Sympathetic Nervous System and Lymphocyte Proliferation in the Fischer 344 Rat Spleen: A Longitudinal Study

Abstract

Aging is associated with reduced cellular immunity, which leads to increased rates of infectious disease, cancer and autoimmunity in the elderly. Previous findings from our laboratory revealed an age-related decline in sympathetic innervation of immune organs that affects immunity. These studies suggested potential sympathetic nervous system involvement in age-induced immune dysregulation. Objectives: The purpose of this study was to longitudinally characterize the effects of age on sympathetic neurotransmission in the spleen and net sympathetic activity/tone in male Fischer 344 rats. Methods: Splenic sympathetic neurotransmission was evaluated between 8 and 24 months of age by (1) splenic norepinephrine (NE) concentration and turnover, (2) β-adrenergic receptor (β-AR) expression and (3) β-AR-stimulated splenocyte cAMP production. Measures of sympathetic neurotransmission were correlated with age-related changes in Concanavalin A (Con A)-stimulated splenocyte proliferation. Results: Splenic NE turnover increased during middle age, then subsequently declined by 18 months of age compared with 8-month-old controls (young). Splenic NE concentration increased at 10 months and decreased at 18–24 months, compared with young rats; however, plasma NE levels were not affected by age. Plasma epinephrine levels were decreased at 24 months. NE synthesis blockade increased and decreased the rate of plasma catecholamine depletion in middle and old age, respectively. β-AR-stimulated cAMP production increased in splenocytes by 15 months. An age-related decrease in Con A-induced splenocyte proliferation was apparent by 10 months and persisted through 24 months. The decline in Con A-induced splenocyte proliferation correlated with the age-related increase in cAMP production. Conclusions: Aging alters sympathetic nervous system metabolism in the spleen to affect β-AR signaling to splenocytes, suggesting that altered sympathetic-immune modulation changes are evident by early middle age.

Sympathetic innervation, norepinephrine content, and norepinephrine turnover in orthotopic and spontaneous models of breast cancer

“…NE turnover was determined based on previous publications (Bellinger et al, 2008; Jones and Musacchia, 1976; Vaughan et al, 2014). On the day of NE turnover determination, 4T1 tumor-bearing mice were divided into 3 groups: 1) No injection (No Inj); 2) injected IP with α-methyl-DL-p-tyrosine methyl ester HCl (300 mg/kg AMPT; Sigma-Aldrich, St. Louis, MO dissolved in sterile saline); or 3) injected IP with sterile saline (VEH).…”

“…Tissue NE concentration is an indicator of the density of sympathetic innervation (e.g. see (Bellinger et al, 2008)), but the majority of tissue NE is located within the neuron and cannot directly be distinguished from released NE (Eisenhofer et al, 2004). With SNS activation, tissue NE concentration can increase, decrease, or not change due to the dynamic balance between processes that regulate tissue NE concentration: NE synthesis, release, reuptake, and metabolism (Eisenhofer et al, 2004).…”

“…With SNS activation, tissue NE concentration can increase, decrease, or not change due to the dynamic balance between processes that regulate tissue NE concentration: NE synthesis, release, reuptake, and metabolism (Eisenhofer et al, 2004). Therefore, NE turnover has been used as an index of sympathetic activation under a variety of conditions (Bellinger et al, 2008; Jones and Musacchia, 1976; Migliorini et al, 1997). …”

“…The rate of NE decline is a function of the rate of released NE and its subsequent metabolism. Quantitative measures of NE turnover include 1) turnover rate, the amount of NE synthesized and degraded per gram of tissue per hour, and 2) turnover time, the time required to synthesize the steady-state tissue pool of NE (Bellinger et al, 2008; Jones and Musacchia, 1976). Under conditions that activate the SNS, a higher rate of NE turnover indicates greater NE utilization as defined by the processes of synthesis, release, reuptake, and metabolism.…”

Prevention of Mammary Tumor Development through Neuroimmunomodulation in the Spleen and Lymph Nodes of Old Female Sprague-Dawley Rats by <smlcap>L</smlcap>-Deprenyl

“…Tissues were homogenized in 0.1 M of HClO 4 containing 0.25 µm of 3,4-dihydroxybenzylamine as the internal standard and centrifuged at 1,000 g for 5 min. The supernatants were used for aluminum oxide extraction as described previously [23]. At the time of HPLC-EC analysis, NE content was determined using HPLC-CD using a CouloChem III HPLC System (ESA, Chelmsford, Mass., USA) and an ESA Model 542 autosampler.…”