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BACKGROUND AND OBJECTIVE: Stroke, a leading cause of mortality and disability, characterized by neuronal death, can be induced by a reduction or interruption of blood flow. In this study, the role of Alamandine, a new peptide of the renin-angiotensin system, was evaluated in in-vitro and in-vivo brain ischemia models. METHODS: In the in-vitro model, hippocampal slices from male C57/Bl6 mice were placed in a glucose-free aCSF solution and bubbled with 95% N2 and 5% CO2 to mimic brain ischemia. An Alamandine concentration-response curve was generated to evaluate cell damage, glutamatergic excitotoxicity, and cell death. In the in-vivo model, cerebral ischemia/ reperfusion was induced by bilateral occlusion of common carotid arteries (BCCAo-untreated) in SD rats. An intracerebroventricular injection of Alamandine was given 20-30 min before BCCAo. Animals were subjected to neurological tests 24 h and 72 h after BCCAo. Cytokine levels, oxidative stress markers, and immunofluorescence were assessed in the brain 72 h after BCCAo. RESULTS: Alamandine was able to protect brain slices from cellular damage, excitotoxicity and cell death. When the Alamandine receptor was blocked, protective effects were lost. ICV injection of Alamandine attenuated neurological deficits of animals subjected to BCCAo and reduced the number of apoptotic neurons/cells. Furthermore, Alamandine induced anti-inflammatory effects in BCCAo animals as shown by reductions in TNFα, IL- 1ß, IL-6, and antioxidant effects through attenuation of the decreased SOD, catalase, and GSH activities in the brain. CONCLUSION: This study showed, for the first time, a neuroprotective role for Alamandine in different ischemic stroke models.
Assuntos
Isquemia Encefálica , AVC Isquêmico , Fármacos Neuroprotetores , Traumatismo por Reperfusão , Acidente Vascular Cerebral , Animais , Isquemia Encefálica/metabolismo , Modelos Animais de Doenças , Humanos , Masculino , Camundongos , Neuroproteção , Fármacos Neuroprotetores/farmacologia , Fármacos Neuroprotetores/uso terapêutico , Oligopeptídeos , Ratos , Ratos Sprague-Dawley , Traumatismo por Reperfusão/metabolismo , Acidente Vascular Cerebral/tratamento farmacológicoRESUMO
Abnormal calcium influx and glutamatergic excitotoxicity have been extensively associated with neuronal death in Huntington's disease (HD), a genetic movement disorder. Currently, there is no effective treatment for this fatal condition. The neurotoxin Phα1ß has demonstrated therapeutic effects as a calcium channel blocker, for example during pain control. However, little is known about its neuroprotective effect in HD. Herein, we investigated if Phα1ß is effective in inhibiting neuronal cell death in the BACHD mouse model for HD. We performed intrastriatal injection of Phα1ß in WT and BACHD mice. No side effects or unusual behaviors were observed upon Phα1ß administration. Using three different motor behavior tests, we observed that injection of the toxin in BACHD mice greatly improved the animals' motor-force as seen in the Wire-hang test, and also the locomotor performance, according to the Open field test. NeuN labeling for mature neuron detection revealed that Phα1ß toxin promoted neuronal preservation in the striatum and cortex, when injected locally. Intrastriatal injection of Phα1ß was not able to preserve neurons from the spinal cord and also not revert muscle atrophy in BACHD mice. Finally, we observed that Phα1ß might, at least in part, exert its protective effect by decreasing L-glutamate, measured in cerebrospinal fluid. Our data provide evidence of a novel neuroprotector effect of Phα1ß, paving a path for the development of new approaches to treat HD motor symptoms.
Assuntos
Doença de Huntington/tratamento farmacológico , Fármacos Neuroprotetores/administração & dosagem , Venenos de Aranha/administração & dosagem , Animais , Modelos Animais de Doenças , Ácido Glutâmico/metabolismo , Doença de Huntington/patologia , Camundongos , Camundongos Transgênicos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/patologia , Neurônios/efeitos dos fármacos , Medula Espinal/efeitos dos fármacos , Medula Espinal/patologiaRESUMO
Stroke is one of the leading causes of mortality and morbidity worldwide. Due to its poor prognosis, there is a major negative impact on the patients and their family's life quality. However, despite the severity of this pathology tissue plasminogen activator (tPA) is the only FDA approved treatment for ischemic stroke. Moreover, there is no effective treatment for hemorrhagic stroke and only some palliative procedures are often performed to improve the patient's quality of life. Considering this, nanotechnology can offer some advantages for the development of new therapies for stroke. Among the various types of nanomaterials, liposomes are the most extensively studied due to their biocompatibility, biodegradability, and low toxicity. Liposomes, as a drug delivery system, are able to mask therapeutic compounds and allow their passage through the blood-brain barrier. Liposomes also protect drugs from degradation in a biological environment, increasing the circulation time and accumulation in the target tissue. Hence, this review highlights the potential of liposomes applications for delivery of therapeutic compounds for treating stroke.
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Sistemas de Liberação de Medicamentos/métodos , Lipossomos/uso terapêutico , Acidente Vascular Cerebral/tratamento farmacológico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Isquemia Encefálica/tratamento farmacológico , Modelos Animais de Doenças , Humanos , Lipossomos/metabolismo , Qualidade de Vida , Ativador de Plasminogênio Tecidual/farmacologiaRESUMO
The complexity of the central nervous system (CNS), its limited self-repairing capacity and the ineffective delivery of most CNS drugs to the brain contribute to the irreversible and progressive nature of many neurological diseases and also the severity of the outcome. Therefore, neurological disorders belong to the group of pathologies with the greatest need of new technologies for diagnostics and therapeutics. In this scenario, nanotechnology has emerged with innovative and promising biomaterials and tools. This review focuses on ischemic stroke, being one of the major causes of death and serious long-term disabilities worldwide, and the recent advances in the study of liposomes and carbon nanomaterials for therapeutic and diagnostic purposes. Ischemic stroke occurs when blood flow to the brain is insufficient to meet metabolic demand, leading to a cascade of physiopathological events in the CNS including local blood brain barrier (BBB) disruption. However, to date, the only treatment approved by the FDA for this pathology is based on the potentially toxic tissue plasminogen activator. The techniques currently available for diagnosis of stroke also lack sensitivity. Liposomes and carbon nanomaterials were selected for comparison in this review, because of their very distinct characteristics and ranges of applications. Liposomes represent a biomimetic system, with composition, structural organization and properties very similar to biological membranes. On the other hand, carbon nanomaterials, which are not naturally encountered in the human body, exhibit new modes of interaction with biological molecules and systems, resulting in unique pharmacological properties. In the last years, several neuroprotective agents have been evaluated under the encapsulated form in liposomes, in experimental models of stroke. Effective drug delivery to the brain and neuroprotection were achieved using stealth liposomes bearing targeting ligands onto their surface for brain endothelial cells and ischemic tissues receptors. Carbon nanomaterials including nanotubes, fullerenes and graphene, started to be investigated and potential applications for therapy, biosensing and imaging have been identified based on their antioxidant action, their intrinsic photoluminescence, their ability to cross the BBB, transitorily decrease the BBB paracellular tightness, carry oligonucleotides and cells and induce cell differentiation. The potential future developments in the field are finally discussed.
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Although High Intensity Interval Training (HIIT) are being associated to increase cardiovascular and metabolic adaptation, there is controversy and limited information about the effects of HIIT on hippocampal oxidative stress, pro- and anti-inflammatory cytokines balance and neurotrophic status. Thus, this study evaluated the effects of six weeks of HIIT on hippocampal redox state (oxidative damage and enzymatic and non-enzymatic antioxidant defenses), neuroimmune mediators (TNFα, IL-6, IL-1ß and IL-10) and brain-derived neurotrophic (BDNF) levels. After six weeks of HIIT young adults male Wistar rats presented reduced oxidative damage and increased enzymatic (superoxide dismutase) and non-enzymatic activity in hippocampus. Moreover HIIT induced a decrease in cytokine content (TNFα, IL-6, IL-1ß and IL-10) and enhanced hippocampal BDNF levels. In conclusion, the present study showed for the first time a positive effect of six weeks of HIIT on reducing hippocampal oxidative stress by decreasing lipoperoxidation and inflammatory markers, as well enhancing antioxidant defenses and BDNF content.
Assuntos
Fator Neurotrófico Derivado do Encéfalo/metabolismo , Citocinas/metabolismo , Treinamento Intervalado de Alta Intensidade , Hipocampo/fisiologia , Homeostase/fisiologia , Estresse Oxidativo/fisiologia , Animais , Antioxidantes/metabolismo , Catalase/metabolismo , Peroxidação de Lipídeos/efeitos dos fármacos , Peroxidação de Lipídeos/fisiologia , Masculino , Ratos , Ratos Wistar , Superóxido Dismutase/metabolismo , Substâncias Reativas com Ácido Tiobarbitúrico/metabolismo , Fatores de TempoRESUMO
Biomaterials composed of mammalian extracellular matrix (ECM) promote constructive tissue remodeling with minimal scar tissue formation in many anatomical sites. However, the optimal shape and form of ECM scaffold for each clinical application can vary markedly. ECM hydrogels have been shown to promote chemotaxis and differentiation of neuronal stem cells, but minimally invasive delivery of such scaffold materials to the central nervous system (CNS) would require an injectable form. These ECM materials can be manufactured to exist in fluid phase at room temperature, while forming hydrogels at body temperature in a concentration-dependent fashion. Implantation into the lesion cavity after a stroke could hence provide a means to support endogenous repair mechanisms. Herein, we characterize the rheological properties of an ECM hydrogel composed of urinary bladder matrix (UBM) that influence its delivery and in vivo interaction with host tissue. There was a notable concentration-dependence in viscosity, stiffness, and elasticity; all characteristics important for minimally invasive intracerebral delivery. An efficient MRI-guided injection with drainage of fluid from the cavity is described to assess in situ hydrogel formation and ECM retention at different concentrations (0, 1, 2, 3, 4, and 8mg/mL). Only ECM concentrations >3mg/mL gelled within the stroke cavity. Lower concentrations were not retained within the cavity, but extensive permeation of the liquid phase ECM into the peri-infarct area was evident. The concentration of ECM hydrogel is hence an important factor affecting gelation, host-biomaterial interface, as well intra-lesion distribution. STATEMENT OF SIGNIFICANCE: Extracellular matrix (ECM) hydrogel promotes constructive tissue remodeling in many tissues. Minimally invasive delivery of such scaffold materials to the central nervous system (CNS) would require an injectable form that exists in fluid phase at room temperature, while forming hydrogels at body temperature in a concentration-dependent fashion. We here report the rheological characterization of an injectable ECM hydrogel and its concentration-dependent delivery into a lesion cavity formed after a stroke based on MRI-guidance. The concentration of ECM determined its retention within the cavity or permeation into tissue and hence influenced its interaction with the host brain. This study demonstrates the importance of understanding the structure-function relationship of biomaterials to guide particular clinical applications.
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Matriz Extracelular/química , Hidrogéis/administração & dosagem , Hidrogéis/química , Infarto da Artéria Cerebral Média/tratamento farmacológico , Bexiga Urinária/química , Animais , Relação Dose-Resposta a Droga , Hemostáticos/administração & dosagem , Hemostáticos/química , Infarto da Artéria Cerebral Média/patologia , Masculino , Teste de Materiais , Transição de Fase , Ratos Sprague-Dawley , Resistência ao Cisalhamento , Suínos , Resultado do Tratamento , ViscosidadeRESUMO
It is well known that estradiol (E2) replacement therapy is effective on restoring memory deficits and mood disorders that may occur during natural menopause or after surgical ovarian removal (ovariectomy, OVX). However, it is still unknown the effectiveness of acute and localized E2 administration on the effects of chronic OVX. Here we tested the hypothesis that the intra-hippocampal E2 infusion, as well as specific agonists of estrogen receptors (ERs) alpha (ERα) and beta (ERß), are able to mend novel object recognition (NOR) memory deficit and depressive-like behavior caused by 12 weeks of OVX. We found that both ERα and ERß activation, at earlier stages of consolidation, recovered the NOR memory deficit caused by 12 w of OVX. Conversely, only the ERß activation was effective in decreasing the depressive-like behavior caused by 12 w of OVX. Furthermore, we investigated the effect of OVX on hippocampal volume and ERs expression. The structural MRI showed no alteration in the hippocampus volume of 12 w OVX animals. Interestingly, ERα expression in the hippocampus decreased after one week of OVX, but increased in 12 w OVX animals. Overall, we may conclude that the chronic estrogen deprivation, induced by 12 weeks of OVX, modulates the hippocampal ERα expression and induces NOR memory deficit and depressive-like behaviors. Nonetheless, it is noteworthy that the acute effects of E2 on NOR memory and depressive-like behavior are still apparent even after 12 weeks of OVX.
Assuntos
Depressão/etiologia , Estradiol/farmacologia , Receptor alfa de Estrogênio/metabolismo , Receptor beta de Estrogênio/metabolismo , Hipocampo/metabolismo , Transtornos da Memória/etiologia , Ovariectomia/efeitos adversos , Animais , Depressão/tratamento farmacológico , Depressão/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Transtornos da Memória/tratamento farmacológico , Transtornos da Memória/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Modelos AnimaisRESUMO
It is well known that physical exercise has positive effects on cognitive functions and hippocampal plasticity. However, the underlying mechanisms have remained to be further investigated. Here we investigated the hypothesis that the memory-enhancement promoted by physical exercise relies on facilitation of the endocannabinoid system. We observed that the spatial memory tested in the object location paradigm did not persist in sedentary mice, but could be improved by 1 week of treadmill running. In addition, exercise up-regulated CB1 receptor and BDNF expression in the hippocampus. To verify if these changes required CB1 activation, we treated the mice with the selective antagonist, AM251, before each period of physical activity. In line with our hypothesis, this drug prevented the exercise-induced memory enhancement and BDNF expression. Furthermore, AM251 reduced CB1 expression. To test if facilitating the endocannabinoid system signaling would mimic the alterations observed after exercise, we treated sedentary animals during 1 week with the anandamide-hydrolysis inhibitor, URB597. Mice treated with this drug recognized the object in a new location and have increased levels of CB1 and BDNF expression in the hippocampus, showing that potentiating the endocanabinoid system equally benefits memory. In conclusion, the favorable effects of exercise upon spatial memory and BDNF expression depend on facilitation of CB1 receptor signaling, which can be mimic by inhibition of anandamide hydrolysis in sedentary animals. Our results suggest that, at least in part, the promnesic effect of the exercise is dependent of CB1 receptor activation and is mediated by BDNF.
Assuntos
Hipocampo/metabolismo , Aprendizagem em Labirinto/fisiologia , Memória/fisiologia , Condicionamento Físico Animal/fisiologia , Receptor CB1 de Canabinoide/metabolismo , Animais , Fator Neurotrófico Derivado do Encéfalo/metabolismo , Moduladores de Receptores de Canabinoides/farmacologia , Endocanabinoides/metabolismo , Masculino , CamundongosRESUMO
The critical window hypothesis predicts that estrogen replacement therapy (ERT) must be administered early on the menopause or ovariectomy (OVX) to positively affect cognition. However, the neural substrates, underling the time dependent efficacy of ERT, are still not completely known. In order to address this issue, we submitted female mice to 12 weeks of OVX followed by 5 weeks of chronic ERT (OVX(E2)). Within the first 12 weeks, the OVX animals showed a progressive compromised performance in the object recognition memory (ORM) task. After ERT, OVXE2 mice, but not the control group (OVXoil), were able to recognize the new object in the test session. Further, we evaluated the c-Fos expression in hippocampus, perirhinal cortex (PC) and central amygdala (CeA) of OVXoil and OVX(E2) mice, after context exposure (CTX) or object exploration (OBJ). We observed that ERT increased c-Fos expression unspecifically for CTX and OBJ. In addition, only the OVX(E2) group showed significantly higher c-Fos expression in the PC and CeA after object exploration. Thus, our results showed that delayed chronic ERT improves ORM (compromised by OVX) and increases constitutive c-Fos expression in temporal lobe regions. Furthermore, we showed for the first time that PC and CeA, but not the hippocampus, present a distinct pattern of activation in response to object exploration in ovariectomized females that underwent delayed-ERT.
Assuntos
Encéfalo/efeitos dos fármacos , Estradiol/farmacologia , Terapia de Reposição de Estrogênios/métodos , Estrogênios/farmacologia , Menopausa/fisiologia , Proteínas Proto-Oncogênicas c-fos/efeitos dos fármacos , Reconhecimento Psicológico/fisiologia , Tonsila do Cerebelo/efeitos dos fármacos , Tonsila do Cerebelo/metabolismo , Animais , Encéfalo/metabolismo , Feminino , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Menopausa/efeitos dos fármacos , Menopausa/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Ovariectomia , Proteínas Proto-Oncogênicas c-fos/metabolismo , Reconhecimento Psicológico/efeitos dos fármacos , Lobo Temporal/efeitos dos fármacos , Lobo Temporal/metabolismo , Fatores de TempoRESUMO
Although it is well known that regular exercise may promote neuroprotection, the mechanisms underlying this effect are still not fully understood. We investigated if swim training promotes neuroprotection by potentiating antioxidant pathways, thereby decreasing the effects of oxidative stress on glutamate and nitric oxide release. Male Wistar rats (n=36) were evenly randomized into a trained group (TRA) (5 days/week, 8 weeks, 30 min) and a sedentary group (SED). Forty-eight hours after the last session of exercise, animals were killed and brain was collected for in vitro ischemia. Cortical slices were divided into two groups: a group in which oxidative stress was induced by oxygen and glucose deprivation (OGD), and a group of non-deprived controls (nOGD). Interestingly, exercise by itself increased superoxide dismutase activity (nOGD, SED vs. TRA animals) with no effect on pro-oxidative markers. In fact, TRA-OGD slices showed lowered levels of lactate dehydrogenase when compared with SED-OGD controls, reinforcing the idea that exercise affords a neuroprotective effect. We also demonstrated that exercise decreased glutamate and nitrite release as well as lipid membrane damage in the OGD cortical slices. Our data suggest that under conditions of metabolic stress, swim training prevents oxidative damage caused by glutamate and nitric oxide release.