Oxidative stress and anxiety
Anxiety, stress and depression are common neuropsychiatric features in diabetic patients. A causal relationship has been found between cellular oxidative stress, . Oxidative stress and anxiety: Relationship and cellular pathways. Oxidat. Neurotoxicologie Alimentaire et Bioactivit, UR AFPA, Universit Paul Verlaine de Metz-INPL, INRA, Metz, France. Received 16 January ;. Oxidative stress has been proposed as a common factor for anxiety and .. R. Oxidative stress and anxiety: relationship and cellular pathways.
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Oxidative Medicine and Cellular Longevity
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Exercise prevents sleep deprivation-associated anxiety-like behavior in rats: Introduction Anxiety is one the most prevalent forms of psychological distress1. Phobic anxiety, in particular, is an important category within the broad dimension of psychological distress, due to its early age-at-onset and chronic and persistent nature1,2. Phobic anxiety has been found to be associated with cardiovascular disease3,4, and sudden death4, and it has been hypothesized to have adverse biological consequences, such as higher oxidative stress and inflammation Potential associations of phobic anxiety with oxidative stress are particularly intriguing, as oxidative damage is hypothesized not only to be a biological consequence of chronic psychological distress but also to play an important role in the development of psychopathology, including anxiety8.
Prior evidence has indicated higher levels of oxidative stress across a range of psychological disorders. For example, in a study conducted by Kuloglu et al. Similarly, higher levels of a calculated oxidative stress index ratio of urine isoprostanes to serum vitamin E levels were observed among 58 participants with high levels of perceived stress Additionally, higher levels of 8-hydrocydeoxyguanosine, a marker of oxidative DNA damage, were found among 90 women with clinical depression in comparison to age-matched controls Although numerous reports have positioned oxidative stress as one of several potential downstream physiologic consequences of chronic adverse psychological states i.
Indeed, some investigators5,6,9,16 have hypothesized an etiologic role of oxidative stress in the development of psychological distress symptoms and psychiatric disorders.
For example, studies conducted in mice found that genes involved with antioxidative metabolism were highly related to anxiety-like phenotypes, pointing to a relation of oxidative stress in the etiology of anxiety Nevertheless, such work remains little explored in humans. Higher levels of oxidative stress in particular, elevated lipid peroxidation products have been associated with depression20, anxiety disorders5, and obsessive-compulsive disorders6,21 but not with post-traumatic stress disorder22 in cross-sectional studies.
Additionally, results from one study indicated that anxious women had impairment of several immune functions, including reduced total antioxidant capacity Overall, gaps remain in understanding how levels of anxiety relate to measures of oxidative stress.
- Oxidative stress and anxiety
Furthermore, there have been very few larger-sample studies conducted among well-characterized participants such that important confounders may be addressed. Thus, the objective of this study was to examine the cross-sectional relations between phobic anxiety and fluorescent oxidation products FlOPs in a large sample of mid-life and older adult women in the Nurses' Health Study. This study design has value in addressing psychological distress-oxidative stress associations for two key reasons: Details regarding the NHS and validation of various health exposures and endpoints have been previously published24, During the questionnaire cycle, participants were asked to complete the Crown-Crisp Index CCI of phobic anxiety26, From to32, NHS participants provided blood samples; details of the blood collection and archival methods have been previously described28, Briefly, blood samples were collected from NHS participants using tubes treated with liquid sodium heparin.
The tubes were then placed on ice packs, stored in Styrofoam containers, returned to the laboratory by overnight courier, centrifuged, and divided into aliquots for storage in liquid-nitrogen freezers oC or colder. The majority of specimens arrived at our lab for processing within 24 hours of collection Blood donors gave written infor-med consent to having their samples used for research purposed. In addition, all data was analyzed anonymously. We excluded women with insufficient CCI data i.
Thus, the sample for analysis included 1, women. Assessment of phobic anxiety: It has been validated in psychiatric outpatient settings and found to discriminate patients with general anxiety and phobias from healthy controls or those with disorders consisting of other symptom dimensions i. The CCI primarily covers aspects of "fear" disorders, such as panic disorder and agoraphobia. It features 8 self-rated questions, and total scores range from 0 to 16 points higher scores indicate higher phobic anxiety.
Oxidative stress and anxiety: relationship and cellular pathways.
As in prior work32, for those missing data on 1 or 2 items, we based the CCI sum score on only the answered items, rather than imputing CCI scores using the mean, as this may be a slightly more conservative approach to missing responses on self-reported symptom measures. CCI scores were are not normally distributed and in keeping with prior work33,34 we categorized CCI scores into 5 groups: The consistency of the score also points to the validity of the CCI in measuring phobic anxiety, as phobic anxiety is expected to be generally stable over time1.
Measurement of FLOPs Fluorescent oxidation products FlOPs result from the interaction of reactive oxygen intermediates and free radicals with macromolecules Our fluorescent method provides a non-specific, but sensitive, measure of oxidative products from lipids, protein, carbohydrate and DNA, and is considered a global measure of oxidation37, Measurement of fluorescent oxidation products FlOPs were performed with procedures previously described37, Briefly, plasma was extracted with ethanol-ether and measurements were obtained using a spectrofluorometer.5 - Understanding relationships - Stress, Anxiety, Conflicts, Depression
FlOPs reflect lipid oxidation products from reactions with protein, DNA, and carbohydrate and the fluorescence was determined as relative fluorescence units per millimeter of plasma. In a previous prospective study involving a parallel cohort of men, we found this global measure of oxidation was stable in plasma samples that had been previously collected and placed in storage for 10 years, and reproducibility of FlOPs is high - with ICCs in paired samples up to three years apart that ranged from 0.
Oxidative stress and anxiety: relationship and cellular pathways.
Furthermore, the measure showed good validity: We measured three different FlOPs: The mean coefficients of variation CVs for FlOPs across the different lab batches used for our study were adequate and ranged from 7.
In addition, FlOPs were shown to have better stability in plasma over hours compared to more specific biomarkers of oxidative stress such as MDA or F2-isoprostanes Assessment of covariates In addition to age-at-blood collection increasing age is well-known to be related to cumulative oxidative stresswe considered numerous variables potentially associated with phobic anxiety and FlOPs.
Using the biennial questionnaire completed proximal to blood collection and a supplemental questionnaire administered at blood collection, we obtained information on numerous health, social and lifestyle factors for inclusion in multi-variable models: Statistical analyses The distributions of FlOPs varied across batch sets from each nested case-control studies and the cognitive study.
Therefore, we adjusted FlOP levels for batch according to methods describe by Rosner et al. Statistical outliers were identified using the generalized extreme studentized deviate many-outlier detection approach To examine the relationship between phobic anxiety and FlOPs, we estimated adjusted least-squares means of the log-transformed FlOPs using generalized linear models. For all analyses, we looked at both age-adjusted and multivariable-adjusted models.
In multivariable analyses, we considered factors that had the largest potential to contribute to confounding and additional covariates identified in prior literature. All statistical analyses were performed using SAS version 9. Women in the highest quartiles of FlOPs were more likely to be current smokers, have hypertension, and consume greater amounts of alcohol. Results from the global F-test demonstrated that none of the means were significantly different across categories of phobic anxiety score for any of the FlOPs.
Findings remained similar after adjusting for other covariates Table 2. In both age-adjusted and multivariable-adjusted logistic regression models there were no statistically significant associations between quartiles of any of the FlOPs with likelihood of having the highest level of phobic anxiety and all tests of trends were statistically non-significant Table 3.
Similarly, in both age-adjusted and multivariable-adjusted polytomous logistic models, there were no statistically significant associations found between the three different FlOPs and levels of phobic anxiety, including sub-threshold and minimal levels of anxiety Supplementary Table 1. Discussion In this cross-sectional study of 1, women, we found no significant associations between phobic anxiety and plasma fluorescent oxidation products, a global measure of oxidative stress measured at three wavelengths.
Furthermore, results did not change after adjustment for numerous potential confounders. The null findings in the current study can be contrasted with previously reported evidence for links between psychological distress conditions, such as anxiety, and other oxidative stress markers. For example, several groups reported associations between MDA a lipid peroxidation product and specific psychiatric disorders, such as social phobia16, panic disorder5 and major depressive disorder20, In addition, oxidative DNA damage has been observed among patients with major depressive disorder47 and bipolar disorder Furthermore, such evidence has not been limited to psychiatric clinical populations.
For example, Irie et al. By contrast, in the current analysis we ascertained phobic anxiety -across a range from no to high levels of symptoms- in a large sample of over 1, community-dwelling participants and we utilized a global marker of oxidative stress. The results in this report are also somewhat surprising in light of recent findings of a significant relation of high phobic anxiety to shorter relative leukocyte telomere lengths Thus, we might have expected an association between phobic anxiety and our plasma measure of oxidative stress, as telomere shortening is influenced by oxidative stress Furthermore, while it would have been useful to examine directly the correlation between telomere length and FlOPs within these same participants, there was not adequate overlap in these two samples in order to undertake this.
Finally, an important potential explanation for the differing findings is that, compared to FLOPs, shorter telomeres may be more likely to reflect the cumulative impacts of oxidative stress over long periods of time.
Thus, the prior work using the telomere measure may have been less affected by the limitations inherent to using one-time biomarker measures in a cross-sectional design. This study has a number of strengths including use of a validated anxiety symptom scale, a large well-characterized sample, and adjustment for a large number of potential confounding factors. Potential limitations should also be considered. FlOPs are sensitive yet non-specific markers of global oxidative stress.
Thus, we could not address whether a more specific biomarker e.
It is possible that phobic anxiety is related to elevations in specific oxidation pathways e. This offers a potential explanation for the different findings in the current analysis and prior studies that identified significant associations between psychological symptoms and specific markers for lipid or DNA oxidation. Furthermore, FlOPs may reflect other products besides oxidation that may generate fluorescence The design of this study was cross-sectional and thus cannot inform the evidence base regarding the temporal relationship between phobic anxiety and systemic oxidative stress.
Lastly, although we were able to adjust for numerous covariates, confounding by unmeasured factors is still possible, as may occur in any observational study. However, the relative homogeneity of our cohort reduces potential influences of many important unmeasured confounders, such as those relate to health knowledge or access to care.
Phobic anxiety and plasma levels of global oxidative stress in women
In summary, phobic anxiety levels were not associated with plasma fluorescent oxidation products measured at three different wavelengths among participants in this large cross-sectional study.
As FlOPs are a non-specific marker of global oxidative stress, future research on this topic may be enhanced by use of more specific biomarkers, such as DNA-related markers. Acknowledgements The funders had no role in the study design, data collection and analysis, decisions to publish, or preparation of the manuscript.
The authors thank Dr. Mary Townsend for her assistance with the data preparation and manuscript.