Systemic infections and inflammation affect chronic neurodegeneration

Perry, V. Hugh; Cunningham, Colm; Holmes, Clive

doi:10.1038/nri2015

Cited by 875 publications

(693 citation statements)

References 88 publications

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“…As stroke induces local inflammation at the site of the insult, 6,37 and infection alters the systemic inflammatory profile in the brain, 38 we hypothesized that the differences in functional outcome might be associated with a change in the inflammatory profile in the brain. Accordingly, we analyzed the number of leukocytes in the affected hemisphere.…”

Section: Discussionmentioning

confidence: 99%

Superiority of Preventive Antibiotic Treatment Compared with Standard Treatment of Poststroke Pneumonia in Experimental Stroke: A Bed to Bench Approach

Hetze

Engel

Römer

et al. 2013

J Cereb Blood Flow Metab

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Stroke patients are prone to life-threatening bacterial pneumonia. Previous experimental stroke studies have demonstrated that preventive antibiotic treatment (PAT) improves outcome compared with placebo treatment, which however does not model the clinical setting properly. Here we investigate whether PAT is superior to the current clinical 'gold standard' for treating poststroke infections. Therefore, we modeled stroke care according to the current stroke guidelines recommending early antibiotic treatment after diagnosing infections. To reliably diagnose pneumonia in living mice, we established a general health score and a magnetic resonance imaging protocol for radiologic confirmation. Compared with standard treatment after diagnosis by these methods, PAT not only abolished pneumonia successfully but also improved general medical outcome. Both, preventive and standard antibiotic treatment using enrofloxacin improved survival in a similar way compared with placebo treatment. However, in contrast to standard treatment, only PAT improved functional outcome assessed by gait analysis. In conclusion, standard and preventive treatment approach reduced poststroke mortality, however at the cost of a worse neurologic outcome compared with preventive approach. These data support the concept of PAT for treating patients at risk for poststroke infections and warrant phase III trials to prove this concept in clinical setting.

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Section: Discussionmentioning

confidence: 99%

Superiority of Preventive Antibiotic Treatment Compared with Standard Treatment of Poststroke Pneumonia in Experimental Stroke: A Bed to Bench Approach

Hetze

Engel

Römer

et al. 2013

J Cereb Blood Flow Metab

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“…Microglia play a central role in the brain inflammatory response (54)(55)(56) and are affected both by aging and WBI (Figures 3 and 4). Our finding that the basal density of microglia in the SGZ did not change with age is consistent with previous studies of the murine hippocampus (57).…”

Section: Discussionmentioning

confidence: 99%

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Schindler¹,

Forbes²,

Robbins³

et al. 2008

International Journal of Radiation Oncology*Biology*Physics

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Purpose-To assess the impact of aging on the radiation response in the adult rat brain.Methods and Materials-Male rats 8, 18, or 28 months of age received a single 10Gy dose of whole brain irradiation (WBI). The hippocampal dentate gyrus (DG) was analyzed one and ten weeks later for sensitive neurobiological markers associated with radiation-induced damage: changes in the density of proliferating cells, immature neurons, total microglia, and activated microglia.Results-A significant reduction in basal levels of proliferating cells and immature neurons and increased microglial activation occurred with normal aging. WBI induced a transient increase in proliferation that was greater in older animals. This proliferation response did not increase the number of immature neurons, which decreased following WBI in young rats but not in old rats. Total microglial number decreased following WBI at all ages but microglial activation increased markedly, particularly in older animals.Conclusions-Age is an important factor to consider when investigating the radiation response of the brain. In contrast to young adults, older rats show no sustained decrease in the number of immature neurons following WBI but have a greater inflammatory response. The latter may play an enhanced role in the development of radiation-induced cognitive dysfunction in older individuals.

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“…Recent reviews suggest that microglia may enter a spectrum of activation states (Mosser and Edwards, 2008;Rivest, 2009) characterized by varying blends of immunophenotypes and cytokine profiles. Importantly, microglia can enter a state called 'primed' (Perry et al, 2007). Here, they show phenotypic signs of activation (eg, upregulated MHCII), but do not secrete increased cytokines.…”

Section: Microglia and Neuroinflammationmentioning

confidence: 99%

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

Fleshner

Frank

Maier

2016

Neuropsychopharmacol

163

106

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Major depressive disorder (MDD) and other mood disorders remain difficult to effectively treat, and innovative interventions and therapeutic targets are needed. Psychological stressors and inappropriate inflammation increase the risk and severity of mood disorders; however, only recently have the importance of sterile inflammatory processes in this effect been revealed. This review will introduce the reader to pathogen vs sterile inflammation, inflammatory receptor-ligand interactions, microbialassociated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), danger-associated molecular patterns (DAMPs), and the more recent discovery of the role of the inflammasome in peripheral and central nervous system cytokine/chemokine inflammatory responses. The review will focus on current preclinical and clinical evidence that sterile inflammation and inflammasome-dependent signaling may contribute to mood disorders. By understanding these inflammatory signaling processes, new approaches for quieting chronic or inappropriate inflammatory states may be revealed and this could serve as novel pharmacological targets for the treatment of mood disorders.

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Systemic infections and inflammation affect chronic neurodegeneration

Cited by 875 publications

References 88 publications

Superiority of Preventive Antibiotic Treatment Compared with Standard Treatment of Poststroke Pneumonia in Experimental Stroke: A Bed to Bench Approach

Superiority of Preventive Antibiotic Treatment Compared with Standard Treatment of Poststroke Pneumonia in Experimental Stroke: A Bed to Bench Approach

Aging-Dependent Changes in the Radiation Response of the Adult Rat Brain

Danger Signals and Inflammasomes: Stress-Evoked Sterile Inflammation in Mood Disorders

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