RESUMEN
Ischemic stroke is a significant global health issue, ranking fifth among all causes of death and a leading cause of serious long-term disability. Ischemic stroke leads to severe outcomes, including permanent brain damage and neuronal dysfunction. Therefore, decreasing and preventing neuronal injuries caused by stroke has been the focus of therapeutic research. In recent years, many studies have shown that fluctuations in hormonal levels influence the prognosis of ischemic stroke. Thus, it is relevant to understand the role of hormones in the pathophysiological mechanisms of ischemic stroke for preventing and treating this health issue. Here, we investigate the contribution of the prolactin/vasoinhibin axis, an endocrine system regulating blood vessel growth, immune processes, and neuronal survival, to the pathophysiology of ischemic stroke. Male mice with brain overexpression of prolactin or vasoinhibin by adeno-associated virus (AAV) intracerebroventricular injection or lacking the prolactin receptor (Prlr-/-) were exposed to transient middle cerebral artery occlusion (tMCAO) for 45 min followed by 48 h of reperfusion. Overexpression of vasoinhibin or the absence of the prolactin receptor led to an increased lesion volume and decreased survival rates in mice following tMCAO, whereas overexpression of prolactin had no effect. In addition, astrocytic distribution in the penumbra was altered, glial fibrillary acidic protein and S100b mRNA expressions were reduced, and interleukin-6 mRNA expression increased in the ischemic hemisphere of mice overexpressing vasoinhibin. Of note, prolactin receptor-null mice (Prlr-/-) showed a marked increase in serum vasoinhibin levels. Furthermore, vasoinhibin decreased astrocyte numbers in mixed hippocampal neuron-glia cultures. These observations suggest that increased vasoinhibin levels may hinder astrocytes' protective reactivity. Overall, this study suggests the involvement of the prolactin/vasoinhibin axis in the pathophysiology of ischemic stroke-induced brain injury and provides insights into the impact of its dysregulation on astrocyte reactivity and lesion size. Understanding these mechanisms could help develop therapeutic interventions in ischemic stroke and other related neurological disorders.
Asunto(s)
Proteínas de Ciclo Celular , Gliosis , Prolactina , Receptores de Prolactina , Animales , Prolactina/metabolismo , Masculino , Ratones , Gliosis/patología , Gliosis/metabolismo , Receptores de Prolactina/metabolismo , Receptores de Prolactina/genética , Proteínas de Ciclo Celular/metabolismo , Proteínas de Ciclo Celular/genética , Ratones Endogámicos C57BL , Astrocitos/metabolismo , Astrocitos/patología , Ratones Noqueados , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Infarto de la Arteria Cerebral Media/patología , Infarto de la Arteria Cerebral Media/metabolismoAsunto(s)
Diplopía/complicaciones , Accidente Cerebrovascular Isquémico/complicaciones , Accidente Cerebrovascular Isquémico/diagnóstico por imagen , Enfermedades del Nervio Oculomotor/diagnóstico por imagen , Enfermedades del Nervio Oculomotor/etiología , Adulto , Femenino , Humanos , Accidente Cerebrovascular Isquémico/patología , Mesencéfalo/diagnóstico por imagen , Mesencéfalo/patología , Neurología/educaciónRESUMEN
Cells undergoing hypoxia experience intense cytoplasmic calcium (Ca2+) overload. High concentrations of intracellular calcium ([Ca2+]i) can trigger cell death in the neural tissue, a hallmark of stroke. Neural Ca2+ homeostasis involves regulation by the Na+/Ca2+ exchanger (NCX). Previous data published by our group showed that a product of the enzymatic depolymerization of heparin by heparinase, the unsaturated trisulfated disaccharide (TD; ΔU, 2S-GlcNS, 6S), can accelerate Na+/Ca2+ exchange via NCX, in hepatocytes and aorta vascular smooth muscle cells. Thus, the objective of this work was to verify whether TD could act as a neuroprotective agent able to prevent neuronal cell death by reducing [Ca2+]i. Pretreatment of N2a cells with TD reduced [Ca2+]i rise induced by thapsigargin and increased cell viability under [Ca2+]I overload conditions and in hypoxia. Using a murine model of stroke, we observed that pretreatment with TD decreased cerebral infarct volume and cell death. However, when mice received KB-R7943, an NCX blocker, the neuroprotective effect of TD was abolished, strongly suggesting that this neuroprotection requires a functional NCX to happen. Thus, we propose TD-NCX as a new therapeutic axis for the prevention of neuronal death induced by [Ca2+]i overload.
Asunto(s)
Disacáridos/farmacología , Heparina/análogos & derivados , Accidente Cerebrovascular Isquémico/prevención & control , Fármacos Neuroprotectores/farmacología , Animales , Calcio/metabolismo , Muerte Celular/efectos de los fármacos , Hipoxia de la Célula/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , Disacáridos/química , Heparina/química , Heparina/farmacología , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Masculino , Ratones Endogámicos C57BL , Neuronas/efectos de los fármacos , Neuronas/patología , Fármacos Neuroprotectores/química , Tapsigargina/farmacología , Tiourea/análogos & derivados , Tiourea/farmacologíaRESUMEN
Neuroinflammation triggered by the expression of damaged-associated molecular patterns released from dying cells plays a critical role in the pathogenesis of ischemic stroke. However, the benefits from the control of neuroinflammation in the clinical outcome have not been established. In this study, the effectiveness of intranasal, a highly efficient route to reach the central nervous system, and intraperitoneal dexamethasone administration in the treatment of neuroinflammation was evaluated in a 60-min middle cerebral artery occlusion (MCAO) model in C57BL/6 male mice. We performed a side-by-side comparison using intranasal versus intraperitoneal dexamethasone, a timecourse including immediate (0 h) or 4 or 12 h poststroke intranasal administration, as well as 4 intranasal doses of dexamethasone beginning 12 h after the MCAO versus a single dose at 12 h to identify the most effective conditions to treat neuroinflammation in MCAO mice. The best results were obtained 12 h after MCAO and when mice received a single dose of dexamethasone (0.25 mg/kg) intranasally. This treatment significantly reduced mortality, neurological deficits, infarct volume size, blood-brain barrier permeability in the somatosensory cortex, inflammatory cell infiltration, and glial activation. Our results demonstrate that a single low dose of intranasal dexamethasone has neuroprotective therapeutic effects in the MCAO model, showing a better clinical outcome than the intraperitoneal administration. Based on these results, we propose a new therapeutic approach for the treatment of the damage process that accompanies ischemic stroke.
Asunto(s)
Antiinflamatorios/administración & dosificación , Lesiones Encefálicas/tratamiento farmacológico , Isquemia Encefálica/tratamiento farmacológico , Dexametasona/administración & dosificación , Accidente Cerebrovascular Isquémico/tratamiento farmacológico , Administración Intranasal , Animales , Barrera Hematoencefálica/efectos de los fármacos , Barrera Hematoencefálica/patología , Encéfalo/efectos de los fármacos , Encéfalo/patología , Lesiones Encefálicas/mortalidad , Lesiones Encefálicas/patología , Isquemia Encefálica/mortalidad , Isquemia Encefálica/patología , Infarto de la Arteria Cerebral Media/tratamiento farmacológico , Infarto de la Arteria Cerebral Media/mortalidad , Infarto de la Arteria Cerebral Media/patología , Accidente Cerebrovascular Isquémico/mortalidad , Accidente Cerebrovascular Isquémico/patología , Masculino , Ratones , Ratones Endogámicos C57BLAsunto(s)
Células Endoteliales/inmunología , Trampas Extracelulares/inmunología , Accidente Cerebrovascular Isquémico/inmunología , Neutrófilos/inmunología , Fosfatidilserinas/metabolismo , Trombosis de la Vena/inmunología , Plaquetas/inmunología , Plaquetas/metabolismo , Plaquetas/patología , Células Endoteliales/metabolismo , Células Endoteliales/patología , Humanos , Accidente Cerebrovascular Isquémico/metabolismo , Accidente Cerebrovascular Isquémico/patología , Terapia Molecular Dirigida/métodos , Neutrófilos/metabolismo , Neutrófilos/patología , Activación Plaquetaria , Trombosis de la Vena/metabolismo , Trombosis de la Vena/patologíaRESUMEN
Depression and anxiety have been reported as the major neuropsychiatric consequences following stroke. Minocycline, a neuroprotective drug has minimized depressive symptoms in patients with major depressive disorders and anxiety-like symptoms. In addition, minocycline demonstrated efficacy and seemed a promising neuroprotective agent in acute stroke patients. The present studied evaluated the effects of minocycline treatment on the depression and anxiety-like behaviors, brain damage and expression of inflammatory and neuroprotective mediators after transient global cerebral ischemia in C57BL/6 mice. Brain ischemia was induced by bilateral occlusion of the common carotids (BCCAo) for 25 min and subsequent reperfusion. Sham and BCCAo animals received minocycline at a dose of 30 mg/kg by intraperitoneal injection during 14 days. The locomotor activity, depression and anxiety-like behaviors were assessed by open field, forced swim and elevated plus maze tests, respectively. Then, the brains were removed and processed to evaluate brain damage by histological and morphometric analysis, hippocampal neurodegeneration using Fluoro-Jade C histochemistry, microglial activity using iba-1 immunohistochemistry, brain levels of TNF, IFN-γ, IL-6, IL-10, IL-12p70 and CCL2 by CBA, CX3CL1 and BDNF by ELISA assays. The animals developed depression and anxiety-like behaviors post-stroke and minocycline treatment prevented those neurobehavioral changes. Moreover, minocycline-treated BCCAo animals showed less intense brain damage in the cerebral cortex, brainstem and cerebellum as well as significantly reduced hippocampal neurodegeneration. BCCAo groups exhibited up-regulation of some cytokines at day 14 after ischemia and brain levels of CX3CL1 and BDNF remained unaltered. Our data indicate that the depression and anxiety-like behavioral improvements promoted by minocycline treatment might be related to its neuroprotective effect after brain ischemia in mice.