T increases than their respective climate zone. Also, average P decreased in arid and cold wetlandscapes, contrarily to P of arid and cold climate zones, suggesting that these wetlandscapes are located in regions of elevated climate pressures. For most wetlandscapes with available runoff (R) data, the decreases were larger in R than in P, which was attributed to aggravation of climate change impacts by enhanced evapotranspiration losses, e.g. caused by land-use changes.
RESUMO
AIMS: Reactive oxygen species (ROS)-mediated formation of mixed disulfides between critical cysteine residues in proteins and glutathione, a process referred to as protein S-glutathionylation, can lead to loss of enzymatic activity and protein degradation. Since mitochondria are a major source of ROS and a number of their proteins are susceptible to protein-S-glutathionylation, we examined if overexpression of mitochondrial thioltranferase glutaredoxin 2a (Grx2a) in macrophages of dyslipidemic atherosclerosis-prone mice would prevent mitochondrial dysfunction and protect against atherosclerotic lesion formation. METHODS AND RESULTS: We generated transgenic Grx2aMac(LDLR-/-) mice, which overexpress Grx2a as an EGFP fusion protein under the control of the macrophage-specific CD68 promoter. Transgenic mice and wild type siblings were fed a high fat diet for 14 weeks at which time we assessed mitochondrial bioenergetic function in peritoneal macrophages and atherosclerotic lesion formation. Flow cytometry and Western blot analysis demonstrated transgene expression in blood monocytes and peritoneal macrophages isolated from Grx2aMac(LDLR-/-) mice, and fluorescence confocal microscopy studies confirmed that Grx2a expression was restricted to the mitochondria of monocytic cells. Live-cell bioenergetic measurements revealed impaired mitochondrial ATP turnover in macrophages isolated from Grx2aMac(LDLR-/-) mice compared to macrophages isolated from non-transgenic mice. However, despite impaired mitochondrial function in macrophages of Grx2aMac(LDLR-/-) mice, we observed no significant difference in the severity of atherosclerosis between wildtype and Grx2aMac(LDLR-/-) mice. CONCLUSION: Our findings suggest that increasing Grx2a activity in macrophage mitochondria disrupts mitochondrial respiration and ATP production, but without affecting the proatherogenic potential of macrophages. Our data suggest that macrophages are resistant against moderate mitochondrial dysfunction and rely on alternative pathways for ATP synthesis to support the energetic requirements.
Assuntos
Doenças da Aorta/enzimologia , Aterosclerose/enzimologia , Glutarredoxinas/metabolismo , Macrófagos Peritoneais/enzimologia , Mitocôndrias/enzimologia , Receptores de LDL/deficiência , Trifosfato de Adenosina/metabolismo , Animais , Aorta/enzimologia , Aorta/patologia , Doenças da Aorta/genética , Doenças da Aorta/patologia , Apoptose , Aterosclerose/genética , Aterosclerose/patologia , Células Cultivadas , Modelos Animais de Doenças , Metabolismo Energético , Glutarredoxinas/genética , Macrófagos Peritoneais/patologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Mitocôndrias/patologia , Placa Aterosclerótica , Receptores de LDL/genética , Índice de Gravidade de DoençaRESUMO
Estradiol-induced plasticity involves changes in dendritic spine density and in the relative proportions of the different dendritic spine types that influence neurons and neural circuits. Such events affect brain structures that control the timing of neuroendocrine and behavioral processes, influencing both reproductive and cognitive functions during the estrous cycle. Accordingly, to investigate the dendritic spine-related plastic changes that may affect the neural processes involved in mating, estradiol-mediated dendritic spine plasticity was studied in type II cells situated in the ventrolateral portion of the ventromedial hypothalamic nucleus (VMN) of female, adult rats. The rats were assigned to four different groups (n=6) in function of their stage in the estrous cycle: proestrus, estrus, metaestrus, and diestrus. Dendritic spine density and the proportions of the different spine types on type II neurons were analyzed in the ventrolateral region of the VMN of these animals. Dendritic spine density on primary dendrites of VMN type II neurons was significantly lower in metaestrus than in diestrus, proestrus and estrus (with no differences between these latter stages). However, a significant variation in the proportional density of the different spine types was found, with a higher proportion of thin spines in diestrus, proestrus and estrus than in metaestrus. Likewise, a higher proportion of mushroom spines was seen in diestrus and proestrus than in metaestrus, and a higher proportion of stubby spines in estrus than in diestrus and metaestrus. Very few branched spines were found during proestrus and they were not detected during estrus or metaestrus. The different types of dendritic spines in non-projection neurons of the VMN could serve to maintain greater synaptic excitatory activity when receptivity and estradiol levels are maximal. However, they may also fulfill an additional functional role when receptivity and estradiol decline. To date specific roles of the different types of spines in neural hypothalamic activity during the estrous cycle remain unknown and they clearly deserve further study.
Assuntos
Espinhas Dendríticas/ultraestrutura , Ciclo Estral/fisiologia , Interneurônios/ultraestrutura , Núcleo Hipotalâmico Ventromedial/citologia , Análise de Variância , Animais , Espinhas Dendríticas/fisiologia , Feminino , Ratos , Ratos Sprague-Dawley , Coloração pela PrataRESUMO
The posterior cerebellum is strongly involved in motor coordination and its maturation parallels the development of motor control. Climbing and mossy fibers from the spinal cord and inferior olivary complex, respectively, provide excitatory afferents to cerebellar Purkinje neurons. From post-natal day 19 climbing fibers form synapses with thorn-like spines located on the lower primary and secondary dendrites of Purkinje cells. By contrast, mossy fibers transmit synaptic information to Purkinje cells trans-synaptically through granule cells. This communication occurs via excitatory synapses between the parallel fibers of granule cells and spines on the upper dendritic branchlets of Purkinje neurons that are first evident at post-natal day 21. Dendritic spines influence the transmission of synaptic information through plastic changes in their distribution, density and geometric shape, which may be related to cerebellar maturation. Thus, spine density and shape was studied in the upper dendritic branchlets of rat Purkinje cells, at post-natal days 21, 30 and 90. At 90 days the number of thin, mushroom and thorn-like spines was greater than at 21 and 30 days, while the filopodia, stubby and wide spines diminished. Thin and mushroom spines are associated with increased synaptic strength, suggesting more efficient transmission of synaptic impulses than stubby or wide spines. Hence, the changes found suggest that the development of motor control may be closely linked to the distinct developmental patterns of dendritic spines on Purkinje cells, which has important implications for future studies of cerebellar dysfunctions.
Assuntos
Cerebelo/citologia , Espinhas Dendríticas/fisiologia , Espinhas Dendríticas/ultraestrutura , Células de Purkinje/ultraestrutura , Animais , Cerebelo/crescimento & desenvolvimento , Feminino , Masculino , Células de Purkinje/fisiologia , Distribuição Aleatória , Ratos , Ratos Sprague-DawleyRESUMO
Dopaminergic activity in the Nucleus Accumbens has been strongly implicated in the motor hyperactivity associated with Attention deficit hyperactivity disorder. Dopaminergic and glutamatergic terminals converge on the dendritic spines of medium spiny neurons of the nucleus accumbens core, which modulate the excitatory glutamatergic activity. In this work, a Golgi study was carried out to investigate the effects of dopamine depletion on the cytoarchitecture of dendritic spines of nucleus accumbens core medium spiny neurons. The dopaminergic system of newborn male rats was lesioned intracisternally by using 6-hydroxydopamine, and subsequently, the motor activity, spine density, and the proportion of thin, stubby, mushroom, wide, branched, and double spines was compared to those in control and intact animals. Motor activity was significantly increased in the dopamine-depleted animals and while the spine density was reduced, there was no change in the proportion of the specific types of spines. Larger thin spines were observed in the dopamine-depleted animals. Indeed, dopamine depletion may lead to spine retraction due to the disregulation of spine development, and/or an increase in glutamatergic activity. The enlargement of thin spines may suggest a compensatory mechanism to increase the efficiency of synaptic inputs in response to a decrease in spines number. Together, the present findings suggest an alteration to the excitatory/inhibitory balance on dendritic spines of medium spiny neurons of the nucleus accumbens core in hyperactive juvenile rats following early dopamine depletion.
Assuntos
Dendritos/patologia , Hipercinese/patologia , Neurônios/patologia , Núcleo Accumbens/patologia , Animais , Masculino , Ratos , Ratos Sprague-DawleyRESUMO
Hippocampal vulnerability to excitotoxicity has been widely studied along with its implication to learning and memory. Neonatal glutamate excitotoxicity induces loss of CA1 pyramidal neurons in adult rats concomitantly with some plastic changes in the dendritic spines of surviving neurons. At least in part, these may underlie the place learning impairments seen in previous studies based on a similar excitotoxicity-inducing model. In the present study, cytoarchitecture of dentate gyrus, CA3 and CA1 fields were evaluated in 120-day-old rats, after they had been neonatally treated with glutamate as monosodium salt. Dentate granule cells and CA1 pyramidal neurons were less than those counted in NaCl-treated control animals. In addition, dentate granule cells had more dendrites as well as more branched spines. Spine density in CA1 pyramidal neurons was greater than in the controls. Additionally, thin and mushroom spines were proportionally more abundant in monosodium glutamate-treated animals. No effects were seen in the hippocampal CA3 field. Our results strongly suggest a long-term induction of plastic changes in the cytoarchitecture of the hippocampal trisynaptic circuit neurons after cell death provoked by the monosodium glutamate-induced excitotoxicity. These plastic events as well as the aberrant expression of the glutamate NMDA receptors resulting from monosodium glutamate neonatal treatment could be strongly associated with the place learning impairments previously reported.