Stress-induced neuroinflammation: mechanisms and new pharmacological targets

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, long-lasting 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-PGJ2 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-D-aspartate (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.

Stress-induced neuroinflammation: mechanisms and new pharmacological targets.

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, long-lasting 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-PGJ2 and its peroxisome proliferator-activated nuclear receptor PPARgamma, 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-D-aspartate (NMDA) glutamate receptor and on the activation of the transcription factor nuclear factor kappa B (NFkappaB). In the case of inducible NO synthase (iNOS), release of the cytokine TNF-alpha 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-alpha activation and release, inhibitors of NFkappaB, specific inhibitors of iNOS and COX-2 activities and PPARgamma agonists. This article reviews recent contributions to this area addressing possible new pharmacological targets for the treatment of stress-induced neuropsychiatric disorders.

Velázquez: farmacología básica y clínica

Prefacio, los directores. Prólogo a la primera edición (1930), Teófilo Hernando. Farmacología básica. Sistema nervioso periférico. Sistema nervioso central. Aparato cardiovascular. Autacoides, inflamación y respuesta inmunológica. Aparato digestivo. Sistema nervioso endocrino. Aparato respiratorio. Sangre. Quimioterapia antiinfecciosa y antitumoral. Miscelánea. Farmacología clínica. Variabilidad de la repsuesta farmacológica. Efectos no deseados de los medicamentos. Evaluación de los efectos de los medicamentos. Evaluación y mejora del uso de medicamentos. Nuevas perspectivas

Velázquez: farmacología básica y clínica

Prefacio, los directores. Prólogo a la primera edición (1930), Teófilo Hernando. Farmacología básica. Sistema nervioso periférico. Sistema nervioso central. Aparato cardiovascular. Autacoides, inflamación y respuesta inmunológica. Aparato digestivo. Sistema nervioso endocrino. Aparato respiratorio. Sangre. Quimioterapia antiinfecciosa y antitumoral. Miscelánea. Farmacología clínica. Variabilidad de la repsuesta farmacológica. Efectos no deseados de los medicamentos. Evaluación de los efectos de los medicamentos. Evaluación y mejora del uso de medicamentos. Nuevas perspectivas