Editor's Comment: In this study, the researchers implicated a peptide named Diazepam Binding Inhibitor (DBI) as a source of fatigue in patients receiving androgen deprivation therapy for prostate cancer, and in patients with ME/CFS. DBI is a natural GABA-A inverse agonist, that is, it produces the opposite effects of anxiolytics (e.g. Valium). Subjects injected with synthetic DBI experience sweating, nausea, palpitations, tightness in the chest, restlessness and generalized anxiety. Certain steroids, among which is DHEA, the precursor to estrogen, bind to GABA-A receptors, producing effects similar to anxiolytics. Other hormones, such as pregnenolone, the precursor to progesterone, have effects similar to DBI. The implication of this study for ME/CFS patients is that increased DBI not only is related to heightened anxiety states (i.e. upregulated sympathetic activity), but to fatigue as well.
By K. C. Light et al.
BACKGROUND: Androgen deprivation therapy (ADT) often worsens fatigue in patients with prostate cancer, producing symptoms similar to chronic fatigue syndrome (CFS). Comparing expression (mRNA) of many fatigue-related genes in patients with ADT-treated prostate cancer versus with CFS versus healthy controls, and correlating mRNA with fatigue severity may clarify the differing pathways underlying fatigue in these conditions.
METHODS: Quantitative real-time PCR was performed on leukocytes from 30 fatigued, ADT-treated prostate cancer patients (PCF), 39 patients with CFS and 22 controls aged 40-79, together with ratings of fatigue and pain severity. 46 genes from these pathways were included: (1) adrenergic/monoamine/neuropeptides, (2) immune, (3) metabolite-detecting, (4) mitochondrial/energy, (5) transcription factors.
RESULTS: PCF patients showed higher expression than controls or CFS of 2 immune transcription genes (NR3C1 and TLR4), chemokine CXCR4, and mitochondrial gene SOD2. They showed lower expression of 2 vasodilation-related genes (ADRB2 and VIPR2), 2 cytokines (TNF and LTA), and 2 metabolite-detecting receptors (ASIC3 and P2RX7). CFS patients showed higher P2RX7 and lower HSPA2 versus controls and PCF. Correlations with fatigue severity were similar in PCF and CFS for only DBI, the GABA-A receptor modulator (r=-0.50, p<0.005 and r=-0.34, p<0.05). Purinergic P2RY1 was correlated only with PCF fatigue and pain severity (r=+0.43 and +0.59, p=0.025 and p=0.001).
CONCLUSIONS: PCF patients differed from controls and CFS in mean expression of 10 genes from all 5 pathways. Correlations with fatigue severity implicated DBI for both patient groups and P2RY1 for PCF only. These pathways may provide new targets for interventions to reduce fatigue.
Copyright © 2013 Elsevier Ltd. All rights reserved.
Source: Psychoneuroendocrinology. 2013 Sep 6. pii: S0306-4530(13)00297-7. doi: 10.1016/j.psyneuen.2013.08.008. [Epub ahead of print]. Light KC, Agarwal N, Iacob E, White AT, Kinney AY, Vanhaitsma TA, Aizad H, Hughen RW, Bateman L, Light AR.Department of Anesthesiology, University of Utah Health Sciences Center, Salt Lake City, UT, USA. Electronic address: email@example.com.