Journal
BRAIN BEHAVIOR AND IMMUNITY
Volume 31, Issue -, Pages 153-160Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
DOI: 10.1016/j.bbi.2012.10.010
Keywords
Interferon-alpha; Dopamine synthesis; Tyrosine metabolism; Tetrahydrobiopterin; Depression; Fatigue
Categories
Funding
- National Institutes of Health [K23 MH064619, R01 MH070553, F32 MH093054, K05 MH069124, R01 HL073921, MHR01MH075102, T32 MH020018]
- Emory Center for AIDS Research [P30 AI050409]
- PHS Grant from the Clinical and Translational Science Award program, National Institutes of Health, National Center for Research Resources [UL1 RR025008]
- PHS Grant from the General Clinical Research Center program, National Institutes of Health, National Center for Research Resources [M01 RR0039]
Ask authors/readers for more resources
Chronic exposure to interferon (IFN)-alpha, an innate immune cytokine, produces high rates of behavioral disturbances, including depression and fatigue. These effects may be mediated by the actions of IFN-alpha on dopamine (DA) metabolism in the basal ganglia. Diminished conversion of phenylalanine (Phen) to tyrosine (Tyr), the primary amino acid precursor of DA, has been associated with inflammation, and may reflect decreased activity of the enzyme phenylalanine-hydroxylase (PAH). This study investigated the peripheral Phen/Tyr ratio in relation to cerebrospinal fluid (CSF) concentrations of DA and its metabolites in subjects treated with IFN-alpha plus ribavirin for hepatitis C and controls awaiting IFN-alpha therapy. Plasma Phen/Tyr ratios were significantly increased in IFN-alpha-treated subjects (n = 25) compared to controls (n = 9), and were negatively correlated with CSF DA (r = -0.59, df = 15, p < 0.05) and its metabolite, homovanillic acid (r = -0.67, df = 15, p < 0.01), and positively correlated with fatigue (r = 0.44, df = 23, p < .05) in IFN-alpha-treated patients but not controls. Given the role of tetrahydrobiopterin (BH4) in the PAH conversion of Phen to Tyr, CSF concentrations of BH4 and its inactive oxidized form, dihydrobiopterin (BH2), were examined along with CSF interleukin (IL)-6 in a subset of patients. BH2 concentrations were significantly increased in IFN-alpha-treated patients (n = 12) compared to controls (n = 7), and decreased CSF BH4 concentrations correlated with increased CSF IL-6 (r = -0.57, df = 12, p < 0.05). These results indicate that IFN-alpha is associated with decreased peripheral conversion of Phen to Tyr, which in turn is associated with reduced DA in the brain as well as fatigue. These alterations may be related to oxidation of BH4 secondary to IFN-alpha-induced activation of a CNS inflammatory response. (c) 2012 Elsevier Inc. All rights reserved.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available