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作者 Perez, Sam David
書名 Aging and Sympathetic Neurotransmission in Two Strains of Rats that Differ in Longevity and Immune Profiles
國際標準書號 9781124824345
book jacket
說明 246 p
附註 Source: Dissertation Abstracts International, Volume: 72-11, Section: B, page: 6563
Adviser: Denise L. Bellinger
Thesis (Ph.D.)--Loma Linda University, 2011
Age-related changes in sympathetic neurotransmission in immune organs may be associated with immunosenescence; however no causal relationship has been established. From previous studies in Fischer rats (F344), we have found that during middle age, sympathetic nerve activity (SNA) rises in the spleen followed by a decline in noradrenergic (NA) innervation. Also, increased sympathetic signaling via beta-adrenergic receptor (beta-AR) and reduced proliferation of lymphocytes are evident with increasing age. Although SNA progressively rises with age, effects of age on sympathetic factors may be different across rat strains. If causal relationships exist between sympathetic activity and immune function, they may be related to genotypic differences. Therefore, our research consisted in two major studies. First, in a longitudinal study, we characterized the age-related change in sympathetic innervation and sympathetic activity/tone in Brown Norway (BN) rats. The BN rat strain has a longer life span, a different aging pattern of NA innervation in the spleen, and a different immune profile compared to the F344 rat. Second, after establishing the time point during which sympathetic activity and NA innervation profiles in the spleens of these rats change, we investigated the role of increased SNA on neurotransmission in the spleen, as an initial step before determining causal relationships between immune decline and altered sympathetic function with age. For the longitudinal study in BN rats, we examined NA innervation in the spleens of animals at 8, 15, 18, 24, 27, and 32 months of age (8M, 15M, 18M, 24M, 27M and 32M) by histofluorescence for catecholamines and confirmed with morphometric analysis. We measured the concentrations of splenic norepinephrine (NE) and circulating catecholamines after decapitation using high-performance liquid chromatography (HPLC). For our second study, middle-aged BN or F344 rats received a 90-day treatment with rilmenidine, a centrally acting antihypertensive drug
In our first study, we observed a decline in NA nerve density in the splenic white pulp (45%) of BN rats at 15M. Lower splenic NE concentrations followed at 18M, and were strongly correlated with nerve density. Circulating catecholamine (CA) levels generally dropped with increasing age. In our second study, 15M male F344 and BN rats were intraperitoneally (i.p.) injected with 0, 0.5 or 1.5 microg/kg/day rilmenidine (Veh-18M, Rilmlo, Rilm hi, respectively). Untreated 3M (Crtl-3M) and 18M rats (Crtl-18M) were used to control for effects of aging and handling/injection stress. We evaluated splenic NE concentration with or without synthesis blockade, NA innervation, beta-AR expression, and beta-AR-stimulated c-AMP production using HPLC, fluorescence histochemistry, beta-AR radioligand binding, and enzyme-linked immunoassay (EIA), respectively. We evaluated beta-AR expression by beta-AR radioligand binding assay. Rilmenidine reduced circulating NE without a change in epinephrine (EPI), and reduced SNA as assessed by reduced NE turnover rate after synthesis blockade in both F344 and BN rats. We observed restorative effects of rilmenidine on splenic NA innervation in both rat strains in a dose-dependent manner, supporting the hypothesis that heightened SNA contributes to nerve destruction. Splenocyte beta-AR density was increased by the optimum dose (Rilmlo), without changing affinity. beta-AR-stimulated cAMP production was further augmented by either dose of rilmenidine in F344 rats; while in BN rats, Rilmlo partially reversed the age-related decline in beta-AR-stimulated cAMP production. Collectively, the results from these studies demonstrate an increase in splenic SNA during middle age that affects NA neurotransmission in the aging spleen in strain-specific manner. Chronic treatment with rilmenidine protected sympathetic nerves, and further enhanced beta-AR-mediated signaling in the spleen of F344 rats. No significant effects on sympathetic nerves or beta-AR-mediated signaling were found in the spleen of BN rats treated with rilmenidine compared with age-matched controls. These findings suggest that rilmenidine could affect host defense against age-related diseases, by modulating sympathetic signaling. Further, they will form the foundation for further development of shorter- and longer-lived rodent models with differing immune phenotypes to investigate causal relationships between sympathetic nervous system (SNS) and immune function in aging
School code: 0106
Host Item Dissertation Abstracts International 72-11B
主題 Biology, Neuroscience
Health Sciences, Pharmacology
Health Sciences, Aging
0317
0419
0493
Alt Author Loma Linda University. Physiology
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