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1.
Am J Physiol Gastrointest Liver Physiol ; 316(1): G217-G227, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30475062

RESUMO

This study aimed to establish mechanistic links between the prolonged intake of desloratadine, a common H1 receptor blocker (i.e., antihistamine), and development of obesity and metabolic syndrome. Male Sprague-Dawley rats were treated for 16 wk with desloratadine. We analyzed the dynamics of body weight gain, tissue fat accumulation/density, contractility of isolated mesenteric lymphatic vessels, and levels of blood lipids, glucose, and insulin, together with parameters of liver function. Prolonged intake of desloratadine induced development of an obesity-like phenotype and signs of metabolic syndrome. These alterations in the body included excessive weight gain, increased density of abdominal subcutaneous fat and intracapsular brown fat, high blood triglycerides with an indication of their rerouting toward portal blood, high HDL, high fasting blood glucose with normal fasting and nonfasting insulin levels (insulin resistance), high liver/body weight ratio, and liver steatosis (fatty liver). These changes were associated with dysfunction of mesenteric lymphatic vessels, specifically high lymphatic tone and resistance to flow together with diminished tonic and abolished phasic responses to increases in flow, (i.e., greatly diminished adaptive reserves to respond to postprandial increases in lymph flow). The role of nitric oxide in this flow-dependent adaptation was abolished, with remnants of these responses controlled by lymphatic vessel-derived histamine. Our current data, considered together with reports in the literature, support the notion that millions of the United States population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication. NEW & NOTEWORTHY Prolonged intake of desloratadine induced development of obesity and metabolic syndrome associated with dysfunction of mesenteric lymphatic vessels, high lymphatic tone, and resistance to flow together with greatly diminished adaptive reserves to respond to postprandial increases in lymph flow. Data support the notion that millions of the USA population are highly likely affected by underevaluated, lymphatic-related side effects of antihistamines and may develop obesity and metabolic syndrome due to the prolonged intake of this medication.


Assuntos
Fígado Gorduroso/tratamento farmacológico , Loratadina/análogos & derivados , Vasos Linfáticos/efeitos dos fármacos , Síndrome Metabólica/etiologia , Obesidade/etiologia , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Animais , Fígado Gorduroso/complicações , Resistência à Insulina/fisiologia , Lipídeos/sangue , Loratadina/farmacologia , Vasos Linfáticos/metabolismo , Masculino , Ratos , Ratos Sprague-Dawley , Aumento de Peso/efeitos dos fármacos
2.
J Trauma Acute Care Surg ; 89(3): 435-440, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32467458

RESUMO

BACKGROUND: Traumatic brain injury (TBI) has significant morbidity and cost implications. Primary treatment modalities aim to decrease intracranial pressure; however, therapies targeting the underlying pathophysiology of a TBI are limited. The TBI-induced microvascular leak and secondary injury are largely due to proteolysis of the blood-brain barrier (BBB) by matrix metalloproteinase-9. We previously observed doxycycline's inhibitory affinity on matrix metalloproteinase-9 resulting in preserved BBB integrity in nonsurvival murine studies. This study sought to determine the effect of doxycycline on functional motor and behavioral outcomes in the setting of a TBI murine survival model. METHODS: C57BL/6J mice were assigned to a sham, TBI, or TBI with doxycycline arm. A moderate TBI was induced utilizing a controlled cortical impactor. The TBI with doxycycline cohort received a dose of doxycycline (20 mg/kg) 2 hours after injury and every 12 hours until postoperative day (POD) 6. All mice underwent preoperative testing for weight, modified neurological severity score, wire grip, and ataxia analysis (DigiGait). Postoperative testing was performed on POD 1, POD 3, and POD 6 for the same measures. SAS 9.4 was used for comparative analysis. RESULTS: Fifteen sham mice, 15 TBI mice, and 10 TBI with doxycycline mice were studied. Mice treated with doxycycline had significantly improved modified neurological severity score and wire grip scores at POD 1 (all p < 0.05). Mice treated with doxycycline had significantly improved ataxia scores by POD 3 and POD 6 (all p < 0.05). There was no significant difference in rate of weight change between the three groups. CONCLUSION: Mice treated with doxycycline following TBI demonstrated improved behavioral and motor function suggesting doxycycline's role in preserving murine BBB integrity. Examining the role of doxycycline in human TBIs is warranted given the relative universal accessibility, affordability, and safety profile of doxycycline.


Assuntos
Barreira Hematoencefálica/metabolismo , Lesões Encefálicas Traumáticas/fisiopatologia , Doxiciclina/uso terapêutico , Animais , Barreira Hematoencefálica/efeitos dos fármacos , Encéfalo/irrigação sanguínea , Células Cultivadas , Modelos Animais de Doenças , Masculino , Metaloproteinase 9 da Matriz/metabolismo , Camundongos , Camundongos Endogâmicos C57BL
3.
Phytother Res ; 23(1): 14-9, 2009 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-19048607

RESUMO

PSAPP mice expressing the 'Swedish' amyloid precursor protein and the M146L presenilin 1 mutations are a well-characterized model for spontaneous amyloid beta plaque formation. Centella asiatica has a long history of use in India as a memory enhancing drug in Ayurvedic literature. The study investigated whether Centella asiatica extract (CaE) can alter the amyloid pathology in PSAPP mice by administering CaE (2.5 or 5.0 g/kg/day) starting at 2 months of age prior to the onset of detectable amyloid deposition and continued for either 2 months or 8 months. A significant decrease in amyloid beta 1-40 and 1-42 was detectable by ELISA following an 8 month treatment with 2.5 mg/kg of CaE. A reduction in Congo Red stained fibrillar amyloid plaques was detected with the 5.0 mg/kg CaE dose and long-term treatment regimen. It was also confirmed that CaE functions as an antioxidant in vitro, scavenging free radicals, reducing lipid peroxidation and protecting against DNA damage. The data indicate that CaE can impact the amyloid cascade altering amyloid beta pathology in the brains of PSAPP mice and modulating components of the oxidative stress response that has been implicated in the neurodegenerative changes that occur with Alzheimer's disease.


Assuntos
Doença de Alzheimer/tratamento farmacológico , Peptídeos beta-Amiloides/antagonistas & inibidores , Centella/química , Hipocampo/efeitos dos fármacos , Triterpenos/farmacologia , Doença de Alzheimer/patologia , Animais , Hipocampo/patologia , Peroxidação de Lipídeos , Ayurveda , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/farmacologia , Estresse Oxidativo , Extratos Vegetais , Placa Amiloide/patologia , Espécies Reativas de Oxigênio/metabolismo
4.
J Alzheimers Dis ; 9(3): 243-51, 2006 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-16914834

RESUMO

PSAPP mice expressing the "Swedish" amyloid precursor protein and M146L presenilin-1 mutations are a well-characterized model for spontaneous amyloid plaque formation. Bacopa monniera has a long history of use in India as an anti-aging and memory-enhancing ethnobotanical therapy. To evaluate the effect of Bacopa monniera extract (BME) on amyloid (Abeta) pathology in PSAPP mice, two doses of BME (40 or 160 mg/kg/day) were administered starting at 2 months of age for either 2 or 8 months. Our present data suggests that BME lowers Abeta 1-40 and 1-42 levels in cortex by as much as 60%, and reverses Y-maze performance and open field hyperlocomotion behavioral changes present in PSAPP mice. The areas encompassed by Congo Red-positive fibrillar amyloid deposits, however, were not altered by BME treatment. The data suggest that BME has potential application in Alzheimer's disease therapeutics.


Assuntos
Precursor de Proteína beta-Amiloide/genética , Amiloide/antagonistas & inibidores , Amiloide/metabolismo , Bacopa/química , Química Encefálica/efeitos dos fármacos , Precursor de Proteína beta-Amiloide/biossíntese , Animais , Comportamento Animal/efeitos dos fármacos , Peso Corporal/efeitos dos fármacos , Cognição/efeitos dos fármacos , Relação Dose-Resposta a Droga , Ensaio de Imunoadsorção Enzimática , Humanos , Aprendizagem em Labirinto/efeitos dos fármacos , Camundongos , Camundongos Transgênicos , Atividade Motora/efeitos dos fármacos , Neurofibrilas/efeitos dos fármacos , Neurofibrilas/metabolismo , Extratos Vegetais/farmacologia , Presenilina-1/biossíntese , Presenilina-1/genética
5.
Phytother Res ; 21(10): 965-9, 2007 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-17604373

RESUMO

Alzheimer's disease is a neurodegenerative disorder characterized by progressive dementia. Bacopa monniera is described in the Ayurvedic Materia Medica, as a therapeutically useful herb for the treatment of cognitive impairment, thus supporting its possible anti-Alzheimer's properties. Our studies have shown that Bacopa monniera reduces beta-amyloid deposits in the brain of an Alzheimer's disease animal model. The objective of this study was to establish the presence of endogenous substances in Bacopa monniera extract (BmE) that will impact components of the oxidative stress cascade such as the reduction of divalent metals, scavenging of reactive oxygen species, alterations of lipoxygenase activity and hydrogen peroxide-induced lipid peroxidation. The extract contained polyphenols and sulfhydryl contents suggestive of endogenous antioxidant activity. The results demonstrated that BmE reduced divalent metals, dose-dependently scavenged reactive oxygen species, decreased the formation of lipid peroxides and inhibited lipoxygenase activity. These data combined with our previous studies that have shown that BmE treatment reduces beta-amyloid levels in the brain of an Alzheimer's disease doubly transgenic mouse model of rapid amyloid deposition (PSAPP mice) suggesting mechanisms of action relevant to the treatment of Alzheimer's disease.


Assuntos
Bacopa/química , Sequestradores de Radicais Livres/farmacologia , Fármacos Neuroprotetores/farmacologia , Animais , Quelantes/química , Quelantes/isolamento & purificação , Quelantes/farmacologia , Dano ao DNA , Flavonoides/química , Flavonoides/isolamento & purificação , Flavonoides/farmacologia , Sequestradores de Radicais Livres/química , Sequestradores de Radicais Livres/isolamento & purificação , Peroxidação de Lipídeos/efeitos dos fármacos , Ayurveda , Camundongos , Camundongos Transgênicos , Fármacos Neuroprotetores/química , Fármacos Neuroprotetores/isolamento & purificação , Estresse Oxidativo/efeitos dos fármacos , Fenóis/química , Fenóis/isolamento & purificação , Fenóis/farmacologia , Extratos Vegetais/química , Extratos Vegetais/isolamento & purificação , Extratos Vegetais/farmacologia , Polifenóis , Compostos de Sulfidrila/química , Compostos de Sulfidrila/isolamento & purificação , Compostos de Sulfidrila/farmacologia
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