RESUMEN
Stroke risk and poor stroke outcomes in postmenopausal women have usually beeen attributed to decreased levels of estrogen. However, two lines of evidence suggest that this hormone may not be solely responsible for elevated stroke risk in this population. First, the increased risk for CVD and stroke occurs much earlier than menopause at a time when estrogen levels are not yet reduced. Second, estrogen therapy has not successfully reduced stroke risk in all studies. Other sex hormones may therefore also contribute to stroke risk. Prior to menopause, levels of the gonadotrophin Follicle Stimulating Hormone (FSH) are elevated while levels of the gonadal peptide inhibin are lowered, indicating an overall decrease in ovarian reserve. Similarly, reduced estrogen levels at menopause significantly increase the ratio of androgens to estrogens. In view of the evidence that androgens may be unfavorable for CVD and stroke, this elevated ratio of testosterone to estrogen may also contribute to the postmenopause-associated stroke risk. This review synthesizes evidence from different clinical populations including natural menopause, surgical menopause, women on chemotherapy, and preclinical stroke models to dissect the role of ovarian hormones and stroke risk and outcomes.
Asunto(s)
Hormonas Esteroides Gonadales/fisiología , Accidente Cerebrovascular/etiología , Estrógenos , Femenino , Hormona Folículo Estimulante/sangre , Hormonas Esteroides Gonadales/sangre , Humanos , Menopausia/sangre , Posmenopausia/sangre , Posmenopausia/fisiología , Accidente Cerebrovascular/sangre , Testosterona/sangreRESUMEN
Opioids are among the most effective and widely prescribed medications for the treatment of pain following spinal cord injury (SCI). Spinally-injured patients receive opioids within hours of arrival at the emergency room, and prolonged opioid regimens are often employed for the management of post-SCI chronic pain. However, previous studies in our laboratory suggest that the effects of opioids such as morphine may be altered in the pathophysiological context of neurotrauma. Specifically, we have shown that morphine administration in a rodent model of SCI increases mortality and tissue loss at the injury site, and decreases recovery of motor and sensory function, and overall health, even weeks after treatment. The literature suggests that opioids may produce these adverse effects by acting as endotoxins and increasing glial activation and inflammation. To better understand the effects of morphine following SCI, in this study we used flow cytometry to assess immune-competent cells at the lesion site. We observed a morphine-induced increase in the overall number of CD11b+ cells, with marked effects on microglia, in SCI subjects. Next, to investigate whether this increase in the inflammatory profile is necessary to produce morphine's effects, we challenged morphine treatment with minocycline. We found that pre-treatment with minocycline reduced the morphine-induced increase in microglia at the lesion site. More importantly, minocycline also blocked the adverse effects of morphine on recovery of function without disrupting the analgesic efficacy of this opioid. Together, our findings suggest that following SCI, morphine may exacerbate the inflammatory response, increasing cell death at the lesion site and negatively affecting functional recovery.
Asunto(s)
Minociclina/metabolismo , Minociclina/farmacología , Traumatismos de la Médula Espinal/tratamiento farmacológico , Analgésicos Opioides/administración & dosificación , Analgésicos Opioides/efectos adversos , Analgésicos Opioides/farmacología , Animales , Inflamación/metabolismo , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Masculino , Microglía/metabolismo , Morfina/efectos adversos , Morfina/metabolismo , Morfina/farmacología , Dolor/metabolismo , Ratas , Ratas Sprague-Dawley , Recuperación de la Función/efectos de los fármacos , Médula Espinal/metabolismo , Traumatismos de la Médula Espinal/metabolismoRESUMEN
Our previous studies showed that Insulin-like Growth Factor (IGF)-1 reduced blood brain barrier permeability and decreased infarct volume caused by middle cerebral artery occlusion (MCAo) in middle aged female rats. Similarly, cultures of primary brain microvessel endothelial cells from middle-aged female rats and exposed to stroke-like conditions (oxygen glucose deprivation; OGD) confirmed that IGF-1 reduced dye transfer across this cell monolayer. Surprisingly, IGF-1 did not attenuate endothelial cell death caused by OGD. To reconcile these findings, the present study tested the hypothesis that, at the earliest phase of ischemia, IGF-1 promotes barrier function by increasing anchorage and stabilizing cell geometry of surviving endothelial cells. Cultures of human brain microvessel endothelial cells were subject to oxygen-glucose deprivation (OGD) in the presence of IGF-1, IGF-1â¯+â¯JB-1 (IGFR inhibitor) or vehicle. OGD disrupted the cell monolayer and reduced cell-cell interactions, which was preserved in IGF-1-treated cultures and reversed by concurrent treatment with JB-1. IGF-1-mediated preservation of the endothelial monolayer was reversed with LY294002 treatment, but not by Rapamycin, indicating that IGF-1â¯s actions on cell-cell contacts are likely mediated via the PI3K pathway. In vivo, microvessel morphology was evaluated in middle-aged female rats that were subjected to ischemia by MCAo, and treated ICV with IGFI, IGF-1â¯+â¯JB-1, or artificial CSF (aCSF; vehicle) after reperfusion. Compared to vehicle controls, IGF-1 treated animals displayed larger microvessel diameters in the peri-infarct area and increased staining density for vinculin, an anchorage protein. Both these measures were reversed by concurrent IGF-1â¯+â¯JB-1 treatment. Moreover these effects were restricted to 24â¯h after ischemia-reperfusion and no treatment effects were seen at 5d post stroke. Collectively, these data suggest that in the earliest hours during ischemia, IGF-1 promotes receptor-mediated anchorage of endothelial cells, and its actions may be accurately characterized as vasculoprotective.
Asunto(s)
Isquemia Encefálica/tratamiento farmacológico , Citoesqueleto/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Microvasos/efectos de los fármacos , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/metabolismo , Isquemia Encefálica/metabolismo , Línea Celular , Citoesqueleto/metabolismo , Endotelio Vascular/metabolismo , Femenino , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Microvasos/metabolismo , Ratas , Ratas Sprague-Dawley , Resultado del TratamientoRESUMEN
Middle aged female rats sustain larger stroke infarction and disability than younger female rats. This older group also shows age-related reduction of insulin like growth factor (IGF)-1 in serum and in astrocytes, a cell type necessary for poststroke recovery. To determine the impact of astrocytic IGF-1 for ischemic stroke, these studies tested the hypothesis that gene transfer of IGF-1 to astrocytes will improve stroke outcomes in middle aged female rats. Middle aged (10-12 month old), acyclic female rats were injected with recombinant adeno-associated virus serotype 5 (AAV5) packaged with the coding sequence of the human (h)IGF-1 gene downstream of an astrocyte-specific promoter glial fibrillary acidic protein (GFAP) (AAV5-GFP-hIGF-1) into the striatum and cortex. The AAV5-control consisted of an identical shuttle vector construct without the hIGF-1 gene (AAV5-GFAP-control). Six to eight weeks later, animals underwent transient (90 min) middle cerebral artery occlusion via intraluminal suture. While infarct volume was not altered, AAV5-GFAP-hIGF-1 treatment significantly improved blood pressure and neurological score in the early acute phase of stroke (2 days) and sensory-motor performance at both the early and late (5 days) acute phase of stroke. AAV5-GFAP-hIGF-1 treatment also reduced circulating serum levels of GFAP, a biomarker for blood brain barrier permeability. Flow cytometry analysis of immune cells in the brain at 24 hr poststroke showed that AAV5-GFAP-hIGF-1 altered the type of immune cells trafficked to the ischemic hemisphere, promoting an anti-inflammatory profile. Collectively, these studies show that targeted enhancement of IGF-1 in astrocytes of middle-aged females improves stroke-induced behavioral impairment and neuroinflammation.
Asunto(s)
Envejecimiento , Astrocitos/fisiología , Infarto de la Arteria Cerebral Media/terapia , Factor I del Crecimiento Similar a la Insulina/uso terapéutico , Transducción Genética/métodos , Animales , Antígenos CD/metabolismo , Presión Sanguínea/fisiología , Peso Corporal/fisiología , Infarto Encefálico/etiología , Infarto Encefálico/terapia , Modelos Animales de Enfermedad , Transportador 1 de Aminoácidos Excitadores/metabolismo , Femenino , Trastornos Neurológicos de la Marcha/etiología , Trastornos Neurológicos de la Marcha/terapia , Fuerza de la Mano/fisiología , Infarto de la Arteria Cerebral Media/complicaciones , Factor I del Crecimiento Similar a la Insulina/genética , Factor I del Crecimiento Similar a la Insulina/metabolismo , Movimiento/fisiología , Examen Neurológico , Ratas , Ratas Sprague-Dawley , Reflejo de Enderezamiento/fisiologíaRESUMEN
In comparison with young females, middle-aged female rats sustain greater cerebral infarction and worse functional recovery after stroke. These poorer stroke outcomes in middle-aged females are associated with an age-related reduction in IGF-I levels. Poststroke IGF-I treatment decreases infarct volume in older females and lowers the expression of cytokines in the ischemic hemisphere. IGF-I also reduces transfer of Evans blue dye to the brain, suggesting that this peptide may also promote blood-brain barrier function. To test the hypothesis that IGF-I may act at the blood-brain barrier in ischemic stroke, 2 approaches were used. In the first approach, middle-aged female rats were subjected to middle cerebral artery occlusion and treated with IGF-I after reperfusion. Mononuclear cells from the ischemic hemisphere were stained for CD4 or triple-labeled for CD4/CD25/FoxP3 and subjected to flow analyses. Both cohorts of cells were significantly reduced in IGF-I-treated animals compared with those in vehicle controls. Reduced trafficking of immune cells to the ischemic site suggests that blood-brain barrier integrity is better maintained in IGF-I-treated animals. The second approach directly tested the effect of IGF-I on barrier function of aging endothelial cells. Accordingly, brain microvascular endothelial cells from middle-aged female rats were cultured ex vivo and subjected to ischemic conditions (oxygen-glucose deprivation). IGF-I treatment significantly reduced the transfer of fluorescently labeled BSA across the endothelial monolayer as well as cellular internalization of fluorescein isothiocyanate-BSA compared with those in vehicle-treated cultures, Collectively, these data support the hypothesis that IGF-I improves blood-brain barrier function in middle-aged females.