Central Taurine Attenuates Hyperthermia and Isolation Stress Behaviors Augmented by Corticotropin-Releasing Factor with Modifying Brain Amino Acid Metabolism in Neonatal Chicks

The objective of this study was to determine the effects of centrally administered taurine on rectal temperature, behavioral responses and brain amino acid metabolism under isolation stress and the presence of co-injected corticotropin-releasing factor (CRF). Neonatal chicks were centrally injected with saline, 2.1 pmol of CRF, 2.5 μmol of taurine or both taurine and CRF. The results showed that CRF-induced hyperthermia was attenuated by co-injection with taurine. Taurine, alone or with CRF, significantly decreased the number of distress vocalizations and the time spent in active wakefulness, as well as increased the time spent in the sleeping posture, compared with the saline- and CRF-injected chicks. An amino acid chromatographic analysis revealed that diencephalic leucine, isoleucine, tyrosine, glutamate, asparagine, alanine, β-alanine, cystathionine and 3-methylhistidine were decreased in response to taurine alone or in combination with CRF. Central taurine, alone and when co-administered with CRF, decreased isoleucine, phenylalanine, tyrosine and cysteine, but increased glycine concentrations in the brainstem, compared with saline and CRF groups. The results collectively indicate that central taurine attenuated CRF-induced hyperthermia and stress behaviors in neonatal chicks, and the mechanism likely involves the repartitioning of amino acids to different metabolic pathways. In particular, brain leucine, isoleucine, cysteine, glutamate and glycine may be mobilized to cope with acute stressors.

Urocortins as biomarkers in cardiovascular disease

The urocortins (Ucns) belong to the corticotropin-releasing factor (CRF) family of peptides and have multiple effects within the central nervous and the cardiovascular systems. With growing evidence indicating significant cardioprotective properties and cardiovascular actions of these peptides, the question arises as to whether the plasma profiles of the Ucns are altered in pathologic settings. While reports have shown conflicting results and findings have not been corroborated in multiple independent cohorts, it seems likely that plasma Ucn concentrations are elevated in multiple cardiovascular conditions. The degree of increase and accurate determination of circulating values of the Ucns requires further validation.

Electroacupuncture and moxibustion-like stimulation activate the cutaneous and systemic hypothalamic–pituitary–adrenal axes in the rat

Objective: To determine whether electroacupuncture (EA) or moxibustion-like stimulation (MLS) can affect the cutaneous and/or systemic hypothalamic–pituitary–adrenal (HPA) axes. Methods: Rats were divided into Control, EA, 37°C MLS and 43.5°C MLS groups. EA and MLS were performed at bilateral ST36 or LI4. The expression of corticotropin-releasing factor (CRF), adrenocorticotropic hormone (ACTH) and the glucocorticoid receptor (GR) was detected in local cutaneous tissues at the site of ST36 and LI4 by immunohistochemical staining. In addition, levels of CRF, ACTH and corticosterone (CORT) in cutaneous tissue and plasma were determined. Results: Cutaneous expression of CRF, ACTH and GR significantly increased after EA at ST36, while only GR increased after 43.5°C MLS at ST36. The results of EA and MLS at LI4 were in parallel with those at ST36. In plasma, compared with the control group, the level of CORT increased after EA at ST36, while both ACTH and CORT were markedly increased after 43.5°C MLS. For LI4, plasma CRF and CORT increased after EA, while the levels of all three hormones increased following 43.5°C MLS. Notably, compared with the effect of EA, 43.5°C MLS at ST36 produced a more substantial increase in plasma CORT, and 43.5°C MLS at LI4 induced a more dramatic increase in plasma CRF and CORT. Conclusion: Both EA and 43.5°C MLS can activate the cutaneous and systemic HPA axes of the rat. EA tended to activate the local cutaneous HPA, while 43.5°C MLS was more likely to activate the systemic HPA axis.

The Antagonism of Corticotropin-Releasing Factor Receptor-1 in Brain Suppress Stress-Induced Propofol Self-Administration in Rats

Propofol addiction has been detected in humans and rats, which may be facilitated by stress. Corticotropin-releasing factor acts through the corticotropin-releasing factor (CRF) receptor-1 (CRF1R) and CRF2 receptor-2 (CRF2R) and is a crucial candidate target for the interaction between stress and drug abuse, but its role on propofol addiction remains unknown. Tail clip stressful stimulation was performed in rats to test the stress on the establishment of the propofol self-administration behavioral model. Thereafter, the rats were pretreated before the testing session at the bilateral lateral ventricle with one of the doses of antalarmin (CRF1R antagonist, 100–500 ng/site), antisauvagine 30 (CRF2R antagonist, 100–500 ng/site), and RU486 (glucocorticoid receptor antagonist, 100–500 ng/site) or vehicle. The dopamine D1 receptor (D1R) in the nucleus accumbens (NAc) was detected to explore the underlying molecular mechanism. The sucrose self-administration establishment and maintenance, and locomotor activities were also examined to determine the specificity. We found that the establishment of propofol self-administration was promoted in the tail clip treated group (the stress group), which was inhibited by antalarmin at the dose of 100–500 ng/site but was not by antisauvagine 30 or RU486. Accordingly, the expression of D1R in the NAc was attenuated by antalarmin, dose-dependently. Moreover, pretreatments fail to change sucrose self-administration behavior or locomotor activities. This study supports the role of CRF1R in the brain in mediating the central reward processing through D1R in the NAc and provided a possibility that CRF1R antagonist may be a new therapeutic approach for the treatment of propofol addiction.

Corticotropin Releasing Factor Binding Protein as a Novel Target to Restore Brain Homeostasis: Lessons Learned From Alcohol Use Disorder Research

Stress is well-known to contribute to the development of many psychiatric illnesses including alcohol and substance use disorder (AUD and SUD). The deleterious effects of stress have also been implicated in the acceleration of biological age, and age-related neurodegenerative disease. The physio-pathology of stress is regulated by the corticotropin-releasing factor (CRF) system, the upstream component of the hypothalamic-pituitary-adrenal (HPA) axis. Extensive literature has shown that dysregulation of the CRF neuroendocrine system contributes to escalation of alcohol consumption and, similarly, chronic alcohol consumption contributes to disruption of the stress system. The CRF system also represents the central switchboard for regulating homeostasis, and more recent studies have found that stress and aberrations in the CRF pathway are implicated in accelerated aging and age-related neurodegenerative disease. Corticotropin releasing factor binding protein (CRFBP) is a secreted glycoprotein distributed in peripheral tissues and in specific brain regions. It neutralizes the effects of CRF by sequestering free CRF, but may also possess excitatory function by interacting with CRF receptors. CRFBP’s dual role in influencing CRF bioavailability and CRF receptor signaling has been shown to have a major part in the HPA axis response. Therefore, CRFBP may represent a valuable target to treat stress-related illness, including: development of novel medications to treat AUD and restore homeostasis in the aging brain. This narrative review focuses on molecular mechanisms related to the role of CRFBP in the progression of addictive and psychiatric disorders, biological aging, and age-related neurodegenerative disease. We provide an overview of recent studies investigating modulation of this pathway as a potential therapeutic target for AUD and age-related neurodegenerative disease.

Hypothalamic Regulation of Corticotropin-Releasing Factor under Stress and Stress Resilience

This review addresses the molecular mechanisms of corticotropin-releasing factor (CRF) regulation in the hypothalamus under stress and stress resilience. CRF in the hypothalamus plays a central role in regulating the stress response. CRF stimulates adrenocorticotropic hormone (ACTH) release from the anterior pituitary. ACTH stimulates glucocorticoid secretion from the adrenal glands. Glucocorticoids are essential for stress coping, stress resilience, and homeostasis. The activated hypothalamic-pituitary-adrenal axis is suppressed by the negative feedback from glucocorticoids. Glucocorticoid-dependent repression of cAMP-stimulated Crf promoter activity is mediated by both the negative glucocorticoid response element and the serum response element. Conversely, the inducible cAMP-early repressor can suppress the stress response via inhibition of the cAMP-dependent Crf gene, as can the suppressor of cytokine signaling-3 in the hypothalamus. CRF receptor type 1 is mainly involved in a stress response, depression, anorexia, and seizure, while CRF receptor type 2 mediates “stress coping” mechanisms such as anxiolysis in the brain. Differential effects of FK506-binding immunophilins, FKBP4 and FKBP5, contribute to the efficiency of glucocorticoids under stress resilience. Together, a variety of factors contribute to stress resilience. All these factors would have the differential roles under stress resilience.