ABSTRACT
PURPOSE: To further elucidate possible immune-modulatory effects of valproate (VPA) or levetiracetam (LEV), we investigated their influence on apoptosis and cytotoxic function of CD8+ T lymphocytes in humans. METHODS: In 15 healthy subjects (9 female (60%), 35.7±12.1 years), apoptosis and cytotoxic function of CD8+ T lymphocytes were measured using flow cytometry following in vitro exposure to LEV (5 mg/L and 50 mg/L) and VPA (10mg/L and 100 mg/L). Apoptosis rates were determined after incubation with LEV or VPA for 1 h or 24 h. Cytotoxic function was assessed following 2h stimulation with mixed virus peptides, using perforin release, CD107a/b expression and proliferation. The presence of synaptic vesicle protein 2A (SV2A) was investigated in human CD8+ T lymphocytes by flow cytometry analysis, Western blot and real time polymerase chain reaction (rtPCR). RESULTS: High concentration of LEV decreased perforin release of CD8+ T lymphocytes (LEV 50 mg/L vs. CEF only: 21.4% (interquartile range (IQR) 16.5-35.9%) vs. 16.6% (IQR 12-24.9%), p=0.002). LEV had no influence on apoptosis and proliferation (p>0.05). VPA (100 mg/L) slowed apoptosis of CD8() T lymphocytes after 24h (VPA 100mg/L vs. control: 7.3% (IQR 5.4-9.5%) vs. 11.3% (IQR 8.2-15.1%), p<0.001), but had no effects on perforin release (p>0.05). SV2A protein was detected in CD8+ T lymphocytes. CONCLUSION: LEV decreased degranulation of CD8+ T lymphocytes which may contribute to the increased incidence of upper respiratory tract infections in LEV treated patients. Inhibition of SV2A may be responsible for this effect.
Subject(s)
Anticonvulsants/pharmacology , CD8-Positive T-Lymphocytes/drug effects , Piracetam/analogs & derivatives , Valproic Acid/pharmacology , Adolescent , Adult , Antigens, CD/metabolism , Apoptosis/drug effects , Cell Proliferation/drug effects , Dose-Response Relationship, Drug , Female , Flow Cytometry , Humans , Levetiracetam , Male , Membrane Glycoproteins/metabolism , Middle Aged , Nerve Tissue Proteins/metabolism , Perforin/metabolism , Piracetam/pharmacology , Statistics, Nonparametric , Young AdultABSTRACT
Arterial aging is a predominant risk factor for the onset of cardiovascular diseases, such as hypertension, myocardial infarction, or stroke. Aging is associated with intravascular renin-angiotensin system activation, increased vascular stiffness, intima-media thickening, and a proinflammatory phenotype. Little is known about the influence of aldosterone on arterial aging. Hence, we hypothesized that aldosterone and mineralocorticoid receptor (MR) activation might contribute to and possibly accelerate the arterial aging process. We demonstrate increased MR expression in whole aortae and early passage aortic vascular smooth muscle cells from aged (30 months) compared with adult (8 months) F344XBN rats. Sensitivity to aldosterone-induced extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase activity is increased in aged cells. MR blockade and extracellular signal-regulated kinase 1/2 mitogen-activated protein kinase inhibition prevent age-associated increases of transforming growth factor-beta, intercellular adhesion molecule 1, and procollagen 1. Aldosterone increases expression of proinflammatory marker proteins, shifting the phenotype of adult vascular smooth muscle cells toward the proinflammatory phenotype of aged rats. Epidermal growth factor receptor expression is increased with age and by aldosterone, and inhibition of epidermal growth factor receptor tyrosine kinase decreases age-associated proinflammatory marker expression. Our data support the hypothesis that increased constitutive MR signaling may promote and amplify age-associated inflammation that accompanies arterial aging through increased angiotensin II-stimulated expression of MR and enhanced sensitivity to aldosterone-mediated extracellular signal-regulated kinase 1/2 activation, likely related to increased epidermal growth factor receptor expression.
