Cytokines, prostaglandins and nitric oxide in the regulation of stress-response systems

Abstract

Hyperactivity of the hypothalamic-pituitary-adrenal (HPA) axis is accepted as one of the fundamental biological mechanisms that underlie major depression. This hyperactivity is caused by diminished feedback inhibition of glucocorticoid (GC)-induced reduction of HPA axis signaling and increased corticotrophin-releasing hormone (CRH) secretion from the hypothalamic paraventricular nucleus (PVN) and extra-hypothalamic neurons. During chronic stress-induced inhibition of systemic feedback, cytosolic glucocorticoid receptor (GR) levels were significantly changed in the prefrontal cortex (PFC) and hippocampus, both structures known to be deeply involved in the pathogenesis of depression. Cytokines secreted by both immune and non-immune cells can markedly affect neurotransmission within regulatory brain circuits related to the expression of emotions; cytokines may also induce hormonal changes similar to those observed following exposure to stress. Proinflammatory cytokines, including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) are implicated in the etiologies of clinical depression and anxiety disorders. Prolonged stress responses and cytokines impair neuronal plasticity and stimulation of neurotransmission. Exposure to acute stress and IL-1β markedly increased IL-1β levels in the PFC, hippocampus and hypothalamus, as well as overall HPA axis activity. Repeated stress sensitized the HPA axis response to IL-1β. Inflammatory responses in the brain contribute to cellular damage associated with neuropsychiatric diseases related to stress. Physical, psychological or combined-stress conditions evoke a proinflammatory response in the brain and other systems, characterized by a complex release of several inflammatory mediators including cytokines, prostanoids, nitric oxide (NO) and transcription factors. Induced CRH release involves IL-1, IL-6 and TNF-α, for stimulation adrenocorticotropic hormone (ACTH) release from the anterior pituitary. NO also participates in signal transduction pathways that result in the release of corticosterone from the adrenal gland. NO participates in multiple interactions between neuroendocrine and neuroimmune systems in physiological and pathological processes. Neuronal NO synthase (nNOS) modulates learning and memory and is involved in development of neuropsychiatric diseases, including depression. Nitric oxide generated in response to stress exposure is associated with depression-like and anxiety-like behaviors. In the central nervous system (CNS), prostaglandins (PG) generated by the cyclooxygenase (COX) enzyme are involved in the regulation of HPA axis activity. Prior exposure to chronic stress alters constitutive (COX-1) and inducible (COX-2) cyclooxygenase responses to homotypic stress differently in the PFC, hippocampus and hypothalamus. Both PG and NO generated within the PVN participate in this modulation. Acute stress affects the functionality of COX/PG and NOS/NO systems in brain structures. The complex responses of central and peripheral pathways to ...

Chronic Hormonal Imbalance and Adipose Redistribution Is Associated with Hypothalamic Neuropathology following Blast Exposure

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Modulation of the stress response in wild fish is associated with variation in dissolved nitrate and nitrite

“…The cellular signalling molecule nitric oxide (NO), which is involved in the control of steroidogenesis in vertebrates (Ducsay and Myers 2011), can be synthesised from nitrate and nitrite (Castiglione et al 2012;Lundberg et al 2008). Nitric oxide is implicated in the regulation of the stress response (Gądek-Michalska et al 2013) although its role is not well-defined and it may exert different effects at different loci within the stress axis (Gulati et al 2015;Mancuso et al 2010). Teleost fish may utilise NO as a modulator of endocrine activity (Lal and Dubey 2013), and at least two of three NO synthase (NOS) isoforms are present in fish (see references in Mueller and O'Brien 2011).…”

Relaxin-3/RXFP3 signalling in mouse hypothalamus: no effect of RXFP3 activation on corticosterone, despite reduced presynaptic excitatory input onto paraventricular CRH neurons in vitro

“…expressed by other neurons in the highly heterogeneous PVN (Bodnar and Klein 2004;Tortorella et al 2007;Biag et al 2012;Gadek-Michalska et al 2013) as well as several transmitters/modulators that reach the PVN via extrinsic inputs from ascending and descending arousal/sensory systems, such as the serotonin and noradrenaline monoamine systems (Myers et al 2017;Ulrich-Lai and Herman 2009;Fox and Lowry 2013;Flak et al 2014). Further characterisation of existing and newly identified regulatory inputs is of interest for biological and therapeutical reasons.…”