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Papers by Kim Gilbert

Shock, 2020

Supplemental Digital Content is available in the text ABSTRACT Secondary brain injury following h... more Supplemental Digital Content is available in the text ABSTRACT Secondary brain injury following hemorrhagic shock (HS) is a frequent complication in patients, even in the absence of direct brain trauma, leading to behavioral changes and more specifically anxiety and depression. Despite preclinical studies showing inflammation and apoptosis in the brain after HS, none have addressed the impact of circulating mediators. Our group demonstrated an increased uric acid (UA) circulation in rats following HS. Since UA is implicated in endothelial dysfunction and inflammatory response, we hypothesized UA could alter the blood–brain barrier (BBB) and impact the brain. Male Wistar rats were randomly assigned to: SHAM, HS (hemorrhagic shock) and HS + U (hemorrhagic shock + 1.5 mg/kg of uricase). The uricase intervention, specifically targeting UA, was administered during fluid resuscitation. It prevented BBB dysfunction (fluorescein sodium salt permeability and expression of intercellular adhesion molecule-1) following HS. As for neuroinflammation, all of the results obtained (MPO activity; Iba1 and GFAP expression) showed a significant increase after HS, also prevented by the uricase. The same pattern was observed after quantification of apoptosis (caspase-3 activity and TUNEL) and neurodegeneration (Fluoro-Jade). Finally, the forced swim, elevated plus maze, and social interaction tests detected anxiety-like behavior after HS, which was blunted in rats treated with the uricase. In conclusion, we have identified UA as a new circulatory inflammatory mediator, responsible for brain alterations and anxious behavior after HS in a murine model. The ability to target UA holds the potential of an adjunctive therapeutic solution to reduce brain dysfunction related to hemorrhagic shock in human.

Journal of Trauma and Acute Care Surgery, 2020

Background: Multi-organ failure is a consequence of severe ischemia-reperfusion injury after trau... more Background: Multi-organ failure is a consequence of severe ischemia-reperfusion injury after traumatic hemorrhagic shock, a major cause of mortality in trauma patients. Circulating uric acid, released from cell lysis, is known to activate pro-inflammatory and pro-apoptotic pathways and has been associated with poor clinical outcomes among critically ill patients. Our group has recently shown a mediator role for uric acid in kidney and lung injury, but its role in liver and enteric damage after hemorrhagic shock remains undefined. Therefore, the objective of this study was to evaluate the role of uric acid on liver and enteric injury after resuscitated hemorrhagic shock. Methods: A murine model of resuscitated hemorrhagic shock was treated during resuscitation with a recombinant uricase, a urate oxidase enzyme (rasburicase, Sanofi), to metabolize and reduce circulating uric acid. Biochemical analyses (liver enzymes, liver apoptotic and inflammatory markers) were performed at 24h and 72h after hemorrhagic shock. Physiological testing for enteric permeability and gut bacterial product translocation measurement (plasma endotoxin) were performed 72h after hemorrhagic shock. In vitro, HT-29 cells were exposed to UA, and the expression of intercellular adhesion proteins (ZO-1, e-cadherin) was measured to evaluate the influence of uric acid on enteric permeability. Results: The addition of Uricase to resuscitation significantly reduced circulating and liver uric acid levels after hemorrhagic shock. It also prevented hemorrhagic shock-induced hepatolysis and liver apoptotic/inflammatory mediators at 24h and 72h. Hemorrhagic shock-induced enteric hyperpermeability and endotoxemia were prevented with uricase.

PLOS ONE, 2019

Caspase-3 activation in the limbic system and depressive-like symptoms are observed after an acut... more Caspase-3 activation in the limbic system and depressive-like symptoms are observed after an acute myocardial infarction (MI) and studies suggest that inflammation may play a significant role. Combined treatment with the probiotic strains Bifidobacterium longum and Lactobacillus helveticus in rats has been shown to attenuate caspase-3 activation and depressive-like behaviour together with a reduction in pro-inflammatory cytokines. The present study was designed to determine the respective contribution of these two strains on caspase-3 activity in the limbic system and on depressive-like behaviour. Sprague-Dawley rats were assigned to one of four groups: Vehicle, L. helveticus R0052, B. longum R0175 and L. salivarius HA-118, administered orally for 14 days (10 9 CFU daily) before inducing MI by occlusion of the left anterior descending artery for 40 min followed by 14 days of reperfusion. Animals were then tested for socialisation, passive avoidance and forced swim test to assess depressive-like behaviour. At day 18 the animals were sacrificed; infarct size was estimated, plasma C-reactive protein concentration and brain caspase-3 activity were measured. Results indicated that infarct size did not vary across the different treatments. Rats treated with B. longum spent more time socializing, learned more rapidly the passive avoidance test and spent less time immobile in the forced swim test compared to the vehicle groups. Caspase-3 activity and plasma C-reactive protein concentrations were reduced in the lateral and medial amygdala as well as in the dentate gyrus of B. longum-supplemented animals. The only significant effect in the two groups receiving Lactobacilli compared to vehicle was that rats receiving L. salivarius learned more rapidly in the step-down passive avoidance test. In conclusion, most of the beneficial effects that we previously reported with the combination of two probiotic strains in our experimentation regarding post-myocardial infarction depression are related to Bifidobacterium longum.

Canadian Journal of Physiology and Pharmacology, 2018

The present study was designed to ascertain the effects of 3 diets with different omega-3/6 fatty... more The present study was designed to ascertain the effects of 3 diets with different omega-3/6 fatty acid ratios on infarct size and the modifications that these diets induce in the lipid composition of cardiac tissue. Sprague-Dawley rats were fed omega-3/6 fatty acid diets with 1:1, 1:5, or 1:20 ratios for at least 10 days, followed by occlusion of the left anterior descending artery for 40 min and 24 h of reperfusion. Infarct size was significantly smaller in the 1:1 group than in the other groups. Significantly higher concentrations of the omega-3 fatty acids eicosapentaenoic acid, docosapentaenoic acid, and docosahexaenoic acid were found in the 1:1 group than in the other groups. Omega-6 polyunsaturated fatty acid levels were similar between groups, although they were higher in the 1:5 and 1:20 groups than in the 1:1 group. Margaric acid concentrations were higher in the 1:1 group than in the other groups. Docosahexaenoic acid levels in cardiac tissue and infarct size were signifi...

Marine Drugs, 2018

The high-fat diet of North Americans has a major impact on cardiovascular disease occurrence. Not... more The high-fat diet of North Americans has a major impact on cardiovascular disease occurrence. Notably, fatty acids have been identified as important factors that could modulate such diseases, especially myocardial infarction (MI). Experimentally, omega-3 polyunsaturated fatty acids (PUFA) have demonstrated positive effects on cardiovascular disorders and have also shown cardioprotection by decreasing MI size. Although many animal experiments have clearly established the benefits of omega-3 PUFA, clinical studies have not reached similar conclusions. In fact, the findings of recent clinical investigations indicate that omega-3 PUFA play only a minor role in cardiovascular health. This dichotomy between experimental and clinical studies may be due to different parameters that are not taken into account in animal experiments. We have recently observed that the high consumption of omega-6 PUFA results in significant attenuation of the beneficial effect of omega-3 PUFA on MI. We believe that part of the dichotomy between experimental and clinical research may be related to the quantity of omega-6 PUFA ingested. This review of the data indicates the importance of considering omega-6 PUFA consumption in omega-3 PUFA studies.

Journal of Trauma and Acute Care Surgery, 2018

; on behalf of the Canadian Critical Care Translational Biology Group (CCCTBG) BACKGROUND: Multip... more ; on behalf of the Canadian Critical Care Translational Biology Group (CCCTBG) BACKGROUND: Multiple organ failure can develop after hemorrhagic shock (HS). Uric acid (UA) is released from dying cells and can be proinflammatory. We hypothesized that UA could be an alternative mediator of organ apoptosis and inflammation after HS. METHODS: Ventilated male Wistar rats were used for the HS model. Two durations of shock (5 minutes vs. 60 minutes) were compared, and shams were instrumented only; animals were resuscitated and observed for 24 hours/72 hours. Caspases-(8/3), myeloperoxidase (MPO), TNF-α were measured in lungs and kidneys. Plasma UA and cytokine (IL-1β, IL-18, TNF-α) were measured. A second set of animals were randomized to vehicle versus Rasburicase intraperitoneal intervention (to degrade UA) during resuscitation. Another group received exogenous UA intraperitoneally without HS. Measures mentioned above, in addition to organs UA, were performed at 24 hours. In vitro, caspases-(8/3) activity was tested in epithelial cells exposed to UA. RESULTS: Hemorrhagic shock increased organ (kidney and lung) TNF-α, MPO, and caspases activity in various patterns while caspase-8 remained elevated over time. Hemorrhagic shock led to increased plasma UA at 2 hours, which remained high until 72 hours; TNF-α and IL-18 were elevated at 24 hours. The exogenous UA administration in sham animals reproduced the activation of caspase-8 and MPO in organs, and TNF-α in the lung. The increased plasma and organ UA levels, plasma and lung TNF-α, as well as organ caspase-(8/3) and MPO, observed at 24 hours after HS, were prevented by the administration of Rasburicase during resuscitation. In vitro, soluble UA induced caspases-(3/8) activity in epithelial cells. CONCLUSION: Uric acid is persistently high after HS and leads to the activation of caspases-8 and organ inflammation; these can be prevented by an intervention to degrade UA. Therefore, UA is an important biomarker and mediator that could be considered a therapeutic target during HS resuscitation in human. (

International Journal of Molecular Sciences, 2018

Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation ... more Myocardial infarction (MI) in animal models induces cognitive deficits as well as the activation of caspase in the limbic system; both can be blocked by 2 weeks of treatment following MI using tricyclic antidepressants or selective serotonin uptake blockers. Here we used three different treatment schedules to test the short- and long-term effects of the combined serotonin-norepinephrine reuptake inhibitor desvenlafaxine on post-MI-associated cognitive deficits and caspase activation. MI was induced in 39 young adult rats, and 39 rats served as sham-operated controls. Desvenlafaxine (3 mg/kg/day, i.p.) or saline was administered according to one of three schedules: (1) for 2 weeks, starting right after surgery; (2) for 16 weeks, starting 2 weeks after surgery; (3) for 16 weeks, starting right after surgery. Behavior was tested 2 weeks (social interaction, passive avoidance) and 16 weeks (forced swimming, Morris water maze) after surgery. Caspase-3 and caspase-6 activities were measur...

Prostaglandins, Leukotrienes and Essential Fatty Acids, 2016

The aim of this project was to investigate the impact of two dietary omega-3 polyunsaturated fatt... more The aim of this project was to investigate the impact of two dietary omega-3 polyunsaturated fatty acids (PUFAs), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), alone or in combination, on infarct size. Adult, male Sprague-Dawley rats were fed for 14 days with different omega-3 diets. The animals were subjected to ischemia for 40min followed by reperfusion. Infarct size, Akt (protein kinase B) activation level, caspase-3 activity and mitochondrial permeability transition pore (mPTP) opening were measured. The results indicate that EPA or DHA alone significantly reduced infarct size compared to the other diets. Akt activity was increased in the group fed EPA or DHA alone, whereas no significant activation was observed in the other groups compared to no omega-3 PUFA. DHA alone reduced caspase-3 activity and conferred resistance to mPTP opening. In conclusion, our results demonstrate that EPA and DHA are individually effective in diminishing infarct size in our experimental model while their combination is not.

The Journal of Nutritional Biochemistry, 2016

We previously observed that resolvin D1 (RvD1), a metabolite of the omega-3 polyunsaturated fatty... more We previously observed that resolvin D1 (RvD1), a metabolite of the omega-3 polyunsaturated fatty acid (PUFA) docosahexaenoic acid, reduces infarct size by a mechanism involving the PI3-K/Akt pathway. In parallel, the beneficial effect of a high omega-3 PUFA diet on infarct size can be attenuated by increased omega-6 PUFA consumption. The present study was designed to determine if augmented linoleic acid (LA), an omega-6 PUFA administered at the same time, attenuates the cardio-protective action of RvD1. Male Sprague-Dawley rats received 0.1 μg RvD1 alone or with 1 of 3 LA doses (1, 5 or 10 μg) directly into the left ventricle chamber 5 min before ischemia. The animals underwent 40 min of ischemia by occlusion of the left descending coronary artery followed by 30 min or 24 h of reperfusion. Infarct size and neutrophil accumulation were evaluated after 24 h of reperfusion while caspase-3,-8,-9 and Akt activities were assessed at 30 min of reperfusion. LA attenuated cardio-protection afforded by RvD1, resulting in significantly increased infarct size. Neutrophil accumulation and Akt activity were similar between groups. Caspase activities, especically caspase-9, which could be activated by ischemia, were stimulated in the presence of LA, suggesting that this omega-6 PUFA accentuates ischemia intensity. The present results indicate that LA significantly attenuates the beneficial effect of RvD1 on infarct size. Therefore, reduction of omega-6 intake should be considered to maintain the protection afforded by RvD1.

Journal of Visualized Experiments, 2016

Myocardial infarction (MI) has dramatic mid-and long-term consequences at the physiological and b... more Myocardial infarction (MI) has dramatic mid-and long-term consequences at the physiological and behavioral levels, but the mechanisms involved are still unclear. Our laboratory has developed a rat model of post-MI syndrome that displays impaired cardiac functions, neuronal loss in the limbic system, cognitive deficits and behavioral signs of depression. At the neuronal level, caspase-3 activation mediates post-MI apoptosis in different limbic regions, such as the amygdala-peaking at 3 days post-MI. Cognitive and behavioral impairments appear 2-3 weeks post-MI and these correlate statistically with measures of caspase-3 activity. The protocol described here is used to induce MI, collect amygdala tissue and measure caspase-3 activity using spectrofluorometry. To induce MI, the descending coronary artery is occluded for 40 min. The protocol for evaluation of caspase-3 activation starts 3 days after MI: the rats are sacrificed and the amygdala isolated rapidly from the brain. Samples are quickly frozen in liquid nitrogen and kept at-80 °C until actual analysis. The technique performed to assess caspase-3 activation is based on cleavage of a substrate (DEVD-AMC) by caspase-3, which releases a fluorogenic compound that can be measured by spectrofluorometry. The methodology is quantitative and reproducible but the equipment required is expensive and the procedure for quantifying the samples is time-consuming. This technique can be applied to other tissues, such as the heart and kidneys. DEVD-AMC can be replaced by other substrates to measure the activity of other caspases.

European journal of pharmacology, Jan 6, 2015

Although controversial, some data suggest that Omega-3 polyunsaturated fatty acids (PUFA) are ben... more Although controversial, some data suggest that Omega-3 polyunsaturated fatty acids (PUFA) are beneficial to cardiovascular diseases, and could reduce infarct size. In parallel, we have reported that the administration of Resolvin D1 (RvD1), a metabolite of docosahexaenoic acid, an Omega-3 PUFA, can reduce infarct size. The present study was designed to determine if the inhibition of two important enzymes involved in the formation of RvD1 from omega-3 PUFA could reduce the cardioprotective effect of omega-3 PUFA. Sprague-Dawley rats were fed with a diet rich in omega-3 PUFA during 10 days before myocardial infarction (MI). Two days before MI, rats received a daily dose of Meloxicam, an inhibitor of cyclooxygenase-2, PD146176, an inhibitor of 15-lipoxygenase, both inhibitors or vehicle. MI was induced by the occlusion of the left coronary artery for 40min followed by reperfusion. Infarct size and neutrophil accumulation were evaluated after 24h of reperfusion while caspase-3, -8 and A...

PharmaNutrition, 2015

Myocardial infarction (MI) induces an inflammatory process that is associated with increased apop... more Myocardial infarction (MI) induces an inflammatory process that is associated with increased apoptosis in the limbic system of rats and the development of post-MI depressive symptoms. Resolvin D1 (RvD1), an omega-3 fatty acid metabolite, is known for its pro-resolution properties; it reduces infarct size and attenuates post-MI depression-like symptoms. The present study was designed to determine if a single RvD1 dose could abate caspase-3 activation, a marker of apoptosis, in the limbic system. Male Sprague-Dawley rats underwent 40 min of myocardial ischemia, followed by 24-h reperfusion. Five min before MI, the animals received a single intra-cardiac RvD1 injection (0.01, 0.1 or 0.3 mg) or vehicle (saline). Infarct size was assessed and caspase-3 activity measured in the amygdala and hippocampus. Rats receiving 0.1 or 0.3 mg RvD1 showed significantly decreased infarct size. Caspase-3 activity was significantly attenuated in the lateral amygdala and dentate gyrus with 0.1 mg RvD1 and in the CA1 region of the hippocampus and medial amygdala with 0.3 mg RvD1. In conclusion, RvD1 could reduce infarct size and caspase-3 activity in the amygdala and hippocampus. 2015 Elsevier B.V. All rights reserved.

Journal of cardiovascular pharmacology, Jan 3, 2015

This study was designed to determine if Resolvin D1 (RvD1), a pro-resolution metabolite of the om... more This study was designed to determine if Resolvin D1 (RvD1), a pro-resolution metabolite of the omega-3 PUFA docosahexaenoic acid, could decrease myocardial infarct size with delivered at the onset of ischemia.Male Sprague-Dawley rats underwent 40 min of myocardial ischemia followed by reperfusion. These animals received 1 intraventricular injection of RvD1 (0.01 μg, 0.1 μg or 0.3 μg RvD1) or vehicle (saline) before coronary occlusion. Infarct size and neutrophil accumulation were evaluated 24 h after the onset of reperfusion. Caspase-3, caspase-8, protein kinase B (Akt) activities were evaluated 30 min after the reperfusion.Rats receiving 0.1μg or 0.3μg RvD1 showed a significant decrease of infarct size as well as caspase-3 and -8 activities compared to the vehicle controls. Neutrophil accumulations were reduced in rats administered RvD1 compared to vehicle, independently of dose level. Akt activation was increased only in animals receiving 0.1μg or 0.3 μg, whereas no change was obs...

Neurogastroenterology and motility : the official journal of the European Gastrointestinal Motility Society, Jan 18, 2015

Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with cli... more Myocardial infarction (MI) is associated with apoptosis in the amygdala and, ultimately, with clinical signs of depression. Different treatments have proven to be beneficial in preventing depression, including combination of the probiotics Lactobacillus helveticus and Bifidobacterium longum for prophylaxis. We have speculated previously that the benefit of these probiotics is due to their anti-inflammatory properties, and evidence suggests that an intact vagus nerve is important for this effect to occur. This study was designed to ascertain vagus nerve involvement in the beneficial influence of probiotics on caspase activities in our post-MI animal model of depression. Probiotics and/or vehicle were administered daily to male adult rats, 14 days before MI and until euthanasia. Vagotomy was performed in subgroups of rats 40 min before MI. They were sacrificed after 3 days of reperfusion, and MI size was assessed along with caspase-3 and -8 activities in the amygdala. Probiotics had n...

Marine drugs, Jan 13, 2014

We hypothesized that inflammation induced by myocardial ischemia plays a central role in depressi... more We hypothesized that inflammation induced by myocardial ischemia plays a central role in depression-like behavior after myocardial infarction (MI). Several experimental approaches that reduce inflammation also result in attenuation of depressive symptoms. We have demonstrated that Resolvin D1 (RvD1), a metabolite of omega-3 polyunsaturated fatty acids (PUFA) derived from docosahexaenoic acid, diminishes infarct size and neutrophil accumulation in the ischemic myocardium. The aim of this study is to determine if a single RvD1 injection could alleviate depressive symptoms in a rat model of MI. MI was induced in rats by occlusion of the left anterior descending coronary artery for 40 min. Five minutes before ischemia or after reperfusion, 0.1 μg of RvD1 or vehicle was injected in the left ventricle cavity. Fourteen days after MI, behavioral tests (forced swim test and socialization) were conducted to evaluate depression-like symptoms. RvD1 reduced infarct size in the treated vs. the ve...

British Journal of Nutrition, 2011

Myocardial infarction (MI) in rats is accompanied by apoptosis in the limbic system and a behavio... more Myocardial infarction (MI) in rats is accompanied by apoptosis in the limbic system and a behavioural syndrome similar to models of depression. We have already shown that probiotics can reduce post-MI apoptosis and designed the present study to determine if probiotics can also prevent post-MI depressive behaviour. We also tested the hypothesis that probiotics achieve their central effects through changes in the intestinal barrier. MI was induced in anaesthetised rats via 40-min transient occlusion of the left anterior coronary artery. Sham rats underwent the same surgical procedure without actual coronary occlusion. For 7 d before MI and between the seventh post-MI day and euthanasia, half the MI and sham rats were given one billion live bacterial cells of Lactobacillus helveticus R0052 and Bifidobacterium longum R0175 per d dissolved in water, while the remaining animals received only the vehicle (maltodextrin). Depressive behaviour was evaluated 2 weeks post-MI in social interacti...

British Journal of Nutrition, 2012

Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the l... more Proinflammatory cytokines play a central role in depression-like behaviour and apoptosis in the limbic system after myocardial infarction (MI). A PUFAn-3 diet or the combination ofLactobacillus helveticusR0052 andBifidobacterium longumR0175 probiotics, when given before the ischaemic period, reduce circulating proinflammatory cytokines as well as apoptosis in the limbic system. The present study was designed to determine if the same nutritional interventions maintain their beneficial effects when started after the onset of the reperfusion period and attenuate depression-like behaviour observed after MI. MI was induced by the occlusion of the left anterior descending coronary artery for 40 min in rats. After the onset of reperfusion, animals were fed with a high- or low-PUFAn-3 diet, combined or not with one billion live bacteria ofL. helveticusandB. longum. At 3 d post-MI, caspase-3 enzymatic activities and terminal 2′-deoxyuridine, 5′-triphosphate (dUTP) nick-end labelling (TUNEL)-...

Agro Food Industry Hi Tech

Intestinal transit is often affected during stressful conditions, suggesting a link between brain... more Intestinal transit is often affected during stressful conditions, suggesting a link between brain and gut. Moreover recent experimental evidence has demonstrated that the gut might also influence the activity of the brain and the behaviour by different mechanisms including nervous transmission, the immune system and the microbiota. Indeed, the gut-brain axis is not only essential for the maintenance of gastrointestinal homeostasis but is also involved in the regulation of cognitive functions and stress. The purpose of this review is to discuss the recent evidence on the gut-brain axis and how modulation of the microbiota using probiotics may be beneficial to our mental and intestinal health.

Brain Research Bulletin, 2014

This study was designed to determine if desvenlafaxine (DV), a serotonin-norepinephrine reuptake ... more This study was designed to determine if desvenlafaxine (DV), a serotonin-norepinephrine reuptake inhibitor, can attenuate apoptosis observed in the limbic system after myocardial infarction (MI). MI was induced in rats by occlusion of the left descending artery for 40 min followed by reperfusion. Another group of sham (control) rats was similarly manipulated, but without occlusion. Half of the full cohort received DV (3 mg/kg/day intraperitoneal), starting 5 min after the onset of reperfusion; the other half received the vehicle (0.5 ml of 0.9% saline). Rats were sacrificed after 3 days for biochemical analyses and MI size measurements. Infarct size was significantly smaller in DV- compared to vehicle-treated rats. At 3 days post-MI, caspase-3 and -8 activities and terminal deoxynucleotidyltransferase-mediated dUTP nick-end labeling-positive cells were decreased in the amygdala of DV-treated rats compared to MI-vehicle controls. No difference was observed between the sham groups. The data indicates that DV given immediately after an acute MI event can reduce MI size and apoptosis in amygdala when measured three days post-MI.