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1.
Neuroimmunomodulation ; 20(3): 141-51, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23445569

RESUMO

BACKGROUND: Development of mammary tumors is an age-associated phenomenon that is likely due to deficits in the neuroendocrine-immune interactions. Previously, we demonstrated that L-deprenyl, a monoamine oxidase-B (MAO-B) inhibitor, can enhance immune responses and restore noradrenergic (NA) innervation in the spleens of rats with carcinogen-induced and spontaneously developing mammary tumors. OBJECTIVES: To investigate whether (1) treatment of early middle-aged female rats would prevent the spontaneous development of mammary tumors accompanied by restoration of immunity in the spleen and draining lymph nodes (DLN) and sympathetic NA innervation in the spleen and (2) deprenyl can influence the proliferation of estrogen receptor (ER)-positive (MCF-7 and T47D) and ER-negative (MDA-MB-231 and Hs 578T) human breast cancer cells. METHODS: Early middle-aged (8- to 9-month-old) female Sprague-Dawley rats were treated with 0, 1.0 or 2.5 mg of deprenyl/kg body weight (BW) daily i.p. for 12 months. Cells of ER-positive (ER+) and ER-negative (ER-) human breast cancer cell lines were incubated with media or 10(-3) to 10(-8) M deprenyl for 1, 2, 4 or 6 days to examine the proliferation of cells. RESULTS: Tumor incidence increased in saline-treated old female rats, while deprenyl treatment significantly reduced the incidence of mammary tumors in these rats. Saline-treated tumor-bearing rats exhibited reduced splenic NA innervation and norepinephrine (NE) content, splenic interleukin (IL)-2 and interferon (IFN)-γ levels and NK cell activity as well as DLN IL-2 and IFN-γ levels compared to young female rats without tumors. In contrast, treatment with 2.5 mg/kg of deprenyl enhanced IL-2 and IFN-γ production in both the spleen and DLN as well as splenic natural killer (NK) cell activity. Deprenyl treatment also increased concanavalin A (Con A)-induced proliferation of T lymphocytes in the DLN. Deprenyl-induced changes in immune responses were accompanied by enhanced NA innervation and NE content in the spleen. In vitro incubation of various concentrations of deprenyl with ER+ human breast cancer cell lines partly inhibited the proliferation of cells, while it had no effect on the ER- breast cancer cells. CONCLUSIONS: These results suggest that (1) development of mammary tumors is mediated through the loss of immunity and sympathetic NA nerve fibers accompanied by reduced NE levels in the spleen, (2) the prevention of mammary tumor development by deprenyl may involve the reversal of the tumor-associated decline in sympathetic NA activity and cell-mediated immune responses in the spleen and DLN and (3) the antitumor effects of deprenyl may be partially mediated through ER-dependent intracellular signaling pathways.


Assuntos
Neoplasias da Mama/patologia , Neoplasias da Mama/prevenção & controle , Linfonodos , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/administração & dosagem , Selegilina/administração & dosagem , Baço , Fatores Etários , Análise de Variância , Animais , Proliferação de Células/efeitos dos fármacos , Concanavalina A/farmacologia , Citocinas/metabolismo , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Feminino , Citometria de Fluxo , Humanos , Células Matadoras Naturais/efeitos dos fármacos , Linfonodos/efeitos dos fármacos , Linfonodos/imunologia , Linfonodos/metabolismo , Transplante de Neoplasias , Ratos , Ratos Sprague-Dawley , Baço/efeitos dos fármacos , Baço/imunologia , Baço/metabolismo
2.
Neuroimmunomodulation ; 20(2): 72-8, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23207416

RESUMO

UNLABELLED: Aging in female rats is associated with cessation of reproductive cycles, development of mammary cancer, and increased incidence of autoimmune diseases. Previously, we demonstrated an age-related decline in sympathetic noradrenergic (NA) innervation in the spleen and lymph nodes of female F344 rats accompanied by significantly reduced natural killer cell activity, interleukin (IL)-2 and interferon (IFN)-γ production, and T- and B-cell proliferation, suggesting possible links between sympathetic activity and immunosenescence. OBJECTIVES: The aim of this study is to investigate the effects of L-(-)-deprenyl, a monoamine oxidase-B inhibitor, on the sympathetic nervous system and cell-mediated immune responses in old female rats. METHODS: Low doses of L-deprenyl (0.25 or 1.0 mg/kg body weight, BW) were administered intraperitoneally to 19- to 21-month-old female F344 rats for 8 weeks. To assess the stereoselectivity of the effects of deprenyl on splenic sympathetic activity and immune responses, the D-enantiomer (D-(+)-deprenyl; 1.0 mg/kg BW) was also included in the studies. Norepinephrine (NE) concentration and content, and mitogen-induced T-cell proliferation and cytokine production were assessed in the splenocytes after deprenyl treatment. RESULTS: Treatment with L-deprenyl reversed the age-related decrease in NE concentration and content and IFN-γ production, and increased IL-2 production in the spleen while D-deprenyl did not affect the age-associated reduction in splenic NE levels or cytokine production. CONCLUSIONS: These findings demonstrate that L-deprenyl exerts neurorestorative and immunostimulatory effects on the sympathetic nervous system and cell-mediated immune responses during aging and provides evidence for a causal relationship between some aspects of immunosenescence and the age-related decline in sympathetic nerves in the spleens of female F344 rats.


Assuntos
Envelhecimento/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Selegilina/farmacologia , Baço/efeitos dos fármacos , Baço/imunologia , Envelhecimento/imunologia , Envelhecimento/metabolismo , Animais , Cromatografia Líquida de Alta Pressão , Ensaio de Imunoadsorção Enzimática , Feminino , Imunidade Celular/efeitos dos fármacos , Imunidade Celular/imunologia , Interferon gama/biossíntese , Interleucina-2/biossíntese , Norepinefrina/biossíntese , Ratos , Ratos Endogâmicos F344 , Baço/metabolismo , Sistema Nervoso Simpático/efeitos dos fármacos , Sistema Nervoso Simpático/imunologia
3.
Cancer ; 117(20): 4764-71, 2011 Oct 15.
Artigo em Inglês | MEDLINE | ID: mdl-21455995

RESUMO

BACKGROUND: The authors reviewed changes in accrual to cancer clinical trials over the last 2 decades at their institution with a focus on minority participation after the implementation of a community clinical oncology program (CCOP) and an aggressive, education-orientated minority outreach program (MOP). METHODS: Data on patient enrollment in clinical trials for the years 1988 to 2010 was obtained from the William Beaumont Hospital (WBH) Cancer Clinical Trials Office. The type and number of cancers diagnosed and treated during the same period were obtained from the WBH tumor registry data. The MOP was initiated in the fall of 2003 with a focus on culture-specific cancer education. RESULTS: With the development of the CCOP, clinical trials accrual increased significantly by 10-fold (P = .001). The primary service area for the CCOP consistently averaged an 85% to 90% Caucasian population. During the same period, the minority population for the service area remained stable between 8.8% and 10% and did not change significantly. From 1999 to 2004, the WBH tumor registry data demonstrated that minorities represented 8.6% of cancers registered, whereas the average yearly minority enrollment from 2002 to 2004 was 5.4%. After initiation of the MOP, minority accrual doubled to 11% by 2010 with stable minority demographics. CONCLUSIONS: The current findings support the importance of a CCOP in supporting the accrual of patients to national clinical trials and increasing access to state-of-the art research. These data also strongly support focusing additional energy and educational efforts on targeting minority representation in clinical trials.


Assuntos
Ensaios Clínicos como Assunto/estatística & dados numéricos , Relações Comunidade-Instituição , Hospitais Comunitários/estatística & dados numéricos , Oncologia/estatística & dados numéricos , Grupos Minoritários/estatística & dados numéricos , Neoplasias , Seleção de Pacientes , Idoso , Idoso de 80 Anos ou mais , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Oncologia/normas , Oncologia/tendências , Michigan/epidemiologia , Neoplasias/diagnóstico , Neoplasias/terapia , Avaliação de Programas e Projetos de Saúde , Distribuição por Sexo
4.
J Neuroimmunol ; 233(1-2): 54-64, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21186063

RESUMO

Normal aging processes, as well as, psychological stress affect the immune system; each can act alone, or interact with each other, to cause dysregulation of immune function substantially altering physical and mental health. The sympathetic nervous system (SNS), a major mediator of stress effects on immune function, is significantly affected by normal aging process, and stress can affect aging of the SNS. Previously, we have shown age-associated changes in sympathetic noradrenergic (NA) innervation of lymphoid organs in male rodents that affect immune regulation. The purpose of this study was to investigate sympathetic innervation of lymphoid organs and associated alterations in immune responses in young and aging female Fischer 344 (F344) rats. Histofluorescence and immunocytochemistry for NA innervation, and neurochemistry for norepinephrine (NE) levels were performed in the thymus, spleen, and mesenteric lymph nodes (MLN) isolated from 3-month-old young (normal estrous cycle), 8- to 9-month-old (onset of irregular estrous cycling), and 24-25 month, and 30-31 month female F344 rats (acyclic) at diestrus based on vaginal smears. Age-related alterations in natural killer (NK) cell activity, interleukin-2 (IL-2) and interferon-γ (IFN-γ) production, T and B lymphocyte proliferation were examined in splenocytes. Sympathetic NA innervation and NE levels increased with aging in the thymus, declined in spleen and MLN, and was accompanied by significant reductions in NK cell activity, IL-2 and IFN-γ production, and T and B cell proliferation in old female rats. In 8-9 mo rats, NE levels in the hilar region of the spleen and IFN-γ production were unaltered, while NE levels in the end region of the spleen and IL-2 production were reduced. Collectively, these results suggest that aging is characterized by significant alterations in sympathetic NA innervation in the thymus, spleen, and MLN associated with immunosuppression, and that there is a marked shift in NA activity and immune reactivity occurring during middle-aged female rats.


Assuntos
Envelhecimento/imunologia , Tecido Linfoide/imunologia , Tecido Linfoide/inervação , Inibição Neural/imunologia , Norepinefrina/fisiologia , Fibras Simpáticas Pós-Ganglionares/patologia , Envelhecimento/patologia , Animais , Modelos Animais de Doenças , Feminino , Tecido Linfoide/patologia , Mesentério/imunologia , Mesentério/inervação , Ratos , Ratos Endogâmicos F344 , Baço/imunologia , Baço/inervação , Baço/patologia , Fibras Simpáticas Pós-Ganglionares/citologia
6.
Exp Gerontol ; 39(9): 1347-60, 2004 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-15489058

RESUMO

We explored the effects of aging on macrophage function in male BALB/c mice from three age groups: young (2 months), middle-aged (12 months), and old (21 months). Macrophages were collected from alveoli, peritonea, and spleens of each age group. Cells were cultured in vitro with LPS or LPS+IFN-gamma and assayed for production of IL-1, IL-12, NO, and TNF-alpha. Using herpes simplex virus-1, age-related changes in intrinsic antiviral resistance (plaque assay) and extrinsic antiviral resistance (NO and TNF-alpha production) were determined in alveolar and/or peritoneal macrophages. Effects of chronic exercise on age-related macrophage changes were examined. In vitro, macrophages from the alveoli and spleen of older mice generally produced more cytokine and NO compared to younger counterparts. Conversely, macrophages from the peritonea of older mice generally produced less cytokine and NO in vitro compared to younger counterparts. Alveolar macrophages from both old and young mice showed higher intrinsic antiviral resistance to HSV-1 compared to middle-aged mice, while peritoneal macrophages from young mice showed reduced intrinsic resistance compared to those from both middle-aged and old mice. When challenged with HSV-1, a trend towards decreased peritoneal macrophage production of TNF-alpha and decreased alveolar macrophage production of IL-12 with advancing age was found. Chronic moderate exercise tended to reverse age-associated changes in macrophage function in old mice.


Assuntos
Envelhecimento/imunologia , Macrófagos/imunologia , Atividade Motora/imunologia , Animais , Células Cultivadas , Citocinas/biossíntese , Herpes Simples/imunologia , Herpesvirus Humano 1 , Ativação de Macrófagos , Macrófagos Alveolares/imunologia , Macrófagos Peritoneais/imunologia , Macrófagos Peritoneais/virologia , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/biossíntese , Baço/imunologia , Replicação Viral/imunologia
7.
Neurobiol Aging ; 25(2): 209-21, 2004 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-14749139

RESUMO

In the present study, young (5-month-old (mo)) and aged (24 mo) adult male Fischer-344 (F344) rats were assigned to experimental groups based upon their performance of a reference memory task in the Morris water maze and reactivity to a novel palatable taste in a gustatory neophobia task. Levels of norepinephrine (NE) and its metabolite 3-methoxy-4-hydroxy-phenylglycol (MHPG) were assayed via high performance liquid chromatography (HPLC) in brain regions associated with the locus coeruleus (LC)-hippocampus-cortex system and A1/A2-hypothalamic system. Binding of ligands specific for alpha-1, alpha-2, beta-1, and beta-2 receptors was assessed in hippocampus and cortex with receptor autoradiography. Impaired acquisition and retention of the water maze task and gustatory neophobia in aged rats was primarily associated with decreased NE activity in cingulate cortex (CC) as indicated by a significant reduction in the MHPG/NE ratio coupled with increased NE content. No significant changes in adrenergic receptor binding were detected in any region sampled. The results suggest that an aging-related reduction in cortical NE neurotransmission is associated with the expression of increased neophobia and deficits in spatial learning and memory performance occurring with advanced age in rats.


Assuntos
Envelhecimento/fisiologia , Transtornos da Memória/fisiopatologia , Norepinefrina/metabolismo , Transtornos Fóbicos/fisiopatologia , Agonistas alfa-Adrenérgicos/farmacocinética , Antagonistas Adrenérgicos alfa/farmacocinética , Antagonistas Adrenérgicos beta/farmacocinética , Animais , Autorradiografia , Aprendizagem da Esquiva , Comportamento Animal , Química Encefálica , Córtex Cerebral/anatomia & histologia , Córtex Cerebral/metabolismo , Córtex Cerebral/fisiopatologia , Cromatografia Líquida de Alta Pressão , Clonidina/farmacocinética , Hipocampo/metabolismo , Hipocampo/fisiopatologia , Iodocianopindolol/farmacocinética , Masculino , Aprendizagem em Labirinto/fisiologia , Metoxi-Hidroxifenilglicol/metabolismo , Prazosina/farmacocinética , Ensaio Radioligante/métodos , Ratos , Ratos Endogâmicos F344 , Percepção Espacial/efeitos dos fármacos
8.
Brain Behav Immun ; 17(2): 94-109, 2003 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-12676572

RESUMO

In susceptible strains of mice, the LP-BM5 mixture of murine retroviruses induces the fatal immunodeficiency disease known as murine acquired immunodeficiency syndrome (murine AIDS or MAIDS). We have previously reported that murine AIDS produces a profound depletion of splenic norepinephrine (NE). Here, we demonstrate that NE depletion is limited to the spleen, a major site affected by LP-BM5 infection. NE depletion in the spleen is first observed at two weeks following LP-BM5 inoculation, concurrent with the onset of splenomegaly, and continues through 12 weeks post-infection. Neuroanatomical studies revealed that the reduction in NE is due to destruction of splenic sympathetic nerve fibers. Administration of the NE reuptake blocker desipramine did not prevent LP-BM5-induced NE depletion, suggesting that destruction is not caused by excess release and reuptake of NE. Elucidating the mechanism of MAIDS-induced sympathetic nerve destruction may provide insight into autonomic and peripheral neuropathies reported in people with AIDS.


Assuntos
Doenças do Sistema Nervoso Autônomo/virologia , Síndrome de Imunodeficiência Adquirida Murina/complicações , Baço/inervação , Inibidores da Captação Adrenérgica/farmacologia , Animais , Doenças do Sistema Nervoso Autônomo/tratamento farmacológico , Doenças do Sistema Nervoso Autônomo/metabolismo , Desipramina/farmacologia , Progressão da Doença , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Norepinefrina/metabolismo , Oxirredução
9.
Mech Ageing Dev ; 123(8): 1065-79, 2002 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-12044956

RESUMO

The aging process is characterized by a decline in cellular functions of diverse systems of the body, including the neuroendocrine-immune network. One neuroendocrinological theory of aging is based on findings that the loss of hypothalamic neurotransmitter functions and an imbalance in hormonal secretion contribute to the cessation of reproductive cycles and the development of mammary and pituitary tumors. One potential cause of immunosenescence is an age-related decline in the regulatory functions of sympathetic noradrenergic nerve fibers whose neurotransmitters signal lymphoid cells in the bone marrow, thymus, spleen, and lymph nodes. In addition to impairment caused by the generation of free radicals during numerous biochemical processes, there is a shift in the pro-oxidant/anti-oxidant balance resulting in cellular oxidative stress and hastening the aging process. Altered interactions between the neuroendocrine system and the immune system are associated with increased incidence, development, and growth of breast cancer and other neoplastic diseases. We have demonstrated that the disruption in the neuroendocrine-immune interactions in old rats, and in female rats with mammary tumors, can be reversed by deprenyl, a monoamine oxidase inhibitor. Deprenyl treatment leads to enhanced central and peripheral catecholaminergic activity and a readjustment of immunological responses. In this brief review, the nature and changes in the bi-directional communication between the neuroendocrine system and immune system and the possible mechanism(s) of actions of deprenyl in restoring these interactions during aging and mammary cancer are discussed.


Assuntos
Envelhecimento/efeitos dos fármacos , Anfetaminas/farmacologia , Neoplasias Mamárias Animais/tratamento farmacológico , Neuroimunomodulação/efeitos dos fármacos , Fármacos Neuroprotetores/farmacologia , Selegilina/farmacologia , Transdução de Sinais/efeitos dos fármacos , Animais , Sistema Cardiovascular/efeitos dos fármacos , Humanos , Sistema Imunitário/efeitos dos fármacos , Sistema Imunitário/imunologia , Sistema Imunitário/fisiologia , Tecido Linfoide , Neoplasias Mamárias Animais/imunologia , Neuroimunomodulação/imunologia , Neuroimunomodulação/fisiologia , Sistemas Neurossecretores/efeitos dos fármacos , Sistemas Neurossecretores/imunologia , Sistemas Neurossecretores/fisiologia
10.
Brain Behav Immun ; 16(3): 247-61, 2002 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-12009685

RESUMO

Previous findings from our laboratory revealed an age-related decline in noradrenergic (NA) sympathetic innervation of the spleen in male Fischer 344 (F344) rats. The purpose of this study was to determine whether other rat strains also progressively lose NA sympathetic nerves in the aging spleen. Sympathetic innervation of spleens from 3- and 21-month-old male F344, Brown Norway (BN), BN X F344 (BNF(1)), and Lewis rats was examined using fluorescence histochemistry to localize catecholamines combined with morphometric analysis and using high-performance liquid chromatography with electrochemical detection for measuring norepinephrine (NE). Neurochemistry revealed a significant age-related decline in NE concentrations in spleens from F344 and Lewis rats. In contrast, there was no effect of age on splenic NE concentrations in BN or BNF(1) rats. Consistent with neurochemical analysis, fluorescence histochemistry revealed a striking decline in NA innervation of spleens from old F344 and Lewis rats not observed in the other two strains. However, in BN and BNF(1) rats, nerve fibers were diminished in distal portions of the spleen but not in the hilar regions. Morphometric analysis confirmed neurochemical and histological findings, revealing approximately 65-70% loss in NA nerve density in spleens from F344 and Lewis rats. These findings indicate that age-related changes in sympathetic innervation of the rat spleen are strain-dependent. Whether the loss of sympathetic nerves in spleens from F344 and Lewis rats is associated with age-related changes in the splenic microenvironment remains to be determined. The functional significance of altered sympathetic innervation of the spleen with advancing age is discussed.


Assuntos
Envelhecimento/fisiologia , Baço/inervação , Sistema Nervoso Simpático/fisiologia , Animais , Arteríolas/inervação , Masculino , Neuroimunomodulação/fisiologia , Norepinefrina/análise , Ratos , Ratos Endogâmicos BN , Ratos Endogâmicos F344 , Ratos Endogâmicos Lew , Especificidade da Espécie , Baço/irrigação sanguínea , Baço/química , Sistema Nervoso Simpático/química
11.
Brain Behav Immun ; 16(2): 118-39, 2002 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-11908922

RESUMO

Numerous studies have shown that alterations in sympathetic nervous system (SNS) function produced by beta-adrenergic receptor blockade or chemical sympathectomy can produce changes in T and B lymphocyte function and both innate and acquired immune responses. However, fewer studies have investigated changes in immune response following SNS alterations in animal models of disease. We tested whether blocking SNS activity using 6-OHDA or the beta-receptor antagonist nadolol alters the typical pattern in production of T helper 1 (Th1) and Th2 cytokines seen in cultures of spleen cells from C57BL/6 mice infected with murine AIDS (MAIDS). We found that neither method of sympathetic blockade affected cytokine response to MAIDS. We also found that the norepinephrine concentration and content of the spleen were reduced dramatically by the MAIDS infection itself at 3 and 6 weeks after LP-BM5 inoculation. This finding has not been previously reported in mice with MAIDS and suggests that the viral infection itself produces a functional sympathectomy in the spleen, a target of that infection.


Assuntos
Antagonistas Adrenérgicos beta/administração & dosagem , Síndrome de Imunodeficiência Adquirida Murina/fisiopatologia , Nadolol/administração & dosagem , Norepinefrina/análise , Baço/efeitos dos fármacos , Baço/imunologia , Simpatectomia/efeitos adversos , Animais , Contagem de Células , Técnicas de Cultura de Células , Cromatografia Líquida de Alta Pressão , Imunoglobulina G/sangue , Injeções Intraperitoneais , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Síndrome de Imunodeficiência Adquirida Murina/imunologia , Norepinefrina/imunologia , Oxidopamina/administração & dosagem , Retroviridae , Baço/virologia , Simpatectomia/métodos , Simpatolíticos/administração & dosagem
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