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1.
Geroscience ; 2020 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-32227279

RESUMO

Increased availability of cannabis and cannabinoid-containing products necessitates the need for an understanding of how these substances influence aging. In this study, zebrafish (Danio rerio) were exposed to different concentrations of THC (0.08, 0.4, 2 µM) during embryonic-larval development and the effects on aging were measured 30 months later and in the offspring of the exposed fish (F1 generation). Exposure to 0.08 µM THC resulted in increased male survival at 30 months of age. As the concentration of THC increased, this protective effect was lost. Treatment with the lowest concentration of THC also significantly increased egg production, while higher concentrations resulted in impaired fecundity. Treatment with the lowest dose of THC significantly reduced wet weight, the incidence of kyphosis, and the expression of several senescence and inflammatory markers (p16ink4ab, tnfα, il-1ß, il-6, pparα and pparγ) in the liver, but not at higher doses indicating a biphasic or hormetic effect. Exposure to THC did not affect the age-related reductions in locomotor behavior. Within the F1 generation, many of these changes were not observed. However, the reduction in fecundity due to THC exposure was worse in the F1 generation because offspring whose parents received high dose of THC were completely unable to reproduce. Together, our results demonstrate that a developmental exposure to THC can cause significant effects on longevity and healthspan of zebrafish in a biphasic manner.

2.
Geroscience ; 42(2): 785-800, 2020 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-32221778

RESUMO

Consumption of cannabinoid-containing products is on the rise, even during pregnancy. Unfortunately, the long-term, age-related consequences of developmental cannabidiol (CBD) exposure remain largely unknown. This is a critical gap given the established Developmental Origins of Health and Disease (DOHaD) paradigm which emphasizes that stressors, like drug exposure, early in life can instigate molecular and cellular changes that ultimately lead to adverse outcomes later in life. Thus, we exposed zebrafish (Danio rerio) to varying concentrations of CBD (0.02, 0.1, 0.5 µM) during larval development and assessed aging in both the F0 (exposed generation) and their F1 offspring 30 months later. F0 exposure to CBD significantly increased survival (~ 20%) and reduced size (wet weight and length) of female fish. While survival was increased, the age-related loss of locomotor function was unaffected and the effects on fecundity varied by sex and dose. Treatment with 0.5 µM CBD significantly reduced sperm concentration in males, but 0.1 µM increased egg production in females. Similar to other model systems, control aged zebrafish exhibited increased kyphosis as well as increased expression markers of senescence, and inflammation (p16ink4ab, tnfα, il1b, il6, and pparγ) in the liver. Exposure to CBD significantly reduced the expression of several of these genes in a dose-dependent manner relative to the age-matched controls. The effects of CBD on size, gene expression, and reproduction were not reproduced in the F1 generation, suggesting the influence on aging was not cross-generational. Together, our results demonstrate that developmental exposure to CBD causes significant effects on the health and longevity of zebrafish.

4.
Am J Health Behav ; 43(6): 1016-1029, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31662162

RESUMO

Objective: In this study, we evaluated whether exercise prior to memory encoding or during memory consolidation can influence episodic memory function after being exposed to a stressful environment. Methods: We conducted 3 between-group randomized controlled experiments among young adults. We assessed episodic memory (via logic memory task) at the beginning of the experiment and approximately 45 minutes later. Across the 3 experiments, we varied the temporal period (eg, before memory encoding or during consolidation) of the acute bout of exercise (15-minute moderate-intensity exercise) and psychological stress induction. Results: Across all 3 experiments there was a statistically significant main effect for time for memory function, but there were no time x group interaction effects. Conclusion: Memory declined across the 2 assessment periods, but for all 3 experiments, exercise was not associated with memory function after being exposed to a stressful stimulus.

5.
J Neurochem ; 151(6): 689-702, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31563149

RESUMO

Insulin-like Growth Factor-1 (IGF-1) has been studied extensively for its ability to promote neuronal growth and excitability. Declining levels of IGF-1 have been correlated with impaired learning and memory as well as an increased risk of neurodegenerative diseases. While neuronal regulation by IGF-1 is well understood, the role of IGF-1 in influencing astrocyte function requires further exploration. Astrocytes regulate many aspects of the brain microenvironment, including controlling glutamate-glutamine cycling, which ultimately supports neuronal metabolism, neurotransmission, and protection from over stimulation. In this study, we examined whether IGF-1 acts through its cognate receptor, IGFR, to alter astrocytic glutamate handling. We utilized both small molecule IGFR inhibitors and Cre-driven genetic approaches to reduce IGFR in vivo and in cultured rodent astrocytes. When IGFR was knocked out of primary astrocytes derived from igfrf/f mice using AAV5-CMV-Cre, significant reductions in glutamate uptake were observed. Similarly, inhibition of IGFR with picropodophyllotoxin for 2 h, as well as 24 h, reduced glutamate uptake in vitro. Mechanistically, short-term inhibition of IGFR resulted in a significant decrease in glutamate transporter availability on the cell surface, as assessed by biotinylation. Long-term inhibition of IGFR led to significant reductions in mRNA expression of glutamate transport machinery, as assessed with qPCR. Reduced glutamate transporter mRNA was also observed in the brains of astrocyte-specific IGFR-deficient mice, three to four months after knock-out was induced with tamoxifen. Interestingly, long-term IGF-1 inhibition also resulted in an increase in adenosine triphosphate-stimulated glutamate release, though no change in adenosine triphosphate-stimulated calcium flux was observed nor were any changes in purinergic receptor protein expression. Together, these data suggest that reduced IGF-1 signaling will favor an accumulation of extrasynaptic glutamate, which may contribute to neurodegeneration in disease states where IGF-1 levels are low. Cover Image for this issue: doi: 10.1111/jnc.14534.

6.
Naunyn Schmiedebergs Arch Pharmacol ; 392(9): 1071-1083, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31049606

RESUMO

The search for new drugs remains an important focus for the safe and effective treatment of cardiovascular diseases. Previous evidence has shown that choline analogs can offer therapeutic benefit for cardiovascular complications. The current study investigates the effects of 2-(4-((1-phenyl-1H-pyrazol-4-yl)methyl)piperazin-1-yl)ethan-1-ol (LQFM032) on cardiovascular function and cholinergic-nitric oxide signaling. Synthesized LQFM032 (0.3, 0.6, or 1.2 mg/kg) was administered by intravenous and intracerebroventricular routes to evaluate the potential alteration of mean arterial pressure, heart rate, and renal sympathetic nerve activity of normotensive and hypertensive rats. Vascular function was further evaluated in isolated vessels, while pharmacological antagonists and computational studies of nitric oxide synthase and muscarinic receptors were performed to assess possible mechanisms of LQFM032 activity. The intravenous and intracerebroventricular administration of LQFM032 elicited a temporal reduction in mean arterial pressure, heart rate, and renal sympathetic nerve activity of rats. The cumulative addition of LQFM032 to isolated endothelium-intact aortic rings reduced vascular tension and elicited a concentration-dependent relaxation. Intravenous pretreatment with L-NAME (nitric oxide synthase inhibitor), atropine (nonselective muscarinic receptor antagonist), pirenzepine, and 4-DAMP (muscarinic M1 and M3 subtype receptor antagonist, respectively) attenuated the cardiovascular effects of LQFM032. These changes may be due to a direct regulation of muscarinic signaling as docking data shows an interaction of choline analog with M1 and M3 but not nitric oxide synthase. Together, these findings demonstrate sympathoinhibitory, hypotensive, and antihypertensive effects of LQFM032 and suggest the involvement of muscarinic receptors.

7.
Neurobiol Aging ; 79: 110-118, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31035036

RESUMO

Numerous aspects of mammalian physiology exhibit cyclic daily patterns known as circadian rhythms. However, studies in aged humans and animals indicate that these physiological rhythms are not consistent throughout the life span. The simultaneous development of disrupted circadian rhythms and age-related impairments suggests a shared mechanism, which may be amenable to therapeutic intervention. Recently, the endocannabinoid system has emerged as a complex signaling network, which regulates numerous aspects of circadian physiology relevant to the neurobiology of aging. Agonists of cannabinoid receptor-1 (CB1) have consistently been shown to decrease neuronal activity, core body temperature, locomotion, and cognitive function. Paradoxically, several lines of evidence now suggest that very low doses of cannabinoids are beneficial in advanced age. One potential explanation for this phenomenon is that these drugs exhibit hormesis-a biphasic dose-response wherein low doses produce the opposite effects of higher doses. Therefore, it is important to determine the dose-, age-, and time-dependent effects of these substances on the regulation of circadian rhythms and other processes dysregulated in aging. This review highlights 3 fields-biological aging, circadian rhythms, and endocannabinoid signaling-to critically assess the therapeutic potential of endocannabinoid modulation in aged individuals. If the hormetic properties of exogenous cannabinoids are confirmed, we conclude that precise administration of these compounds may bidirectionally entrain central and peripheral circadian clocks and benefit multiple aspects of aging physiology.


Assuntos
Envelhecimento/fisiologia , Canabinoides/farmacologia , Ritmo Circadiano , Animais , Ritmo Circadiano/efeitos dos fármacos , Relação Dose-Resposta a Droga , Cronoterapia Farmacológica , Endocanabinoides/metabolismo , Endocanabinoides/fisiologia , Hormese/efeitos dos fármacos , Humanos , Camundongos , Receptor CB1 de Canabinoide/agonistas , Transdução de Sinais/efeitos dos fármacos
8.
Molecules ; 24(3)2019 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-30699965

RESUMO

Although 4-O-Methylhonokiol (MH) effects on neuronal and immune cells have been established, it is still unclear whether MH can cause a change in the structure and function of the cardiovascular system. The overarching goal of this study was to evaluate the effects of MH, isolated from Magnolia grandiflora, on the development of the heart and vasculature in a Japanese medaka model in vivo to predict human health risks. We analyzed the toxicity of MH in different life-stages of medaka embryos. MH uptake into medaka embryos was quantified. The LC50 of two different exposure windows (stages 9⁻36 (0⁻6 days post fertilization (dpf)) and 25⁻36 (2⁻6 dpf)) were 5.3 ± 0.1 µM and 9.9 ± 0.2 µM. Survival, deformities, days to hatch, and larval locomotor response were quantified. Wnt 1 was overexpressed in MH-treated embryos indicating deregulation of the Wnt signaling pathway, which was associated with spinal and cardiac ventricle deformities. Overexpression of major proinflammatory mediators and biomarkers of the heart were detected. Our results indicated that the differential sensitivity of MH in the embryos was developmental stage-specific. Furthermore, this study demonstrated that certain molecules can serve as promising markers at the transcriptional and phenotypical levels, responding to absorption of MH in the developing embryo.


Assuntos
Compostos de Bifenilo/farmacologia , Lignanas/farmacologia , Animais , Sistema Cardiovascular/efeitos dos fármacos , Sistema Cardiovascular/embriologia , Modelos Animais de Doenças , Embrião não Mamífero/efeitos dos fármacos , Medicina Herbária , Inflamação/tratamento farmacológico , Magnolia/química , Masculino , Oryzias , Distribuição Aleatória , Transdução de Sinais/efeitos dos fármacos
9.
Neurobiol Aging ; 71: 1-12, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30059797

RESUMO

Cerebral microcirculation is critical for the preservation of brain health, and vascular impairment is associated with age-related neurodegenerative diseases. Because the retina is a component of the central nervous system, cellular changes that occur in the aging retina are likely relevant to the aging brain, and the retina provides the advantage that the entire vascular bed is visible, en face. In this study, we tested the hypothesis that normal, healthy aging alters the contractile vascular smooth muscle cell (VSMC) coverage of retinal arterioles. We found that aging results in a significant reduction of contractile VSMCs in focal patches along arterioles. Focal loss of contractile VSMCs occurs at a younger age in mice deficient in the senescence-associated protein, caveolin-1. Age-related contractile VSMC loss is not exacerbated by genetic depletion of insulin-like growth factor-1. The patchy loss of contractile VSMCs provides a cellular explanation for previous clinical studies showing focal microirregularities in retinal arteriolar responsiveness in healthy aged human subjects and is likely to contribute to age-related retinal vascular complications.


Assuntos
Envelhecimento , Caveolina 1/fisiologia , Contração Muscular , Músculo Liso Vascular/fisiologia , Artéria Retiniana/fisiologia , Animais , Apoptose , Arteríolas/fisiologia , Caveolina 1/genética , Fator de Crescimento Insulin-Like I/genética , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Camundongos Endogâmicos C57BL , Camundongos Knockout
10.
Geroscience ; 39(2): 129-145, 2017 04.
Artigo em Inglês | MEDLINE | ID: mdl-28409331

RESUMO

Reduced circulating levels of IGF-1 have been proposed as a conserved anti-aging mechanism that contributes to increased lifespan in diverse experimental models. However, IGF-1 has also been shown to be essential for normal development and the maintenance of tissue function late into the lifespan. These disparate findings suggest that IGF-1 may be a pleiotropic modulator of health and aging, as reductions in IGF-1 may be beneficial for one aspect of aging, but detrimental for another. We postulated that the effects of IGF-1 on tissue health and function in advanced age are dependent on the tissue, the sex of the animal, and the age at which IGF-1 is manipulated. In this study, we examined how alterations in IGF-1 levels at multiple stages of development and aging influence overall lifespan, healthspan, and pathology. Specifically, we investigated the effects of perinatal, post-pubertal, and late-adult onset IGF-1 deficiency using genetic and viral approaches in both male and female igf f/f C57Bl/6 mice. Our results support the concept that IGF-1 levels early during lifespan establish the conditions necessary for subsequent healthspan and pathological changes that contribute to aging. Nevertheless, these changes are specific for each sex and tissue. Importantly, late-life IGF-1 deficiency (a time point relevant for human studies) reduces cancer risk but does not increase lifespan. Overall, our results indicate that the levels of IGF-1 during development influence late-life pathology, suggesting that IGF-1 is a developmental driver of healthspan, pathology, and lifespan.


Assuntos
Pleiotropia Genética , Nível de Saúde , Fator de Crescimento Insulin-Like I/fisiologia , Longevidade , Caracteres Sexuais , Animais , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL
11.
J Biol Chem ; 291(46): 23895-23905, 2016 Nov 11.
Artigo em Inglês | MEDLINE | ID: mdl-27655914

RESUMO

Protein tyrosine phosphatase MEG2 (PTP-MEG2) is a unique nonreceptor tyrosine phosphatase associated with transport vesicles, where it facilitates membrane trafficking by dephosphorylation of the N-ethylmaleimide-sensitive fusion factor. In this study, we identify the neurotrophin receptor TrkA as a novel cargo whose transport to the cell surface requires PTP-MEG2 activity. In addition, TrkA is also a novel substrate of PTP-MEG2, which dephosphorylates both Tyr-490 and Tyr-674/Tyr-675 of TrkA. As a result, overexpression of PTP-MEG2 down-regulates NGF/TrkA signaling and blocks neurite outgrowth and differentiation in PC12 cells and cortical neurons.


Assuntos
Neuritos/enzimologia , Proteínas Tirosina Fosfatases não Receptoras/metabolismo , Receptor trkA/metabolismo , Transdução de Sinais/fisiologia , Animais , Camundongos , Células PC12 , Transporte Proteico/fisiologia , Proteínas Tirosina Fosfatases não Receptoras/genética , Ratos
12.
Age (Dordr) ; 38(4): 273-289, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27613724

RESUMO

Strong epidemiological and experimental evidence indicate that both age and hypertension lead to significant functional and structural impairment of the cerebral microcirculation, predisposing to the development of vascular cognitive impairment (VCI) and Alzheimer's disease. Preclinical studies establish a causal link between cognitive decline and microvascular rarefaction in the hippocampus, an area of brain important for learning and memory. Age-related decline in circulating IGF-1 levels results in functional impairment of the cerebral microvessels; however, the mechanistic role of IGF-1 deficiency in impaired hippocampal microvascularization remains elusive. The present study was designed to characterize the additive/synergistic effects of IGF-1 deficiency and hypertension on microvascular density and expression of genes involved in angiogenesis and microvascular regression in the hippocampus. To achieve that goal, we induced hypertension in control and IGF-1 deficient mice (Igf1 f/f  + TBG-Cre-AAV8) by chronic infusion of angiotensin II. We found that circulating IGF-1 deficiency is associated with decreased microvascular density and exacerbates hypertension-induced microvascular rarefaction both in the hippocampus and the neocortex. The anti-angiogenic hippocampal gene expression signature observed in hypertensive IGF-1 deficient mice in the present study provides important clues for subsequent studies to elucidate mechanisms by which hypertension may contribute to the pathogenesis and clinical manifestation of VCI. In conclusion, adult-onset, isolated endocrine IGF-1 deficiency exerts deleterious effects on the cerebral microcirculation, leading to a significant decline in cortical and hippocampal capillarity and exacerbating hypertension-induced cerebromicrovascular rarefaction. The morphological impairment of the cerebral microvasculature induced by IGF-1 deficiency and hypertension reported here, in combination with neurovascular uncoupling, increased blood-brain barrier disruption and neuroinflammation reported in previous studies likely contribute to the pathogenesis of vascular cognitive impairment in elderly hypertensive humans.


Assuntos
Envelhecimento/metabolismo , Hipocampo/irrigação sanguínea , Hipertensão/complicações , Fator de Crescimento Insulin-Like I/deficiência , Rarefação Microvascular/patologia , Neocórtex/irrigação sanguínea , Envelhecimento/patologia , Doença de Alzheimer/metabolismo , Doença de Alzheimer/fisiopatologia , Angiotensina II/efeitos adversos , Angiotensina II/metabolismo , Animais , Biomarcadores/sangue , Barreira Hematoencefálica/metabolismo , Disfunção Cognitiva/fisiopatologia , Expressão Gênica , Humanos , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Rarefação Microvascular/etiologia , RNA Mensageiro/metabolismo
13.
Age (Dordr) ; 38(4): 239-258, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-27566308

RESUMO

Epidemiological findings support the concept of Developmental Origins of Health and Disease, suggesting that early-life hormonal influences during a sensitive period of development have a fundamental impact on vascular health later in life. The endocrine changes that occur during development are highly conserved across mammalian species and include dramatic increases in circulating IGF-1 levels during adolescence. The present study was designed to characterize the effect of developmental IGF-1 deficiency on the vascular aging phenotype. To achieve that goal, early-onset endocrine IGF-1 deficiency was induced in mice by knockdown of IGF-1 in the liver using Cre-lox technology (Igf1 f/f mice crossed with mice expressing albumin-driven Cre recombinase). This model exhibits low-circulating IGF-1 levels during the peripubertal phase of development, which is critical for the biology of aging. Due to the emergence of miRNAs as important regulators of the vascular aging phenotype, the effect of early-life IGF-1 deficiency on miRNA expression profile in the aorta was examined in animals at 27 months of age. We found that developmental IGF-1 deficiency elicits persisting late-life changes in miRNA expression in the vasculature, which significantly differed from those in mice with adult-onset IGF-1 deficiency (TBG-Cre-AAV8-mediated knockdown of IGF-1 at 5 month of age in Igf1 f/f mice). Using a novel computational approach, we identified miRNA target genes that are co-expressed with IGF-1 and associate with aging and vascular pathophysiology. We found that among the predicted targets, the expression of multiple extracellular matrix-related genes, including collagen-encoding genes, were downregulated in mice with developmental IGF-1 deficiency. Collectively, IGF-1 deficiency during a critical period during early in life results in persistent changes in post-transcriptional miRNA-mediated control of genes critical targets for vascular health, which likely contribute to the deleterious late-life cardiovascular effects known to occur with developmental IGF-1 deficiency.


Assuntos
Envelhecimento/fisiologia , Aorta/fisiologia , Regulação da Expressão Gênica/fisiologia , Fator de Crescimento Insulin-Like I/deficiência , MicroRNAs/metabolismo , Análise de Variância , Animais , Regulação para Baixo , Fator de Crescimento Insulin-Like I/análise , Fator de Crescimento Insulin-Like I/genética , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , MicroRNAs/genética , Estresse Oxidativo/fisiologia , Transcrição Genética
14.
Age (Dordr) ; 38(2): 38, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26968399

RESUMO

Advanced aging is associated with the loss of structural and biomechanical properties in bones, which increases the risk for bone fracture. Aging is also associated with reductions in circulating levels of the anabolic signaling hormone, insulin-like growth factor (IGF)-1. While the role of IGF-1 in bone development has been well characterized, the impact of the age-related loss of IGF-1 on bone aging remains controversial. Here, we describe the effects of reducing IGF-1 at multiple time points in the mouse life span--early in postnatal development, early adulthood, or late adulthood on tibia bone aging in both male and female igf (f/f) mice. Bone structure was analyzed at 27 months of age using microCT. We find that age-related reductions in cortical bone fraction, cortical thickness, and tissue mineral density were more pronounced when IGF-1 was reduced early in life and not in late adulthood. Three-point bone bending assays revealed that IGF-1 deficiency early in life resulted in reduced maximum force, maximum bending moment, and bone stiffness in aged males and females. The effects of IGF-1 on bone aging are microenvironment specific, as early-life loss of IGF-1 resulted in decreased cortical bone structure and strength along the diaphysis while significantly increasing trabecular bone fraction and trabecular number at the proximal metaphysis. The increases in trabecular bone were limited to males, as early-life loss of IGF-1 did not alter bone fraction or number in females. Together, our data suggest that the age-related loss of IGF-1 influences tibia bone aging in a sex-specific, microenvironment-specific, and time-dependent manner.


Assuntos
Envelhecimento , Densidade Óssea , Fator de Crescimento Insulin-Like I/deficiência , Tíbia/metabolismo , Fraturas da Tíbia/metabolismo , Animais , Modelos Animais de Doenças , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Tíbia/diagnóstico por imagem , Fraturas da Tíbia/diagnóstico , Fraturas da Tíbia/etiologia , Microtomografia por Raio-X
15.
J Bone Miner Res ; 31(2): 443-54, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26260312

RESUMO

Advanced aging is associated with increased risk of bone fracture, especially within the vertebrae, which exhibit significant reductions in trabecular bone structure. Aging is also associated with a reduction in circulating levels of insulin-like growth factor (IGF-1). Studies have suggested that the reduction in IGF-1 compromises healthspan, whereas others report that loss of IGF-1 is beneficial because it increases healthspan and lifespan. To date, the effect of decreases in circulating IGF-1 on vertebral bone aging has not been thoroughly investigated. Here, we delineate the consequences of a loss of circulating IGF-1 on vertebral bone aging in male and female Igf(f/f) mice. IGF-1 was reduced at multiple specific time points during the mouse lifespan: early in postnatal development (crossing albumin-cyclic recombinase [Cre] mice with Igf(f/f) mice); and in early adulthood and in late adulthood using hepatic-specific viral vectors (AAV8-TBG-Cre). Vertebrae bone structure was analyzed at 27 months of age using micro-computed tomography (µCT) and quantitative bone histomorphometry. Consistent with previous studies, both male and female mice exhibited age-related reductions in vertebral bone structure. In male mice, reduction of circulating IGF-1 induced at any age did not diminish vertebral bone loss. Interestingly, early-life loss of IGF-1 in females resulted in a 67% increase in vertebral bone volume fraction, as well as increased connectivity density and increased trabecular number. The maintenance of bone structure in the early-life IGF-1-deficient females was associated with increased osteoblast surface and an increased ratio of osteoprotegerin/receptor-activator of NF-κB-ligand (RANKL) levels in circulation. Within 3 months of a loss of IGF-1, there was a 2.2-fold increase in insulin receptor expression within the vertebral bones of our female mice, suggesting that local signaling may compensate for the loss of circulating IGF-1. Together, these data suggest the age-related loss of vertebral bone density in females can be reduced by modifying circulating IGF-1 levels early in life.


Assuntos
Envelhecimento/metabolismo , Densidade Óssea , Fator de Crescimento Insulin-Like I/metabolismo , Caracteres Sexuais , Transdução de Sinais , Coluna Vertebral/metabolismo , Envelhecimento/genética , Animais , Feminino , Fator de Crescimento Insulin-Like I/genética , Masculino , Camundongos , Camundongos Transgênicos , Osteoporose/genética , Osteoporose/metabolismo , Ligante RANK/biossíntese , Ligante RANK/genética , Receptor de Insulina/genética , Receptor de Insulina/metabolismo , Fatores de Tempo
16.
Aging Cell ; 14(6): 1034-44, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26172407

RESUMO

Aging is associated with marked deficiency in circulating IGF-1, which has been shown to contribute to age-related cognitive decline. Impairment of moment-to-moment adjustment of cerebral blood flow (CBF) via neurovascular coupling is thought to play a critical role in the genesis of age-related cognitive impairment. To establish the link between IGF-1 deficiency and cerebromicrovascular impairment, neurovascular coupling mechanisms were studied in a novel mouse model of IGF-1 deficiency (Igf1(f/f) -TBG-Cre-AAV8) and accelerated vascular aging. We found that IGF-1-deficient mice exhibit neurovascular uncoupling and show a deficit in hippocampal-dependent spatial memory test, mimicking the aging phenotype. IGF-1 deficiency significantly impaired cerebromicrovascular endothelial function decreasing NO mediation of neurovascular coupling. IGF-1 deficiency also impaired glutamate-mediated CBF responses, likely due to dysregulation of astrocytic expression of metabotropic glutamate receptors and impairing mediation of CBF responses by eicosanoid gliotransmitters. Collectively, we demonstrate that IGF-1 deficiency promotes cerebromicrovascular dysfunction and neurovascular uncoupling mimicking the aging phenotype, which are likely to contribute to cognitive impairment.


Assuntos
Envelhecimento/genética , Circulação Cerebrovascular/fisiologia , Transtornos Cognitivos/genética , Fator de Crescimento Insulin-Like I/genética , Acoplamento Neurovascular/genética , Envelhecimento/fisiologia , Animais , Encéfalo/fisiologia , Transtornos Cognitivos/fisiopatologia , Modelos Animais de Doenças , Fator de Crescimento Insulin-Like I/deficiência , Fator de Crescimento Insulin-Like I/metabolismo , Masculino , Aprendizagem em Labirinto/fisiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Microvasos/fisiologia , Óxido Nítrico/biossíntese , Memória Espacial/fisiologia
17.
Neuropharmacology ; 97: 464-75, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-26071110

RESUMO

Aberrant increases in NMDA receptor (NMDAR) signaling contributes to central nervous system sensitization and chronic pain by activating neuronal nitric oxide synthase (nNOS) and generating nitric oxide (NO). Because the scaffolding protein postsynaptic density 95kDA (PSD95) tethers nNOS to NMDARs, the PSD95-nNOS complex represents a therapeutic target. Small molecule inhibitors IC87201 (EC5O: 23.94 µM) and ZL006 (EC50: 12.88 µM) directly inhibited binding of purified PSD95 and nNOS proteins in AlphaScreen without altering binding of PSD95 to ErbB4. Both PSD95-nNOS inhibitors suppressed glutamate-induced cell death with efficacy comparable to MK-801. IC87201 and ZL006 preferentially suppressed phase 2A pain behavior in the formalin test and suppressed allodynia induced by intraplantar complete Freund's adjuvant administration. IC87201 and ZL006 suppressed mechanical and cold allodynia induced by the chemotherapeutic agent paclitaxel (ED50s: 2.47 and 0.93 mg/kg i.p. for IC87201 and ZL006, respectively). Efficacy of PSD95-nNOS disruptors was similar to MK-801. Motor ataxic effects were induced by MK-801 but not by ZL006 or IC87201. Finally, MK-801 produced hyperalgesia in the tail-flick test whereas IC87201 and ZL006 did not alter basal nociceptive thresholds. Our studies establish the utility of using AlphaScreen and purified protein pairs to establish and quantify disruption of protein-protein interactions. Our results demonstrate previously unrecognized antinociceptive efficacy of ZL006 and establish, using two small molecules, a broad application for PSD95-nNOS inhibitors in treating neuropathic and inflammatory pain. Collectively, our results demonstrate that disrupting PSD95-nNOS protein-protein interactions is effective in attenuating pathological pain without producing unwanted side effects (i.e. motor ataxia) associated with NMDAR antagonists.


Assuntos
Ácidos Aminossalicílicos/farmacologia , Analgésicos/farmacologia , Benzilaminas/farmacologia , Clorofenóis/farmacologia , Triazóis/farmacologia , Animais , Ataxia/induzido quimicamente , Encéfalo/efeitos dos fármacos , Encéfalo/fisiologia , Morte Celular/efeitos dos fármacos , Morte Celular/fisiologia , Células Cultivadas , Modelos Animais de Doenças , Maleato de Dizocilpina/efeitos adversos , Maleato de Dizocilpina/farmacologia , Relação Dose-Resposta a Droga , Hiperalgesia/tratamento farmacológico , Hiperalgesia/metabolismo , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Proteínas de Membrana/antagonistas & inibidores , Proteínas de Membrana/metabolismo , Camundongos Endogâmicos C57BL , Neurônios/efeitos dos fármacos , Neurônios/fisiologia , Fármacos Neuroprotetores/efeitos adversos , Fármacos Neuroprotetores/farmacologia , Óxido Nítrico Sintase Tipo I/antagonistas & inibidores , Óxido Nítrico Sintase Tipo I/metabolismo , Dor Nociceptiva/tratamento farmacológico , Dor Nociceptiva/fisiopatologia , Ratos Sprague-Dawley
18.
J Cereb Blood Flow Metab ; 35(4): 527-30, 2015 Mar 31.
Artigo em Inglês | MEDLINE | ID: mdl-25605292

RESUMO

Stability of myogenic tone in middle cerebral arteries (MCA) is essential for adequate control over penetration of pressure waves into the distal portion of the cerebral microcirculation. Because the increased pulse pressure observed in advanced aging is associated with cerebromicrovascular injury, the effect of aging on myogenic response of mouse MCAs was determined. Aging did not affect the myogenic constriction in response to static increases in pressure, whereas it significantly impaired pulsatile pressure-induced myogenic tone. Impaired myogenic adaptation of MCAs to pulsatile pressure may allow high pressure to penetrate the distal portion of the cerebral microcirculation, contributing to microvascular damage.


Assuntos
Envelhecimento , Encéfalo/irrigação sanguínea , Artéria Cerebral Média/fisiologia , Fluxo Pulsátil , Vasoconstrição , Adaptação Fisiológica , Animais , Pressão Sanguínea , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Artéria Cerebral Média/fisiopatologia
19.
Exp Gerontol ; 68: 76-81, 2015 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-25300732

RESUMO

Growth hormone (GH) and insulin-like growth factor (IGF)-1 regulate the development and function of cells throughout the body. Several clinical diseases that result in a decline in physical and mental functions are marked by mutations that disrupt GH or IGF-1 signaling. During the lifespan there is a robust decrease in both GH and IGF-1. Because GH and IGF-1 are master regulators of cellular function, impaired GH and IGF-1 signaling in aging/disease states leads to significant alterations in tissue structure and function, especially within the brain. This review is intended to highlight the effects of the GH and IGF-1 on neuronal structure, function, and plasticity. Furthermore, we address several potential mechanisms through which the age-related reductions in GH and IGF-1 affect cognition. Together, the studies reviewed here highlight the importance of maintaining GH and IGF-1 signaling in order to sustain proper brain function throughout the lifespan.


Assuntos
Envelhecimento/fisiologia , Encéfalo/fisiologia , Hormônio do Crescimento/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Adolescente , Adulto , Envelhecimento/metabolismo , Animais , Encéfalo/crescimento & desenvolvimento , Encéfalo/metabolismo , Criança , Hormônio do Crescimento/metabolismo , Hormônio do Crescimento/farmacologia , Hormônio do Crescimento Humano/deficiência , Hormônio do Crescimento Humano/metabolismo , Hormônio do Crescimento Humano/fisiologia , Humanos , Fator de Crescimento Insulin-Like I/metabolismo , Camundongos , Modelos Biológicos , Plasticidade Neuronal/fisiologia , Ratos , Receptores de N-Metil-D-Aspartato/fisiologia , Transdução de Sinais/fisiologia
20.
J Gerontol A Biol Sci Med Sci ; 69(11): 1353-62, 2014 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-25098324

RESUMO

Aging is a major risk factor for cerebrovascular disease. Growth hormone (GH) and its anabolic mediator, insulin-like growth factor (IGF)-1, decrease with advancing age and this decline has been shown to promote vascular dysfunction. In addition, lower GH/IGF-1 levels are associated with higher stroke mortality in humans. These results suggest that decreased GH/IGF-1 level is an important factor in increased risk of cerebrovascular diseases. This study was designed to assess whether GH/IGF-1-deficiency influences the outcome of cerebral ischemia. We found that endothelin-1-induced middle cerebral artery occlusion resulted in a modest but nonsignificant decrease in cerebral infarct size in GH/IGF-1 deficient dw/dw rats compared with control heterozygous littermates and dw/dw rats with early-life GH treatment. Expression of endothelin receptors and endothelin-1-induced constriction of the middle cerebral arteries were similar in the three experimental groups. Interestingly, dw/dw rats exhibited reduced brain edema and less astrocytic infiltration compared with their heterozygous littermates and this effect was reversed by GH-treatment. Because reactive astrocytes are critical for the regulation of poststroke inflammatory processes, maintenance of the blood-brain barrier and neural repair, further studies are warranted to determine the long-term functional consequences of decreased astrocytic activation in GH/IGF-1 deficient animals after cerebral ischemia.


Assuntos
Envelhecimento/patologia , Envelhecimento/fisiologia , Isquemia Encefálica/etiologia , Endotelina-1/fisiologia , Hormônio do Crescimento/deficiência , Fator de Crescimento Insulin-Like I/deficiência , Animais , Astrócitos/patologia , Astrócitos/fisiologia , Edema Encefálico/etiologia , Edema Encefálico/patologia , Edema Encefálico/fisiopatologia , Isquemia Encefálica/patologia , Isquemia Encefálica/fisiopatologia , Infarto Cerebral/etiologia , Infarto Cerebral/patologia , Infarto Cerebral/fisiopatologia , Modelos Animais de Doenças , Nanismo/genética , Nanismo/patologia , Nanismo/fisiopatologia , Feminino , Hormônio do Crescimento/fisiologia , Fator de Crescimento Insulin-Like I/fisiologia , Masculino , Ratos , Ratos Endogâmicos Lew , Ratos Mutantes
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