de Pablos, R. M. et al. Stress increases vulnerability to inflammation in the rat prefrontal cortex. J. Neurosci. 26, 5709-5719

Departamento de Bioquímica, Bromatología, Toxicología y Medicina Legal, Facultad de Farmacia, Universidad de Sevilla, 41012 Sevilla, Spain.
The Journal of Neuroscience : The Official Journal of the Society for Neuroscience (Impact Factor: 6.34). 06/2006; 26(21):5709-19. DOI: 10.1523/JNEUROSCI.0802-06.2006
Source: PubMed


Inflammation could be involved in some neurodegenerative disorders that accompany signs of inflammation. However, because sensitivity to inflammation is not equal in all brain structures, a direct relationship is not clear. Our aim was to test whether some physiological circumstances, such as stress, could enhance susceptibility to inflammation in the prefrontal cortex (PFC), which shows a relative resistance to inflammation. PFC is important in many brain functions and is a target for some neurodegenerative diseases. We induced an inflammatory process by a single intracortical injection of 2 microg of lipopolysaccharide (LPS), a potent proinflammogen, in nonstressed and stressed rats. We evaluated the effect of our treatment on inflammatory markers, neuronal populations, BDNF expression, and behavior of several mitogen-activated protein (MAP) kinases and the transcription factor cAMP response element-binding protein. Stress strengthens the changes induced by LPS injection: microglial activation and proliferation with an increase in the levels of the proinflammatory cytokine tumor necrosis factor-alpha; loss of cells such as astroglia, seen as loss of glial fibrillary acidic protein immunoreactivity, and neurons, studied by neuronal-specific nuclear protein immunohistochemistry and GAD67 and NMDA receptor 1A mRNAs expression by in situ hybridization. A significant increase in the BDNF mRNA expression and modifications in the levels of MAP kinase phosphorylation were also found. In addition, we observed a protective effect from RU486 [mifepristone (11beta-[p-(dimethylamino)phenyl]-17beta-hydroxy-17-(1-propynyl)estra-4,9-dien-3-one)], a potent inhibitor of the glucocorticoid receptor activation. All of these data show a synergistic effect between inflammation and stress, which could explain the relationship described between stress and some neurodegenerative pathologies.

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    • "Previously, we showed for the first time that LPS given peripherally decreased more BDNF expression in the amygdala and hippocampus of female rats subjected to chronic social stress than in non-stressed rats (Nowacka et al., 2014). It has been reported that a single central LPS administration followed by prolonged stress resulted in an enhancement of BDNF level in the prefrontal cortex (De Pablos et al., 2006) and hippocampus (Espinosa-Oliva et al., 2011) in male lab animals. The opposite effect of LPS in the stressed rats in our research compared with the cited studies is most probably due to the above-mentioned essential differences in the applied experimental procedures. "
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    ABSTRACT: Imbalance of brain neural circuitry induced by chronic stress leads to dysregulation of the HPA axis and dysfunction of neuroplasticity. The aim of the study was to investigate the influence of acute immunostimulation on the expression and protein level of BDNF and VEGF in the hypothalamus, pituitary and plasma of female rats subjected to chronic social instability stress. Rats were subjected to 4-week stress procedure, including phases of isolation and crowding, alternated in an unpredictable manner. On the last experimental day, the rats in the estrus phase were injected ip. with LPS (1 mg/kg). All experiments were performed on females being in the same phase of the estrus cycle to avoid alterations in neurotrophin expression. An increase in relative adrenal and thymus weights in the stressed rats were observed. Chronic stress affected more strongly VEGF but not BDNF in the hypothalamus and pituitary gland. In the stressed rats, LPS decreased BDNF and VEGF mRNA levels in both structures and plasma BDNF concentrations. Optical density of VEGF immunoreactivity in the supraoptic nucleus was increased after LPS administration in the stressed rats as compared to the saline-treated stressed group. It may be assumed that chronic social stress makes the SOR neurons sensitive to a peripheral proinflammatory stimulus. Our results indicate that chronic stress enhances vulnerability of BDNF and VEGF response to neuroinflammation in the examined structures, which may be one of the reasons for its role in triggering affective diseases.
    Neuropeptides 09/2015; DOI:10.1016/j.npep.2015.09.003 · 2.64 Impact Factor
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    • "We and others have demonstrated that chronic stress potentiate the microglial pro - inflammatory response ( de Pablos et al . , 2006 , 2014 ; Tynan et al . , 2010 ; Espinosa - Oliva et al . , 2011 ; Wohleb et al . , 2011 ; Hinwood et al . , 2012 ) . Psychological chronic stress - induced inflammatory changes in microglia / macrophages were blocked by propranolol , an indication of an active role of β - adrenergic receptors in stress - induced microglial pro - inflamma"
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    ABSTRACT: This review is aimed to highlight the importance of stress and glucocorticoids (GCs) in modulating the inflammatory response of brain microglia and hence its potential involvement in Parkinson's disease (PD). The role of inflammation in PD has been reviewed extensively in the literature and it is supposed to play a key role in the course of the disease. Historically, GCs have been strongly associated as anti-inflammatory hormones. However, accumulating evidence from the peripheral and central nervous system have clearly revealed that, under specific conditions, GCs may promote brain inflammation including pro-inflammatory activation of microglia. We have summarized relevant data linking PD, neuroinflamamation and chronic stress. The timing and duration of stress response may be critical for delineating an immune response in the brain thus probably explain the dual role of GCs and/or chronic stress in different animal models of PD.
    Frontiers in Cellular Neuroscience 08/2015; 9:312. DOI:10.3389/fncel.2015.00312 · 4.29 Impact Factor
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    • "LPS, a bacterial endotoxin often used in experimental studies , when given intraperitoneally (ip.) causes complex systemic and central neurochemical and endocrine changes observed as a result of inflammation (Raetz and Whitfield, 2002; Dantzer, 2004). Up till now, to the best of our knowledge, the effect of interaction between stress and inflammatory challenge (LPS or pro-inflammatory cytokines) on neurotrophins was a subject of only a few studies carried out on male lab animals (De Pablos et al., 2006; Espinosa-Oliva et al., 2011; Lin and Wang, 2014). "
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    ABSTRACT: Animal models of chronic stress represent valuable tools for investigation of the neurobiological changes underlying the stress-related psychopathologies in which neuroinflammation also plays an important role. The aim of the present study was to estimate the influence of antidepressants given chronically on brain-derived neurotrophic factor (BDNF) alterations induced by lipopolysaccharide (LPS) in the amygdala and hippocampus of female rats subjected to chronic social instability stress (CSIS) for 29-30 days. This stress paradigm known to be more stressful for females was applied because stress induces affective disorders more frequently in women than men. The model was based on alternating stressful situations, including phases of isolation and crowding, in an unpredictable manner. An increased relative adrenal weight and a tendency towards the enhanced plasma corticosterone concentration were found in the stressed rats. CSIS did not change sucrose preference. Desipramine (10mg/kg), fluoxetine (5mg/kg), tianeptine (10mg/kg) or saline was administered ip once daily. On the last day of the experiment, the rats in the estrus phase were injected ip with LPS (1mg/kg) or saline. In the stressed rats, LPS administration decreased BDNF mRNA levels in both limbic structures. The studied antidepressants reversed the effect of the combined stress and LPS, and tianeptine induced the strongest effects. These results indicate that chronic stress enhances vulnerability of BDNF response to deleterious influence of neuroinflammation in the examined limbic structures, what may account for its role in triggering neuropsychiatric diseases. The observed effect of antidepressants may be of significance for their therapeutic effects in the stress-induced affective disorders in females.
    Neuroscience Research 08/2014; 88. DOI:10.1016/j.neures.2014.08.008 · 1.94 Impact Factor
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