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Fulltext Social stress-induced serotonin dysfunction activates spexin in male Nile tilapia (Oreochromis Niloticus)

Lim CH, Soga T, Parhar IS

Proc Natl Acad Sci U S A, 2023 Jan 17;120(3):e2117547120.
PMID: 36623187 DOI: 10.1073/pnas.2117547120

Social disturbance in interpersonal relationships is the primary source of stress in humans. Spexin (SPX, SPX1a in cichlid), an evolutionarily conserved neuropeptide with diverse physiological functions, is up-regulated in the brain during chronic social defeat stress in teleost. On the other hand, repeated exposure to social stress can lead to dysregulation of the monoaminergic system and increase the vulnerability of developing depression. Since dysfunction of the serotonin (5-hydroxytryptamine, 5-HT) system is associated with social stress and the pathophysiology of depression, the present study investigated the regulatory relationship between the central 5-HT system and SPX1a in the male teleost, Nile tilapia (Oreochromis niloticus). To identify stress factors that regulate SPX1a gene expression, cortisol, dexamethasone (DEX), and 5-HT were used to treat tilapia brain primary cultures. Our study shows cortisol and DEX treatment had no effect on SPX1a gene expression, but SPX1a gene expression was down-regulated following 5-HT treatment. Anatomical localization showed a close association between 5-HT immunoreactive projections and SPX1a neurons in the semicircular torus. In addition, 5-HT receptors (5-HT2B) were expressed in SPX1a neurons. SPX1a immunoreactive neurons and SPX1a gene expression were significantly increased in socially defeated tilapia. On the other hand, citalopram (antidepressant, 5-HT antagonist) treatment to socially defeated tilapia normalized SPX1a gene expression to control levels. Taken together, the present study shows that 5-HT is an upstream regulator of SPX1a and that the inhibited 5-HT activates SPX1a during social defeat.

Matched MeSH terms: Hydrocortisone/metabolism
Fusion of heart rate variability and salivary cortisol for stress response identification based on adverse childhood experience

Aimie-Salleh N, Malarvili MB, Whittaker AC

Med Biol Eng Comput, 2019 Jun;57(6):1229-1245.
PMID: 30734153 DOI: 10.1007/s11517-019-01958-3

Adverse childhood experiences have been suggested to cause changes in physiological processes and can determine the magnitude of the stress response which might have a significant impact on health later in life. To detect the stress response, biomarkers that represent both the Autonomic Nervous System (ANS) and Hypothalamic-Pituitary-Adrenal (HPA) axis are proposed. Among the available biomarkers, Heart Rate Variability (HRV) has been proven as a powerful biomarker that represents ANS. Meanwhile, salivary cortisol has been suggested as a biomarker that reflects the HPA axis. Even though many studies used multiple biomarkers to measure the stress response, the results for each biomarker were analyzed separately. Therefore, the objective of this study is to propose a fusion of ANS and HPA axis biomarkers in order to classify the stress response based on adverse childhood experience. Electrocardiograph, blood pressure (BP), pulse rate (PR), and salivary cortisol (SCort) measures were collected from 23 healthy participants; 11 participants had adverse childhood experience while the remaining 12 acted as the no adversity control group. HRV was then computed from the ECG and the HRV features were extracted. Next, the selected HRV features were combined with the other biomarkers using Euclidean distance (ed) and serial fusion, and the performance of the fused features was compared using Support Vector Machine. From the result, HRV-SCort using Euclidean distance achieved the most satisfactory performance with 80.0% accuracy, 83.3% sensitivity, and 78.3% specificity. Furthermore, the performance of the stress response classification of the fused biomarker, HRV-SCort, outperformed that of the single biomarkers: HRV (61% Accuracy), Cort (59.4% Accuracy), BP (78.3% accuracy), and PR (53.3% accuracy). From this study, it was proven that the fused biomarkers that represent both ANS and HPA (HRV-SCort) able to demonstrate a better classification performance in discriminating the stress response. Furthermore, a new approach for classification of stress response using Euclidean distance and SVM named as ed-SVM was proven to be an effective method for the HRV-SCort in classifying the stress response from PASAT. The robustness of this method is crucial in contributing to the effectiveness of the stress response measures and could further be used as an indicator for future health. Graphical abstract ᅟ.

Matched MeSH terms: Hydrocortisone/metabolism*
Caffeine neuroprotects against dexamethasone-induced anxiety-like behaviour in the Zebrafish (Danio rerio)

Khor YM, Soga T, Parhar IS

Gen Comp Endocrinol, 2013 Jan 15;181:310-5.
PMID: 23044054 DOI: 10.1016/j.ygcen.2012.09.021

The early-life stress has critical impact on brain development which can lead to long-term effects on brain functions during adulthood. It has been reported that caffeine possesses a protective effect in neurodegenerative diseases. Thus, this study investigates the potential of caffeine to protect brain functions from adverse effects due to stress exposure during early-life development in the male zebrafish. In the first part of this study, synthetic glucocorticoid, dexamethasone (DEX) (2-200 mg/L for 24 h) was used to induce stress effects in the zebrafish larvae from 4 to 5 days post-fertilisation (dpf) and the effect of DEX administration on zebrafish larvae on anxiety-like behaviour during adulthood in novel tank test was investigated. Next, the possible protective effect of caffeine pre-treatment (5-50 mg/L for 24 h from 3 to 4dpf) before DEX administration was studied. DEX-treated adult male zebrafish showed higher anxiety levels in behavioural tests, as seen in longer latency to enter the top part of the tank, lower transition numbers between the top and bottom parts with more time spent at the bottom and lesser time spent at the top and lower distance travelled at top part. The effect of DEX on anxiety-like behaviour was dose-dependent. Importantly, adult male zebrafish pre-treated with caffeine before DEX treatment did not show any anxiety-like behaviour. These results show that exposure to stress during early-life leads to anxiety-like behaviour in the adult male zebrafish but pre-treatment with caffeine protects from stress-induced anxiety.

Matched MeSH terms: Hydrocortisone/metabolism
Fulltext Stress and female reproductive function: a study of daily variations in cortisol, gonadotrophins, and gonadal steroids in a rural Mayan population

Nepomnaschy PA, Welch K, McConnell D, Strassmann BI, England BG

Am J Hum Biol, 2004 Sep-Oct;16(5):523-32.
PMID: 15368600 DOI: 10.1002/ajhb.20057

We report here on a longitudinal study of stress and women's reproduction in a small Kaqchikel Mayan community in rural Guatemala. Current understanding of the effects of stress on the reproductive axis in women is mostly derived from clinical studies of individual stressors. Little is known, however, about the cumulative effects of "real life" stress. Cortisol increases in response to a broad variety of individual stressors (Tilbrook et al., 2002). In this article, we evaluate the association between daily fluctuations in women's urinary cortisol and reproductive hormones: estrone conjugates (E(1)C), pregnandiol glucuronide (PdG), luteinizing hormone (LH), and follicle stimulating hormone (FSH). To assess the association between daily changes in cortisol levels and changes in the profiles of the reproductive hormones, we used a random coefficients model based on polynomial regression. The sample includes 92 menstrual cycles provided by 24 participants over a year-long prospective study. Increases in urinary cortisol levels were associated with significant increases in gonadotrophin and progestin levels during the follicular phase. Also, in a time window between days 4 and 10 after ovulation, increased cortisol levels were associated with significantly lower progestin levels. These results are significant because untimely increases in gonadotrophins and low midluteal progesterone levels have previously been reported to impinge on the ovulatory and luteinization processes and to reduce the chances of successful implantation (Ferin, 1999; Baird et al., 1999). Future research should consider the possibility that stress may affect fecundability and implantation without necessarily causing amenorrhoea or oligomenorrhoea.

Matched MeSH terms: Hydrocortisone/metabolism*
The debate over neurotransmitter interaction in aspartame usage

Choudhary AK, Lee YY

J Clin Neurosci, 2018 Oct;56:7-15.
PMID: 30318075 DOI: 10.1016/j.jocn.2018.06.043

Aspartame (NutraSweet®, Equal®) is a widely used artificial sweetener, has been reported to be accountable for neurological and behavioural disturbances in people. Upon ingestion, aspartame is hydrolyzed in gut and provides its metabolite; such as essential amino acid phenylalanine (Phy) (50%), aspartic acid (40%), and methanol (10%). Altered brain neurochemical compositions [such as dopamine (DA), norepinephrine (NE), and serotonin (5-HT)] have long been a concern and being involved in observed neurophysiological symptom (such as headaches, memory loss, mood changes, as well as depression) in aspartame consumers. Aspartames might act as chemical stressor through increasing plasma cortisol level. Aspartame consumption similarly altered gut microbiota. Taken together all this factors, we reviewed to search for convincing evidence, in what manner aspartame metabolites, stress hormones (cortisol), and gut dysbiosisis involved in altering brain neurochemical composition. We concluded that aspartame metabolite; mainly Phy and its interaction with neurotransmitter and aspartic acid by acting as excitatory neurotransmitter causes this pattern of impairments. Along with elevated cortisol and gut dysbiosis via interactions with different biogenic amine may also have additional impact to modulate neuronal signaling lead to neurobiological impairments. Hence ongoing research is instantly needed to understand the specific roles of aspartame metabolite, elevated cortisol, and gut dysbiosis with emerging neurophysiological symptom in aspartame consumers to improve healthy life in its consumers.

Matched MeSH terms: Hydrocortisone/metabolism
Fulltext Adrenal insufficiency in acute coronary syndrome

Norasyikin AW, Norlela S, Rozita M, Masliza M, Shamsul AS, Nor Azmi K

Singapore Med J, 2009 Oct;50(10):962-6.
PMID: 19907885

Acute coronary syndrome (ACS) is an acute stressful condition which stimulates the hypothalamus-pituitary-adrenal axis that regulates neurovascular and hormonal responses. Functional hypoadrenalism has been shown to be associated with significant morbidity and mortality in the critically-ill patient, but there is to date no known study done to determine its prevalence in patients with ACS.

Matched MeSH terms: Hydrocortisone/metabolism
Biomarker triterpenoids of Centella asiatica as potential antidepressant agents: Combining in vivo and in silico studies

Mando Z, Mando H, Afzan A, Shaari K, Hassan Z, Mohamad Taib MNA, et al.

Behav Brain Res, 2024 May 28;466:114976.
PMID: 38599249 DOI: 10.1016/j.bbr.2024.114976

Although there are various treatments available for depression, some patients may experience resistance to treatment or encounter adverse effects. Centella asiatica (C. asiatica) is an ancient medicinal herb used in Ayurvedic medicine for its rejuvenating, neuroprotective and psychoactive properties. This study aims to explore the antidepressant-like effects of the major constituents found in C. asiatica, i.e., asiatic acid, asiaticoside, madecassic acid, and madecassoside at three doses (1.25, 2.5, and 5 mg/kg, i.p), on the behavioural and cortisol level of unpredictable chronic stress (UCS) zebrafish model. Based on the findings from the behavioural study, the cortisol levels in the zebrafish body after treatment with the two most effective compounds were measured using enzyme-linked immunosorbent assay (ELISA). Furthermore, a molecular docking study was conducted to predict the inhibitory impact of the triterpenoid compounds on serotonin reuptake. The in vivo results indicate that madecassoside (1.25, 2.5, and 5 mg/kg), asiaticoside and asiatic acid (5 mg/kg) activated locomotor behaviour. Madecassoside at all tested doses and asiaticoside at 2.5 and 5 mg/kg significantly decreased cortisol levels compared to the stressed group, indicating the potential regulation effect of madecassoside and asiaticoside on the hypothalamic-pituitary-adrenal axis overactivity. This study highlights the potential benefits of madecassoside and asiaticoside in alleviating depressive symptoms through their positive effects on behaviour and the hypothalamic-pituitary-adrenal (HPA)- axis in a chronic unpredictable stress zebrafish model. Furthermore, the in silico study provided additional evidence to support these findings. These promising results suggest that C. asiatica may be a valuable and cost-effective therapeutic option for depression, and further research should be conducted to explore its potential benefits.

Matched MeSH terms: Hydrocortisone/metabolism
Fulltext Environmental tobacco smoke and stress as risk factors for miscarriage and preterm births

Arffin F, Al-Bayaty FH, Hassan J

Arch Gynecol Obstet, 2012 Nov;286(5):1187-91.
PMID: 22718098 DOI: 10.1007/s00404-012-2417-0

BACKGROUND: Exposure of pregnant women to environmental tobacco smoke has been shown to be associated with low birth weight. Many studies have suggested that stress have a role in the etiology of preterm birth.
AIMS: This study carried out from June 2008 to March 2009 to find the relation between environmental tobacco smoke, stress and miscarriage and preterm births.
METHODS: A total of 33 subjects consisted of multiparous pregnant women that were in their early third trimester were chosen for this investigation. Subjects were divided into test group women with adverse pregnancy outcome, control group women with successful pregnancy. Four ml of unstimulated whole saliva were collected. The concentrations of cotinine and cortisol were evaluated using commercially available ELISA kit.
RESULTS: Pregnancies in which the average standardized cortisol during history of previous miscarriage(s) which occurred within 6th-27th week or/and history of preterm labor which occurred within 28th-36th weeks of gestation, demonstrated higher cortisol level (1.0201 ± 0.1855 ng/ml) compared to control group 0.9757 ± 0.2860 ng/ml (P = 0.323); statistical analysis showed no significant differences. Women of control group were more likely to be environmental tobacco smoke exposed (1.2714 ± 1.7639 ng/ml) than women with miscarriage and preterm births (0.9889 ± 0.5498 ng/ml).
CONCLUSION: The results from this primarily study demonstrated no association between cotinine, cortisol, miscarriage and preterm births.

Matched MeSH terms: Hydrocortisone/metabolism
Fulltext Mitragynine attenuates withdrawal syndrome in morphine-withdrawn zebrafish

Khor BS, Jamil MF, Adenan MI, Shu-Chien AC

PLoS One, 2011;6(12):e28340.
PMID: 22205946 DOI: 10.1371/journal.pone.0028340

A major obstacle in treating drug addiction is the severity of opiate withdrawal syndrome, which can lead to unwanted relapse. Mitragynine is the major alkaloid compound found in leaves of Mitragyna speciosa, a plant widely used by opiate addicts to mitigate the harshness of drug withdrawal. A series of experiments was conducted to investigate the effect of mitragynine on anxiety behavior, cortisol level and expression of stress pathway related genes in zebrafish undergoing morphine withdrawal phase. Adult zebrafish were subjected to two weeks chronic morphine exposure at 1.5 mg/L, followed by withdrawal for 24 hours prior to tests. Using the novel tank diving tests, we first showed that morphine-withdrawn zebrafish display anxiety-related swimming behaviors such as decreased exploratory behavior and increased erratic movement. Morphine withdrawal also elevated whole-body cortisol levels, which confirms the phenotypic stress-like behaviors. Exposing morphine-withdrawn fish to mitragynine however attenuates majority of the stress-related swimming behaviors and concomitantly lower whole-body cortisol level. Using real-time PCR gene expression analysis, we also showed that mitragynine reduces the mRNA expression of corticotropin releasing factor receptors and prodynorphin in zebrafish brain during morphine withdrawal phase, revealing for the first time a possible link between mitragynine's ability to attenuate anxiety during opiate withdrawal with the stress-related corticotropin pathway.

Matched MeSH terms: Hydrocortisone/metabolism