Stress-induced neuroinflammation: mechanisms and new pharmacological targets

Abstract

Stress is triggered by numerous unexpected environmental, social or pathological stimuli occurring during the life of animals, including humans, which determine changes in all of their systems. Although acute stress is essential for survival, chronic, longlasting stress can be detrimental. In this review, we present data supporting the hypothesis that stress-related events are characterized by modifications of oxidative/nitrosative pathways in the brain in response to the activation of inflammatory mediators. Recent findings indicate a key role for nitric oxide (NO) and an excess of pro-oxidants in various brain areas as responsible for both neuronal functional impairment and structural damage. Similarly, cyclooxygenase-2 (COX-2), another known source of oxidants, may account for stress-induced brain damage. Interestingly, some of the COX-2-derived mediators, such as the prostaglandin 15d-PGJ 2 and its peroxisome proliferator-activated nuclear receptor PPARγ, are activated in the brain in response to stress, constituting a possible endogenous anti-inflammatory mechanism of defense against excessive inflammation. The stress-induced activation of both biochemical pathways depends on the activation of the N-methyl-Daspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFκB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-α also accounts for its expression. Different pharmacological strategies directed towards different sites in iNOS or COX-2 pathways have been shown to be neuroprotective in stress-induced brain damage: NMDA receptor blockers, inhibitors of TNF-α activation and release, inhibitors of NFκB, specific inhibitors of iNOS and COX-2 activities and PPARγ agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

Protective effects of selective and non-selective cyclooxygenase inhibitors in an animal model of chronic stress

“…However, the etiology of chronic stress remains still unclear. Studies in patients with CFS have revealed alterations of the hypothalamic-pituitary-adrenal (HPA) axis [1,27] .…”

“…Although acute stress is necessary for survival, chronic and long-lasting stress can be detrimental [1] . Chronic stress is characterized by persistent fatigue, infection, and rheumatological and neuropsychiatric symptoms [2] , and it has affected thousands of people.…”

“…Recently, increases in COX-2 expression and activity have been observed in rat cortex after a short-time exposure (4-6 h) to restraint stress. Moreover, specific pharmacological tools that inhibit COX-2 activity (NS-398) could prevent the increase in membrane lipid peroxidation mediators and restore the antioxidant (glutathione) system, suggesting that COX isoform is involved in the accumulation of oxidative damage during stress [1] . Studies have also indicated the neuroprotective effects of COX-2 inhibitors in various central nervous system (CNS)-related disorders [13][14][15][16] .…”

Impact of Noni Juice on Myelin Components, Neurotransmittory and Behavioural Status in Rats Exposed to Immobilization Stress

“…Stressful occasions elicit alterations in various organ systems, including gastrointestinal, cardiovascular 1 and central nervous system 2 . Stress is connected with post-traumatic stress conditions, major depression, schizophrenia and neurodegenerative diseases 1 .…”

“…Stressful occasions elicit alterations in various organ systems, including gastrointestinal, cardiovascular 1 and central nervous system 2 . Stress is connected with post-traumatic stress conditions, major depression, schizophrenia and neurodegenerative diseases 1 . Exposure to stress stimuli steers hyperactivation of hypothalamus-pituitary adrenal axis, behavioural changes, autonomic function and changes in adrenocorticotropin hormone as well as in corticosterone 3 .…”