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Cognitive decline in Parkinson's Disease (PD) is a prevalent and undertreated aspect of disease. Currently, no therapeutics adequately improve this aspect of disease. It has been previously shown that MAS receptor agonism via the glycosylated Angiotensin (1-7) peptide, PNA5, effectively reduces cognitive decline in models of vascular contributions to cognitive impairment and dementia (VCID). PNA5 has a brain/plasma ratio of 0.255 indicating good brain penetration. The goal of the present study was to determine if (1) systemic administration of PNA5 rescued cognitive decline in a mouse model of PD, and (2) if improvements in cognitive status could be correlated with changes to histopathological or blood plasma-based changes. Mice over-expressing human, wild-type α-synuclein (αSyn) under the Thy1 promoter (Thy1-αSyn mice, "line 61") were used as a model of PD with cognitive decline. Thy1-αSyn mice were treated with a systemic dose of PNA5, or saline (1 mg/kg/day) beginning at 4 months of age and underwent behavioral testing at 6 months, compared to WT. Subsequently, mice brains were analyzed for changes to brain pathology, and blood plasma was examined with a Multiplex Immunoassay for peripheral cytokine changes. Treatment with PNA5 reversed cognitive dysfunction measured by Novel Object Recognition and spontaneous alteration in a Y-maze in Thy1-αSyn mice. PNA5 treatment was specific to cognitive deficits, as fine-motor disturbances were unchanged. Enhanced cognition was associated with decreases in hippocampal inflammation and reductions in circulating levels of Macrophage Induced Protein (MIP-1ß). Additionally, neuronal loss was blunted within the CA3 hippocampal region of PNA5-treated αsyn mice. These data reveal that PNA5 treatment reduces cognitive dysfunction in a mouse model of PD. These changes are associated with decreased MIP-1ß levels in plasma identifying a candidate biomarker for target engagement. Thus, PNA5 treatment could potentially fill the therapeutic gap for cognitive decline in PD.
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Pain is the most significant impairment and debilitating challenge for patients with bone metastasis. Therefore, the primary objective of current therapy is to mitigate and prevent the persistence of pain. Thus, cancer-induced bone pain is described as a multifaceted form of discomfort encompassing both inflammatory and neuropathic elements. We have developed a novel non-addictive pain therapeutic, PNA6, that is a derivative of the peptide Angiotensin-(1-7) and binds the Mas receptor to decrease inflammation-related cancer pain. In the present study, we provide evidence that PNA6 attenuates inflammatory, chemotherapy-induced peripheral neuropathy (CIPN) and cancer pain confined to the long bones, exhibiting longer-lasting efficacious therapeutic effects. PNA6, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-ß-Lact)-amide, was successfully synthesized using solid phase peptide synthesis (SPPS). PNA6 significantly reversed inflammatory pain induced by 2% carrageenan in mice. A second murine model of platinum drug-induced painful peripheral neuropathy was established using oxaliplatin. Mice in the oxaliplatin-vehicle treatment groups demonstrated significant mechanical allodynia compared to the oxaliplatin-PNA6 treatment group mice. In a third study modeling a complex pain state, E0771 breast adenocarcinoma cells were implanted into the femur of female C57BL/6J wild-type mice to induce cancer-induced bone pain (CIBP). Both acute and chronic dosing of PNA6 significantly reduced the spontaneous pain behaviors associated with CIBP. These data suggest that PNA6 is a viable lead candidate for treating chronic inflammatory and complex neuropathic pain.
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Antineoplásicos , Neoplasias Ósseas , Neoplasias da Mama , Dor do Câncer , Neuralgia , Humanos , Camundongos , Feminino , Animais , Oxaliplatina/efeitos adversos , Dor do Câncer/tratamento farmacológico , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Neuralgia/induzido quimicamente , Neuralgia/tratamento farmacológico , Neuralgia/complicações , Hiperalgesia/induzido quimicamente , Hiperalgesia/tratamento farmacológico , Hiperalgesia/complicações , Neoplasias da Mama/tratamento farmacológico , Neoplasias Ósseas/complicações , Neoplasias Ósseas/tratamento farmacológico , Antineoplásicos/efeitos adversosRESUMO
It is well established that decreased brain blood flow, increased reactive oxygen species production (ROS), and pro-inflammatory mechanisms accelerate neurodegenerative disease progressions, including vascular cognitive impairment and dementia (VCID). Previous studies in our laboratory have shown that our novel glycosylated Angiotensin-(1-7) Mas receptor agonist PNA5 reverses cognitive deficits, decreases ROS production, and inhibits inflammatory cytokine production in our preclinical mouse model of VCID that is induced by chronic heart failure (VCID-HF). In the present study, the effects of VCID-HF and treatment with PNA5 on microglia activation, blood-brain-barrier (BBB) integrity, and neurovascular coupling were assessed in our mouse model of VCID-HF. Three-month-old male C57BL/6J mice were subjected to myocardial infarction (MI) to induce heart failure for four weeks and then treated with subcutaneous injections of extended-release PNA5. Microglia activation, BBB permeability, cerebral perfusion, and neurovascular coupling were assessed. Results show that in our VCID-HF model, there was an increase in microglial activation and recruitment within the CA1 and CA3 regions of the hippocampus, a disruption in BBB integrity, and a decrease in neurovascular coupling. Treatment with PNA5 reversed these neuropathological effects of VCID-HF, suggesting that PNA5 may be an effective disease-modifying therapy to treat and prevent VCID. This study identifies potential mechanisms by which heart failure may induce VCID and highlights the possible mechanisms by which treatment with our novel glycosylated Angiotensin-(1-7) Mas receptor agonist, PNA5, may protect cognitive function in our model of VCID.
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Introduction: Traumatic brain injury (TBI) is a leading cause of disability in the US. Angiotensin 1-7 (Ang-1-7), an endogenous peptide, acts at the G protein coupled MAS1 receptors (MASR) to inhibit inflammatory mediators and decrease reactive oxygen species within the CNS. Few studies have identified whether Ang-(1-7) decreases cognitive impairment following closed TBI. This study examined the therapeutic effect of Ang-(1-7) on secondary injury observed in a murine model of mild TBI (mTBI) in a closed skull, single injury model. Materials and methods: Male mice (n = 108) underwent a closed skull, controlled cortical impact injury. Two hours after injury, mice were administered either Ang-(1-7) (n = 12) or vehicle (n = 12), continuing through day 5 post-TBI, and tested for cognitive impairment on days 1-5 and 18. pTau, Tau, GFAP, and serum cytokines were measured at multiple time points. Animals were observed daily for cognition and motor coordination via novel object recognition. Brain sections were stained and evaluated for neuronal injury. Results: Administration of Ang-(1-7) daily for 5 days post-mTBI significantly increased cognitive function as compared to saline control-treated animals. Cortical and hippocampal structures showed less damage in the presence of Ang-(1-7), while Ang-(1-7) administration significantly changed the expression of pTau and GFAP in cortical and hippocampal regions as compared to control. Discussion: These are among the first studies to demonstrate that sustained administration of Ang-(1-7) following a closed-skull, single impact mTBI significantly improves neurologic outcomes, potentially offering a novel therapeutic modality for the prevention of long-term CNS impairment following such injuries.
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Heart failure (HF) causes decreased brain perfusion in older adults, and increased brain and systemic inflammation increases the risk of cognitive impairment and Alzheimer's disease (AD). Glycosylated Ang-(1-7) MasR agonists (PNA5) has shown improved bioavailability, stability, and brain penetration compared to Ang-(1-7) native peptide. Despite promising results and numerous potential applications, clinical applications of PNA5 glycopeptide are limited by its short half-life, and frequent injections are required to ensure adequate treatment for cognitive impairment. Therefore, sustained-release injectable formulations of PNA5 glycopeptide are needed to improve its bioavailability, protect the peptide from degradation, and provide sustained drug release over a prolonged time to reduce injection administration frequency. Two types of poly(D,L-lactic-co-glycolic acid) (PLGA) were used in the synthesis to produce nanoparticles (≈0.769−0.35 µm) and microparticles (≈3.7−2.4 µm) loaded with PNA5 (ester and acid-end capped). Comprehensive physicochemical characterization including scanning electron microscopy, thermal analysis, molecular fingerprinting spectroscopy, particle sizing, drug loading, encapsulation efficiency, and in vitro drug release were conducted. The data shows that despite the differences in the size of the particles, sustained release of PNA5 was successfully achieved using PLGA R503H polymer with high drug loading (% DL) and high encapsulation efficiency (% EE) of >8% and >40%, respectively. While using the ester-end PLGA, NPs showed poor sustained release as after 72 h, nearly 100% of the peptide was released. Also, lower % EE and % DL values were observed (10.8 and 3.4, respectively). This is the first systematic and comprehensive study to report on the successful design, particle synthesis, physicochemical characterization, and in vitro glycopeptide drug release of PNA5 in PLGA nanoparticles and microparticles.
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In critically ill COVID-19 patients, the risk of long-term neurological consequences is just beginning to be appreciated. While recent studies have identified that there is an increase in structural injury to the nervous system in critically ill COVID-19 patients, there is little known about the relationship of COVID-19 neurological damage to the systemic inflammatory diseases also observed in COVID-19 patients. The purpose of this pilot observational study was to examine the relationships between serum neurofilament light protein (NfL, a measure of neuronal injury) and co-morbid cardiovascular disease (CVD) and neurological complications in COVID-19 positive patients admitted to the intensive care unit (ICU). In this observational study of one-hundred patients who were admitted to the ICU in Tucson, Arizona between April and August 2020, 89 were positive for COVID-19 (COVID-pos) and 11 was COVID-negative (COVID-neg). A healthy control group (n=8) was examined for comparison. The primary outcomes and measures were subject demographics, serum NfL, presence and extent of CVD, diabetes, sequential organ failure assessment score (SOFA), presence of neurological complications, and blood chemistry panel data. COVID-pos patients in the ICU had significantly higher mean levels of Nfl (229.6 ± 163 pg/ml) compared to COVID-neg ICU patients (19.3 ± 5.6 pg/ml), Welch's t-test, p =.01 and healthy controls (12.3 ± 3.1 pg/ml), Welch's t-test p =.005. Levels of Nfl in COVID-pos ICU patients were significantly higher in patients with concomitant CVD and diabetes (n=35, log Nfl 1.6±.09), and correlated with higher SOFA scores (r=.5, p =.001). These findings suggest that in severe COVID-19 disease, the central neuronal and axonal damage in these patients may be driven, in part, by the level of systemic cardiovascular disease and peripheral inflammation. Understanding the contributions of systemic inflammatory disease to central neurological degeneration in these COVID-19 survivors will be important to the design of interventional therapies to prevent long-term neurological and cognitive dysfunction.
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The peptide hormone, angiotensin (Ang-(1-7)), produces anti-inflammatory and protective effects by inhibiting production and expression of many cytokines and adhesion molecules that are associated with a cytokine storm. While Ang-(1-7) has been shown to reduce inflammation and airway hyperreactivity in models of asthma, little is known about the effects of Ang-(1-7) during live respiratory infections. Our studies were developed to test if Ang-(1-7) is protective in the lung against overzealous immune responses during an infection with Mycoplasma pneumonia (Mp), a common respiratory pathogen known to provoke exacerbations in asthma and COPD patients. Wild type mice were treated with infectious Mp and a subset of was given either Ang-(1-7) or peptide-free vehicle via oropharyngeal delivery within 2 h of infection. Markers of inflammation in the lung were assessed within 24 h for each set of animals. During Mycoplasma infection, one high dose of Ang-(1-7) delivered to the lungs reduced neutrophilia and Muc5ac, as well as Tnf-α and chemokines (Cxcl1) associated with acute respiratory distress syndrome (ARDS). Despite decreased inflammation, Ang-(1-7)-treated mice also had significantly lower Mp burden in their lung tissue, indicating decreased airway colonization. Ang-(1-7) also had an impact on RAW 264.7 cells, a commonly used macrophage cell line, by dose-dependently inhibiting TNF-α production while promoting Mp killing. These new findings provide additional support to the protective role(s) of Ang1-7 in controlling inflammation, which we found to be highly protective against live Mp-induced lung inflammation.
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BACKGROUND: Decreased cerebral blood flow and systemic inflammation during heart failure (HF) increase the risk for vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer disease-related dementias (ADRD). We previously demonstrated that PNA5, a novel glycosylated angiotensin 1-7 (Ang-(1-7)) Mas receptor (MasR) agonist peptide, is an effective therapy to rescue cognitive impairment in our preclinical model of VCID. Neurofilament light (NfL) protein concentration is correlated with cognitive impairment and elevated in neurodegenerative diseases, hypoxic brain injury, and cardiac disease. The goal of the present study was to determine (1) if treatment with Ang-(1-7)/MasR agonists can rescue cognitive impairment and decrease VCID-induced increases in NfL levels as compared to HF-saline treated mice and, (2) if NfL levels correlate with measures of cognitive function and brain cytokines in our VCID model. METHODS: VCID was induced in C57BL/6 male mice via myocardial infarction (MI). At 5 weeks post-MI, mice were treated with daily subcutaneous injections for 24 days, 5 weeks after MI, with PNA5 or angiotensin 1-7 (500 microg/kg/day or 50 microg/kg/day) or saline (n = 15/group). Following the 24-day treatment protocol, cognitive function was assessed using the Novel Object Recognition (NOR) test. Cardiac function was measured by echocardiography and plasma concentrations of NfL were quantified using a Quanterix Simoa assay. Brain and circulating cytokine levels were determined with a MILLIPLEX MAP Mouse High Sensitivity Multiplex Immunoassay. Treatment groups were compared via ANOVA, significance was set at p < 0.05. RESULTS: Treatment with Ang-(1-7)/MasR agonists reversed VCID-induced cognitive impairment and significantly decreased NfL levels in our mouse model of VCID as compared to HF-saline treated mice. Further, NfL levels were significantly negatively correlated with cognitive scores and the concentrations of multiple pleiotropic cytokines in the brain. CONCLUSIONS: These data show that treatment with Ang-(1-7)/MasR agonists rescues cognitive impairment and decreases plasma NfL relative to HF-saline-treated animals in our VCID mouse model. Further, levels of NfL are significantly negatively correlated with cognitive function and with several brain cytokine concentrations. Based on these preclinical findings, we propose that circulating NfL might be a candidate for a prognostic biomarker for VCID and may also serve as a pharmacodynamic/response biomarker for therapeutic target engagement.
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Angiotensina I/agonistas , Angiotensina I/metabolismo , Disfunção Cognitiva/metabolismo , Citocinas/metabolismo , Demência Vascular/metabolismo , Proteínas de Neurofilamentos/metabolismo , Fragmentos de Peptídeos/agonistas , Fragmentos de Peptídeos/metabolismo , Angiotensina I/uso terapêutico , Animais , Biomarcadores/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/patologia , Demência Vascular/tratamento farmacológico , Demência Vascular/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fragmentos de Peptídeos/uso terapêutico , Prognóstico , Volume Sistólico/fisiologiaRESUMO
The peptide hormone Angiotensin (1-7), Ang (1-7) or (Asp-Arg-Val-Tyr-Ile-His-Pro), is an essential component of the renin-angiotensin system (RAS) peripherally and is an agonist of the Mas receptor centrally. Activation of this receptor in the CNS stimulates various biological activities that make the Ang (1-7)/MAS axis a novel therapeutic approach for the treatment of many diseases. The related O-linked glycopeptide, Asp-Arg-Val-Tyr-Ile-His-Ser-(O-ß-D-Glc)-amide (PNA5), is a biousian revision of the native peptide hormone Ang (1-7) and shows enhanced stability in vivo and greater levels of brain penetration. We have synthesized the native Ang (1-7) peptide and the glycopeptide, PNA5, and have formulated them for targeted respiratory delivery as inhalable dry powders. Solid phase peptide synthesis (SPPS) successfully produced Ang (1-7) and PNA5. Measurements of solubility and lipophilicity of raw Ang (1-7) and raw PNA5 using experimental and computational approaches confirmed that both the peptide and glycopeptide have high-water solubility and are amphipathic. Advanced organic solution spray drying was used to engineer the particles and produce spray-dried powders (SD) of both the peptide and the glycopeptide, as well as co-spray-dried powders (co-SD) with the non-reducing sugar and pharmaceutical excipient, trehalose. The native peptide, glycopeptide, SD, and co-SD powders were comprehensively characterized, and exhibited distinct glass transitions (Tg) consistent with the amorphous glassy state formation with Tgs that are compatible with use in vivo. The homogeneous particles displayed small sizes in the nanometer size range and low residual water content in the solid-state. Excellent aerosol dispersion performance with a human DPI device was demonstrated. In vitro human cell viability assays showed that Ang (1-7) and PNA5 are biocompatible and safe for different human respiratory and brain cells.
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PURPOSE OF REVIEW: Precision Aging® is a novel concept that we have recently employed to describe how the model of precision medicine can be used to understand and define the multivariate risks that drive age-related cognitive impairment (ARCI). Hypertension and cardiovascular disease are key risk factors for both brain function and cognitive aging. In this review, we will discuss the common mechanisms underlying the risk factors for both hypertension and ARCI and how the convergence of these mechanisms may be amplified in an individual to drive changes in brain health and accelerate cognitive decline. RECENT FINDINGS: Currently, our cognitive health span does not match our life span. Age-related cognitive impairment and preventing and treating ARCI will require an in-depth understanding of the interrelated risk factors, including individual genetic profiles, that affect brain health and brain aging. Hypertension and cardiovascular disease are important risk factors for ARCI. And, many of the risk factors for developing hypertension, such as diabetes, smoking, stress, viral infection, and age, are shared with the development of ARCI. We must first understand the mechanisms common to the converging risk factors in hypertension and ARCI and then design person-specific therapies to optimize individual brain health. The understanding of the convergence of shared risk factors between hypertension and ARCI is required to develop individualized interventions to optimize brain health across the life span. We will conclude with a discussion of possible steps that may be taken to decrease ARCI and optimize an individual's cognitive life span.
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Envelhecimento , Encéfalo/fisiopatologia , Disfunção Cognitiva , Hipertensão/complicações , Humanos , Medicina de Precisão , Fatores de RiscoRESUMO
Peptides are an important class of molecules with diverse biological activities. Many endogenous peptides, especially neuropeptides and peptide hormones, play critical roles in development and regulating homeostasis. Furthermore, as drug candidates their high receptor selectivity and potent binding leads to reduced off-target interactions and potential negative side effects. However, the therapeutic potential of peptides is severely hampered by their poor stability in vivo and low permeability across biological membranes. Several strategies have been successfully employed over the decades to address these concerns, and one of the most promising strategies is glycosylation. It has been demonstrated in numerous cases that glycosylation is an effective synthetic approach to improve the pharmacokinetic profiles and membrane permeability of peptides. The effects of glycosylation on peptide stability and peptide-membrane interactions in the context of blood-brain barrier penetration will be explored. Numerous examples of glycosylated analogues of endogenous peptides targeting class A and B G-protein coupled receptors (GPCRs) with an emphasis on O-linked glycopeptides will be reviewed. Notable examples of N-, S-, and C-linked glycopeptides will also be discussed. A small section is devoted to synthetic methods for the preparation of glycopeptides and requisite amino acid glycoside building blocks.
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Produtos Biológicos/farmacologia , Barreira Hematoencefálica/metabolismo , Glicopeptídeos/farmacologia , Peptídeos Opioides/farmacologia , Receptores Acoplados a Proteínas G/metabolismo , Sequência de Aminoácidos , Aminoácidos , Produtos Biológicos/isolamento & purificação , Produtos Biológicos/metabolismo , Barreira Hematoencefálica/efeitos dos fármacos , Sistema Nervoso Central/efeitos dos fármacos , Sistema Nervoso Central/metabolismo , Técnicas de Química Sintética , Glicopeptídeos/síntese química , Glicopeptídeos/classificação , Glicopeptídeos/metabolismo , Glicosídeos/química , Glicosídeos/metabolismo , Glicosilação , Humanos , Peptídeos Opioides/síntese química , Peptídeos Opioides/metabolismo , Estabilidade Proteica , Proteólise , Receptores Acoplados a Proteínas G/agonistas , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/genéticaRESUMO
The current "one size fits all" approach to our cognitive aging population is not adequate to close the gap between cognitive health span and lifespan. In this review article, we present a novel model for understanding, preventing, and treating age-related cognitive impairment (ARCI) based on concepts borrowed from precision medicine. We will discuss how multiple risk factors can be classified into risk categories because of their interrelatedness in real life, the genetic variants that increase sensitivity to, or ameliorate, risk for ARCI, and the brain drivers or common mechanisms mediating brain aging. Rather than providing a definitive model of risk for ARCI and cognitive decline, the Precision Aging model is meant as a starting point to guide future research. To that end, after briefly discussing key risk categories, genetic risks, and brain drivers, we conclude with a discussion of steps that must be taken to move the field forward.
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In humans, a first-degree family history of dementia (FH) is a well-documented risk factor for Alzheimer's disease (AD); however, the influence of FH on cognition across the lifespan is poorly understood. To address this issue, we developed an internet-based paired-associates learning (PAL) task and tested 59,571 participants between the ages of 18-85. FH was associated with lower PAL performance in both sexes under 65 years old. Modifiers of this effect of FH on PAL performance included age, sex, education, and diabetes. The Apolipoprotein E ε4 allele was also associated with lower PAL scores in FH positive individuals. Here we show, FH is associated with reduced PAL performance four decades before the typical onset of AD; additionally, several heritable and non-heritable modifiers of this effect were identified.
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Doença de Alzheimer/genética , Doença de Alzheimer/fisiopatologia , Cognição , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Apolipoproteína E4/genética , Escolaridade , Feminino , Humanos , Aprendizagem , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
Increasing evidence indicates that decreased brain blood flow, increased reactive oxygen species (ROS) production, and proinflammatory mechanisms accelerate neurodegenerative disease progression such as that seen in vascular contributions to cognitive impairment and dementia (VCID) and Alzheimer's disease and related dementias. There is a critical clinical need for safe and effective therapies for the treatment and prevention of cognitive impairment known to occur in patients with VCID and chronic inflammatory diseases such as heart failure (HF), hypertension, and diabetes. This study used our mouse model of VCID/HF to test our novel glycosylated angiotensin-(1-7) peptide Ang-1-6-O-Ser-Glc-NH2 (PNA5) as a therapy to treat VCID and to investigate circulating inflammatory biomarkers that may be involved. We demonstrate that PNA5 has greater brain penetration compared with the native angiotensin-(1-7) peptide. Moreover, after treatment with 1.0/mg/kg, s.c., for 21 days, PNA5 exhibits up to 10 days of sustained cognitive protective effects in our VCID/HF mice that last beyond the peptide half-life. PNA5 reversed object recognition impairment in VCID/HF mice and rescued spatial memory impairment. PNA5 activation of the Mas receptor results in a dose-dependent inhibition of ROS in human endothelial cells. Last, PNA5 treatment decreased VCID/HF-induced activation of brain microglia/macrophages and inhibited circulating tumor necrosis factor α, interleukin (IL)-7, and granulocyte cell-stimulating factor serum levels while increasing that of the anti-inflammatory cytokine IL-10. These results suggest that PNA5 is an excellent candidate and "first-in-class" therapy for treating VCID and other inflammation-related brain diseases.
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Angiotensina I/química , Angiotensina I/farmacologia , Disfunção Cognitiva/complicações , Disfunção Cognitiva/tratamento farmacológico , Demência Vascular/complicações , Memória/efeitos dos fármacos , Fragmentos de Peptídeos/química , Fragmentos de Peptídeos/farmacologia , Proteínas Proto-Oncogênicas/agonistas , Receptores Acoplados a Proteínas G/agonistas , Angiotensina I/farmacocinética , Angiotensina I/uso terapêutico , Animais , Comportamento Animal/efeitos dos fármacos , Biomarcadores/metabolismo , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Disfunção Cognitiva/metabolismo , Disfunção Cognitiva/fisiopatologia , Eletrocardiografia , Glicosilação , Meia-Vida , Insuficiência Cardíaca/complicações , Células Endoteliais da Veia Umbilical Humana/efeitos dos fármacos , Células Endoteliais da Veia Umbilical Humana/metabolismo , Humanos , Inflamação/fisiopatologia , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Fragmentos de Peptídeos/farmacocinética , Fragmentos de Peptídeos/uso terapêutico , Proto-Oncogene Mas , Ratos , Ratos Sprague-Dawley , Espécies Reativas de Oxigênio/metabolismo , Memória Espacial/efeitos dos fármacos , Remodelação Ventricular/efeitos dos fármacosRESUMO
Patients with congestive heart failure (CHF) have increased hospital readmission rates and mortality if they are concomitantly diagnosed with cognitive decline and memory loss. Accordingly, we developed a preclinical model of CHF-induced cognitive impairment with the goal of developing novel protective therapies against CHF related cognitive decline. CHF was induced by ligation of the left coronary artery to instigate a myocardial infarction (MI). By 4- and 8-weeks post-MI, CHF mice had approximately a 50% and 70% decline in ejection fraction as measured by echocardiography. At both 4- and 8-weeks post-MI, spatial memory performance in CHF mice as tested using the Morris water task was significantly impaired as compared with sham. In addition, CHF mice had significantly worse performance on object recognition when compared with shams as measured by discrimination ratios during the novel object recognition NOR task. At 8-weeks post-MI, a subgroup of CHF mice were given Angiotensin (Ang)-(1-7) (50mcg/kg/hr) subcutaneously for 4 weeks. Following 3 weeks treatment with systemic Ang-(1-7), the CHF mice NOR discrimination ratios were similar to shams and significantly better than the performance of CHF mice treated with saline. Ang-(1-7) also improved spatial memory in CHF mice as compared with shams. Ang-(1-7) had no effect on cardiac function. Inflammatory biomarker studies from plasma revealed a pattern of neuroprotection that may underlie the observed improvements in cognition. These results demonstrate a preclinical mouse model of CHF that exhibits both spatial memory and object recognition dysfunction. Furthermore, this CHF-induced cognitive impairment is attenuated by treatment with systemic Ang-(1-7). (PsycINFO Database Record
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Angiotensina I/administração & dosagem , Disfunção Cognitiva/prevenção & controle , Modelos Animais de Doenças , Insuficiência Cardíaca/complicações , Fragmentos de Peptídeos/administração & dosagem , Angiotensina I/uso terapêutico , Animais , Disfunção Cognitiva/etiologia , Insuficiência Cardíaca/fisiopatologia , Inflamação/metabolismo , Masculino , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Endogâmicos C57BL , Infarto do Miocárdio , Fragmentos de Peptídeos/uso terapêutico , Remodelação Ventricular/efeitos dos fármacos , Acuidade Visual/efeitos dos fármacosRESUMO
Many cancerous solid tumors metastasize to the bone and induce pain (cancer-induced bone pain [CIBP]). Cancer-induced bone pain is often severe because of enhanced inflammation, rapid bone degradation, and disease progression. Opioids are prescribed to manage this pain, but they may enhance bone loss and increase tumor proliferation, further compromising patient quality of life. Angiotensin-(1-7) (Ang-(1-7)) binds and activates the Mas receptor (MasR). Angiotensin-(1-7)/MasR activation modulates inflammatory signaling after acute tissue insult, yet no studies have investigated whether Ang-(1-7)/MasR play a role in CIBP. We hypothesized that Ang-(1-7) inhibits CIBP by targeting MasR in a murine model of breast CIBP. 66.1 breast cancer cells were implanted into the femur of BALB/cAnNHsd mice as a model of CIBP. Spontaneous and evoked pain behaviors were assessed before and after acute and chronic administration of Ang-(1-7). Tissues were collected from animals for ex vivo analyses of MasR expression, tumor burden, and bone integrity. Cancer inoculation increased spontaneous pain behaviors by day 7 that were significantly reduced after a single injection of Ang-(1-7) and after sustained administration. Preadministration of A-779 a selective MasR antagonist prevented this reduction, whereas pretreatment with the AT2 antagonist had no effect; an AT1 antagonist enhanced the antinociceptive activity of Ang-(1-7) in CIBP. Repeated Ang-(1-7) administration did not significantly change tumor burden or bone remodeling. Data here suggest that Ang-(1-7)/MasR activation significantly attenuates CIBP, while lacking many side effects seen with opioids. Thus, Ang-(1-7) may be an alternative therapeutic strategy for the nearly 90% of patients with advanced-stage cancer who experience excruciating pain.
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Analgésicos/uso terapêutico , Angiotensina I/uso terapêutico , Neoplasias Ósseas/complicações , Dor do Câncer/tratamento farmacológico , Dor do Câncer/etiologia , Fragmentos de Peptídeos/uso terapêutico , Análise de Variância , Bloqueadores do Receptor Tipo 1 de Angiotensina II/uso terapêutico , Bloqueadores do Receptor Tipo 2 de Angiotensina II/uso terapêutico , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Hiperalgesia/tratamento farmacológico , Hiperalgesia/fisiopatologia , Imidazóis/uso terapêutico , Losartan/uso terapêutico , Camundongos , Camundongos Endogâmicos BALB C , Comportamento de Nidação/efeitos dos fármacos , Piridinas/uso terapêutico , Teste de Desempenho do Rota-RodRESUMO
NEW FINDINGS: What is the topic of this review? This review summarizes recent data on the role of ovarian hormones and sex in inflammation-related hypertension. What advances does it highlight? The adaptive immune system has recently been implicated in the development of hypertension in males but not in females. The role of the immune system in the development of hypertension in women and its relationship to ovarian hormone production are highlighted. The immune system is known to contribute to the development of high blood pressure in males. However, the role of the immune system in the development of high blood pressure in females and the role of ovarian hormones has only recently begun to be studied. In animal studies, both the sex of the host and the T cell are critical biological determinants of susceptibility and resistance to hypertension induced by angiotensin II. In women, natural menopause is known to result in significant changes in the expression of genes regulating the immune system. Likewise, in animal models, ovariectomy results in hypertension and an upregulation in T-cell tumour necrosis factor-α-related genes. Oestrogen replacement results in decreases in inflammatory genes in the brain regions involved in blood pressure regulation. Together, these studies suggest that the response of the adaptive immune system to ovarian hormone deficiency is a significant contributor to hypertension in women.
Assuntos
Hormônios Esteroides Gonadais/deficiência , Hipertensão/imunologia , Hipertensão/fisiopatologia , Sistema Imunitário/imunologia , Ovário/metabolismo , Pressão Sanguínea/imunologia , Pressão Sanguínea/fisiologia , Feminino , Hormônios Esteroides Gonadais/imunologia , Humanos , Hipertensão/metabolismo , Ovário/imunologia , Ovário/fisiologia , Caracteres SexuaisRESUMO
Hypertension is a major contributor to worldwide morbidity and mortality rates related to cardiovascular disease. There are important sex differences in the onset and rate of hypertension in humans. Compared with age-matched men, premenopausal women are less likely to develop hypertension. However, after age 60, the incidence of hypertension increases in women and even surpasses that seen in older men. It is thought that changes in levels of circulating ovarian hormones as women age may be involved in the increase in hypertension in older women. One of the key mechanisms involved in the development of hypertension in both men and women is an increase in sympathetic nerve activity (SNA). Brain regions important for the regulation of SNA, such as the subfornical organ, the paraventricular nucleus and the rostral ventral lateral medulla, also express specific subtypes of oestrogen receptors. Each of these brain regions has also been implicated in mechanisms underlying risk factors for hypertension such as obesity, stress and inflammation. The present review brings together evidence that links actions of oestrogen at these receptors to modulate some of the common brain mechanisms involved in the ability of hypertensive risk factors to increase SNA and blood pressure. Understanding the mechanisms by which oestrogen acts at key sites in the brain for the regulation of SNA is important for the development of novel, sex-specific therapies for treating hypertension.