COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats

Günther, Mattias; Plantman, Stefan; Davidsson, Johan; Angéria, Maria; Mathiesen, Tiit; Risling, Mårten

doi:10.1007/s00701-014-2331-2

Cited by 46 publications

(40 citation statements)

References 44 publications

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“…Thus, lower COX-2 expression and activity has been noted in the macula densa of female rats compared to males, contributing to the major protection of female to the blood pressure increment and renal damage 30 . Moreover, the inferior susceptibility to traumatic brain injury of male versus female rats has been related to a robust higher expression of COX-2 in the brain of male rats 31 . In addition, long-term testosterone treatment augmented COX-2 levels in male rat brain blood vessels, whereas treatment of male rats with 17β-estradiol significantly impaired cerebrovascular COX-2 levels after an inflammatory stimulus 21 .…”

Section: Discussionmentioning

confidence: 99%

Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Pace

Rossi

Krauth

et al. 2017

Sci Rep

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The severity and course of inflammatory processes differ between women and men, but the biochemical mechanisms underlying these sex differences are elusive. Prostaglandins (PG) and leukotrienes (LT) are lipid mediators linked to inflammation. We demonstrated superior LT biosynthesis in human neutrophils and monocytes, and in mouse macrophages from females, and we confirmed these sex differences in vivo where female mice produced more LTs during zymosan-induced peritonitis versus males. Here, we report sex differences in PG production in neutrophils during acute inflammation. In the late phase (4–8 hrs) of mouse zymosan-induced peritonitis and rat carrageenan-induced pleurisy, PG levels in males were higher versus females, seemingly due to higher PG production in infiltrated neutrophils. Accordingly, human neutrophils from males produced more PGE2 than cells from females. Increased PG biosynthesis in males was accompanied by elevated cyclooxygenase (COX)-2 expression connected to increased nuclear factor-kappa B activation, and was abolished when LT synthesis was pharmacologically blocked, suggesting that elevated PG production in males might be caused by increased COX-2 expression and by shunting phenomena due to suppressed LT formation. Conclusively, our data reveal that the biosynthesis of pro-inflammatory PGs and LTs is conversely regulated by sex with consequences for the inflammatory response.

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Section: Discussionmentioning

confidence: 99%

Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Pace

Rossi

Krauth

et al. 2017

Sci Rep

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“…Although the data are limited, microglia may have sex‐specific responses to TBI in animal models. Gunther et al () demonstrated sex differences in COX‐2 regulation after a penetrating brain injury in male and female rats; however, they found no difference in microglial activation between sexes in the perilesional area or contralateral side. There is conflicting evidence about the influence of sex hormones on the microglial response after TBI (Barreto et al, ; Bruce‐Keller et al, ; Acaz‐Fonseca et al, ).…”

Section: Sex Differences In Microglial Activation and Tbimentioning

confidence: 99%

“…Gunther et al (), using a penetrating brain injury model, found that male rats had an increased COX‐2 response compared with females at 24 and 72 hr, which was associated with increased inflammation. Furthermore, inducible nitric oxide synthase (iNOS) expression in the perilesional area was significantly higher in female rats than in males, but there was no difference in iNOS expression in the ipsilateral cortex or contralateral side between sexes (Gunther et al, ).…”

Section: Inflammatory Markersmentioning

confidence: 99%

Do microglia play a role in sex differences in TBI?

Caplan¹,

Cox²,

Bedi³

2016

J of Neuroscience Research

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Traumatic brain injury (TBI) is one of the leading causes of morbidity and mortality for both males and females and is, thus, a major focus of current study. Although the overall death rate of TBI for males is roughly three times higher than that for females, males have been disproportionately represented in clinical and preclinical studies. Gender differences are known to exist in many neurologic disorders, such as multiple sclerosis and stroke, and differences appear to exist in TBI. Furthermore, it is known that microglia have sexually dimorphic roles in CNS development and other neurologic conditions; however, most animal studies of microglia and TBI have focused on male subjects. Microglia are a current target of many preclinical and clinical therapeutic trials for TBI. Understanding the relationship among sex, sex hormones, and microglia is critical to truly understanding the pathophysiology of TBI. However, the evidence for sex differences in TBI centers mainly on sex hormones, and evidenced-based conclusions are often contradictory. In an attempt to review the current literature, it is apparent that sex differences likely exist, but the contradictory nature and magnitude of such differences in the existing literature does not allow definite conclusions to be drawn, except that more investigation of this issue is necessary. © 2016 Wiley Periodicals, Inc.

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“…Inflammatory reactions and cell death after TBI can be different in males and females (Gunther et al, 2015). Role of biomarkers in PTSD and mTBI 5…”

Section: Clinicalmentioning

confidence: 99%

The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury

Huang

Risling

Baker

2016

Psychoneuroendocrinology

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SummaryBackground: Pervasive use of improvised explosive devices (IEDs), rocket-propelled grenades, and land mines in the recent conflicts in Iraq and Afghanistan has brought traumatic brain injury (TBI) and its impact on health outcomes into public awareness. Blast injuries have been deemed signature wounds of these wars. War-related TBI is not new, having become prevalent during WWI and remaining medically relevant in WWII and beyond. Medicine's past attempts to accurately diagnose and disentangle the pathophysiology of war-related TBI parallels current lines of inquiry and highlights limitations in methodology and attribution of symptom etiology, be it organic, psychological, or behavioral. New approaches and biomarkers are needed. Preclinical: Serological biomarkers and biomarkers of injury obtained with imaging techniques represent cornerstones in the translation between experimental data and clinical observations. Experimental models for blast related TBI and PTSD can generate critical data on injury threshold, for example for white matter injury from acceleration. Carefully verified and validated models can be evaluated with gene expression arrays and proteomics to identify new candidates for serological biomarkers. Such models can also be analyzed with diffusion MRI and microscopy in order to identify criteria for detection of diffuse white matter injuries, such as DAI (diffuse axonal injury). The experimental models can also be analyzed with focus on injury outcome in brain stem regions, such as locus coeruleus or nucleus raphe magnus that can be involved in response to anxiety changes. * Corresponding author at: UCSD Radiology Imaging Laboratory, San Diego, CA 92121, USA. Tel.: +1 858 534 1254; fax: +1 8585346046. E-mail address: mxhuang@ucsd.edu (M. Huang). Clinical: Mild (and some moderate) TBI can be difficult to diagnose because the injuries are often not detectable on conventional MRI or CT. There is accumulating evidence that injured brain tissues in TBI patients generate abnormal low-frequency magnetic activity (ALFMA, peaked at 1-4 Hz) that can be measured and localized by magnetoencephalography (MEG). MEG imaging detects TBI abnormalities at the rates of 87% for the mild TBI, group (blast-induced plus non-blast causes) and 100% for the moderate group. Among the mild TBI patients, the rates of abnormalities are 96% and 77% for the blast and non-blast TBI groups, respectively. There is emerging evidence based on fMRI and MEG studies showing hyper-activity in the amygdala and hypo-activity in prefrontal cortex in individuals with PTSD. MEG signal may serve as a sensitive imaging marker for mTBI, distinguishable from abnormalities generated in association with PTSD. More work is needed to fully describe physiological mechanisms of post-concussive symptoms.Published by Elsevier Ltd. BackgroundBlast injuries are deemed the signature wounds of the first wars (Afghanistan and Iraq) of the 21st century (Lancet, 2007;Galarneau et al., 2008). According to a recent U.S. Department Veterans Affairs (DVA) ...

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COX-2 regulation and TUNEL-positive cell death differ between genders in the secondary inflammatory response following experimental penetrating focal brain injury in rats

Cited by 46 publications

References 44 publications

Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation

Do microglia play a role in sex differences in TBI?

The role of biomarkers and MEG-based imaging markers in the diagnosis of post-traumatic stress disorder and blast-induced mild traumatic brain injury

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