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Janne Bredehöft,1 Amalia M Dolga,2 Birgit Honrath,2,3 Sybille Wache,1 Sybille Mazurek,1 Carsten Culmsee,3,4 Regien G Schoemaker,5 Rüdiger Gerstberger,1 Joachim Roth,1,4 Christoph Rummel1,4 1Institute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Giessen, Germany; 2Department of Molecular Pharmacology, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, Netherlands; 3Institute of Pharmacology and Clinical Pharmacy, Philipps University of Marburg, Marburg, Germany; 4Center for Mind, Brain and Behavior-CMBB, Giessen and Marburg, Germany; 5Department of Neurobiology, GELIFES, University of Groningen, Groningen, NetherlandsCorrespondence: Christoph RummelInstitute of Veterinary Physiology and Biochemistry, Justus Liebig University Giessen, Frankfurter Strasse 100, Giessen D-35392, GermanyTel +49 641 99 38155Fax +49 641 99 38159Email Christoph.D.Rummel@vetmed.uni-giessen.dePurpose: Previously, we have shown that CyPPA (cyclohexyl-[2-(3,5-dimethyl-pyrazol-1-yl)-6-methyl-pyrimidin-4-yl]-amine), a pharmacological small-conductance calcium-activated potassium (SK)–channel positive modulator, antagonizes lipopolysaccharide (LPS)-induced cytokine expression in microglial cells. Here, we aimed to test its therapeutic potential for brain-controlled sickness symptoms, brain inflammatory response during LPS-induced systemic inflammation, and peripheral metabolic pathways in mice.Methods: Mice were pretreated with CyPPA (15 mg/kg IP) 24 hours before and simultaneously with LPS stimulation (2.5 mg/kg IP), and the sickness response was recorded by a telemetric system for 24 hours. A second cohort of mice were euthanized 2 hours after CyPPA or solvent treatment to assess underlying CyPPA-induced mechanisms. Brain, blood, and liver samples were analyzed for inflammatory mediators or nucleotide concentrations using immunohistochemistry, real-time PCR and Western blot, or HPLC. Moreover, we investigated CyPPA-induced changes of UCP1 expression in brown adipose tissue (BAT)–explant cultures.Results: CyPPA treatment did not affect LPS-induced fever, anorexia, adipsia, or expression profiles of inflammatory mediators in the hypothalamus or plasma or microglial reactivity to LPS (CD11b staining and CD68 mRNA expression). However, CyPPA alone induced a rise in core body temperature linked to heat production via altered metabolic pathways like reduced levels of adenosine, increased protein content, and increased UCP1 expression in BAT-explant cultures, but no alteration in ATP/ADP concentrations in the liver. CyPPA treatment was accompanied by altered pathways, including NFκB signaling, in the hypothalamus and cortex, while circulating cytokines remained unaltered.Conclusion: Overall, while CyPPA has promise as a treatment strategy, in particular according to results from in vitro experiments, we did not reveal anti-inflammatory effects during severe LPS-induced systemic inflammation. Interestingly, we found that CyPPA alters metabolic pathways inducing short hyperthermia, most likely due to increased energy turnover in the liver and heat production in BAT.Keywords: neuroinflammation, fever, inflammatory markers, small-conductance calcium-activated potassium channels, locomotor activity, brown adipose tissue

The gut-brain axis is regarded as a bidirectional communication system that integrates signals from the gut microbiome into behavioral aspects and vice versa. The aim of the present study was to investigate the gut microbiome-behavior interaction in relation to aggression. For that, male rats from a group-housed colony were individually housed with a female to become territorial. Next, a coping strategy was assigned to them, by evaluating their aggression levels against an intruder, during the Resident-Intruder test (RI). To investigate if their microbiome would change as a consequence of the developed coping strategy, fecal samples were collected before and after the RI test. We found that the relative abundances of Ruminococcaceae UCG-5 and Gram-negative bacterium cTPY-13 in rats sampled before the RI test were negatively correlated with the aggression that was demonstrated during the RI test. After the RI test, several bacterial taxa could be assigned to each coping strategy, with Clostridium sensu stricto 1 being strongly associated with less aggressive rats and higher abundances of Bifidobacterium. Furthermore, the family of Lachnospiraceae was not only associated with more aggressive rats, but functional prediction analysis found it to be the main contributor of betaine reductase; an enzyme catalyzing betaine production that was indicative of aggressive rats. This amino acid derivative, which has been connected with higher energy and testosterone levels, could potentially explain the connection of Lachnospiraceae with demonstrated aggression. Overall, our data revealed that the gut bacterial communities are responsive to the imposed social challenge of building and defending territoriality in co-habitation with a female. At the same time, predisposing microbiome characteristics may have predictive value for the development of a coping strategy., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Voulgari-Kokota et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Whole body vibration (WBV) is a form of passive exercise that offers an alternative physical training to aged individuals with limitations in their physical and mental capabilities. The aim of the present study was to explore the therapeutic potential of five weeks of WBV on anxiety-like behaviors as well as learning and memory abilities in senescent thirty months old rats. Animals were exposed to 5 min vibration twice per day, five times per week during the five consecutive weeks. Pseudo WBV treated animals served as controls. After five weeks of WBV treatment, animals were tested for anxiety-like behavior by the open field test and for spatial and object memory functions by the novel and spatial object recognition tests, respectively. As a result, anxiety-like and exploratory behaviors were significantly improved in the WBV treated group compared to the pseudo WBV group. Furthermore, WBV treatment increased discrimination performance in both spatial and object memory function testing. These results indicate that WBV treatment in thirty months old rats seems to have comparable beneficial effects on age-related emotional and cognitive performance as what has been reported in younger age groups., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Authors.)

Vulnerable patients are at risk for neuroinflammation-mediated post-operative complications, including depression (POD) and cognitive dysfunction (POCD). Zucker rats, expressing multiple risk factors for post-operative complications in humans, may provide a clinically relevant model to study pathophysiology and explore potential interventions. J147, a newly developed anti-dementia drug, was shown to prevent POCD in young healthy rats, and improved early post-surgical recovery in Zucker rats. Aim of the present study was to investigate POCD and the therapeutic potential of J147 in male Zucker rats. Risk factors in the Zucker rat strain were evaluated by comparison with lean littermates. Zucker rats were subjected to major abdominal surgery. Acute J147 treatment was provided by a single iv injection (10 mg/kg) at the start of surgery, while chronic J147 treatment was provided in the food (aimed at 30 mg/kg/day), starting one week before surgery and up to end of protocol. Effects on behavior were assessed, and plasma, urine and brain tissue were collected and processed for immunohistochemistry and molecular analyses. Indeed, Zucker rats displayed increased risk factors for POCD, including obesity, high plasma triglycerides, low grade systemic inflammation, impaired spatial learning and decreased neurogenesis. Surgery in Zucker rats reduced exploration and increased anxiety in the Open Field test, impaired short-term spatial memory, induced a shift in circadian rhythm and increased plasma neutrophil gelatinase-associated lipocalin (NGAL), microglia activity in the CA1 and blood brain barrier leakage. Chronic, but not acute J147 treatment reduced anxiety in the Open Field test and protected against the spatial memory decline. Moreover, chronic J147 increased glucose sensitivity. Acute J147 treatment improved long-term spatial memory and reversed the circadian rhythm shift. No anti-inflammatory effects were seen for J147. Although Zucker rats displayed risk factors, surgery did not induce extensive POCD. However, increased anxiety may indicate POD. Treatment with J147 showed positive effects on behavioral and metabolic parameters, but did not affect (neuro)inflammation. The mixed effect of acute and chronic treatment may suggest a combination for optimal treatment., Competing Interests: Declaration of Competing Interest All authors have no competing interest to declare., (Copyright © 2023. Published by Elsevier Inc.)

Background: Females with cardiovascular disease seem more vulnerable to develop concomitant mental problems, such as depression and cognitive decline. Although exercise is shown beneficial in cardiovascular disease as well as in mental functions, these patients may be incapable or unmotivated to perform exercise. Whole body vibration (WBV) could provide a passive alternative to exercise. Aim of the present study was to compare WBV to exercise after isoproterenol (ISO)-induced myocardial damage in female rats, regarding effects on heart, brain and behavior., Methods: One week after ISO (70 mg/kg s.c., on 2 consecutive days) or saline injections, 12 months old female rats were assigned to WBV (10 minutes daily), treadmill running (30 minutes daily) or pseudo intervention for 5 weeks. During the last 10 days, behavioral tests were performed regarding depressive-like behavior, cognitive function, and motor performance. Rats were sacrificed, brains and hearts were dissected for (immuno)histochemistry., Results: Significant ISO-induced cardiac collagen deposition (0.67 ± 0.10 vs 0.18 ± 0.03%) was absent after running (0.45 ± 0.26 vs 0.46 ± 0.08%), but not after WBV (0.83 ± 0.12 vs 0.41 ± 0.05%). However, WBV as well as running significantly reduced hippocampal (CA3) collagen content in ISO-treated rats. Significant regional differences in hippocampal microglia activity and brain derived neurotrophic factor (BDNF) expression were observed. Significant ISO-induced CA1 microglia activation was reduced after WBV as well as running, while opposite effects were observed in the CA3; significant reduction after ISO that was restored by WBV and running. Both WBV and running reversed the ISO-induced increased BDNF expression in the CA1, Dentate gyrus and Hilus, but not in the CA3 area. Whereas running had no significant effect on behavior in the ISO-treated rats, WBV may be associated with short-term spatial memory in the novel location recognition test., Conclusion: Although the female rats did not show the anticipated depressive-like behavior or cognitive decline after ISO, our data indicated regional effects on neuroinflammation and BDNF expression in the hippocampus, that were merely normalized by both WBV and exercise. Therefore, apart from the potential concern about the lack of cardiac collagen reduction, WBV may provide a relevant alternative for physical exercise., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The handling editor RT is currently organizing a Research Topic with the author EZ., (Copyright © 2023 Tóth, Oroszi, Nyakas, van der Zee and Schoemaker.)

Although exercise is usually associated with beneficial effects on physical and mental health, patients recovering from surgery may be hampered to perform active exercise. Whole body vibration (WBV) is suggested a passive alternative for physical training. Aim of the present study was to explore the therapeutic potential of WBV compared to physical exercise during early post-surgery recovery. Male three months old Wistar rats underwent major abdominal surgery. Starting the day after surgery, rats were subjected to either daily WBV or exercise (treadmill running) for 15 consecutive days. Control rats underwent pseudo treatment. During the first week after surgery, effects of interventions were obtained from continuous recording of hemodynamic parameters, body temperature and activity (via an implanted transducer). Behavioral tests were performed during the second post-surgical week to evaluate anxiety-like behavior, short and long-term memory functions, cognitive flexibility and motor performance. Animals were sacrificed 15 days after surgery and brain tissue was collected for analysis of hippocampal neuroinflammation and neurogenesis. Surgery significantly impacted all parameters measured during the first post-surgery week, irrespective of the type of surgery. Effect on cognitive performance was limited to cognitive flexibility; both WBV and exercise prevented the surgery-induced decline. Exercise, but not WBV increased anxiety-like behavior and grip strength. WBV as well as exercise prevented the surgery-induced declined neurogenesis, but surgery-associated hippocampal neuroinflammation was not affected. Our results indicated that active exercise and WBV share similar therapeutic potentials in the prevention of surgery induced decline in cognitive flexibility and hippocampal neurogenesis. In contrast to exercise, WBV did not increase anxiety-like behavior. Since neither intervention affected hippocampal neuroinflammation, other mechanisms and/or brain areas may be involved in the behavioral effects. Taken together, we conclude that WBV may provide a relevant alternative to active exercise during the early stage of post-operative recovery., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Authors.)

Acute cardiac damage can be induced by isoproterenol injections in animals. The associated inflammatory response could be reflected in the brain as neuroinflammation, with potential consequences for brain function and behavior. Although cardiac responses are reported age and sex-related, for neuroinflammation and brain function this is virtually unknown. Therefore, cardiac damage and its consequences for neuroinflammation, brain function and behavior were compared in aged male and female rats. Wistar rats of 24 months of age were treated with isoproterenol (ISO, twice s.c.) or saline. Four weeks after injections, exploratory behavior and short-term memory were tested. Then, rats were sacrificed. Hearts were collected to measure cardiac damage. Brain tissue was collected to obtain measures of neuroinflammation and brain function. In male-, but not in female rats, ISO induced significant cardiac damage. Accordingly, mortality was higher in males than in females. Baseline hippocampal microglia activity was lower in females, while ISO induced neuroinflammation in both sexes, Hippocampal brain-derived neurotrophic factor expression appeared lower in females, without effects of ISO. In the open field test, ISO-treated males, but not females, displayed anxiety-like behavior. No effects of ISO were observed on short-term memory in either sex. In conclusion, sex dimorphism in effects of ISO was observed for cardiac damage and open field behavior. However, these effects could not be related to differences in hippocampal neuroinflammation or neuronal function., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Tóth, Oroszi, van der Zee, Nyakas and Schoemaker.)

Women with cardiovascular disease may be more susceptible to concomitant mental health problems, such as depression and cognitive decline. Exercise training has beneficial effects on the cardiovascular system as well as on mental functions. Aim of the present study was to study the effects of exercise training on heart, brain and behavior in the isoproterenol (ISO) model in middle-aged female rats. Twelve months old female Wistar rats were submitted to ISO injections (70 mg/kg s.c., on two consecutive days) or received saline. One week later, rats were assigned to either exercise training (treadmill running) or control handling for five weeks. During the last 7 days, tests were performed regarding depressive-like behavior and cognitive function. Then, rats were sacrificed and heart and brains were dissected for (immuno)histochemistry. ISO-induced cardiac effects were eminent from cardiac fibrosis and declined cardiac function. Exercise training reversed cardiac damage and partly restored ISO-induced cardiac dysfunction. However, ISO treatment could not be associated with neuroinflammation, nor impaired hippocampal neurogenesis or neuronal function. Accordingly, no cognitive impairment or depressive-like behavior were observed. Actually, hippocampal microglia hyper-ramification was observed after ISO. Exercise left neuroinflammation and behavior merely unaltered, and even reduced neuronal function. Our data indicated that the cardiac damage after ISO in middle-aged female rats, and the subsequent beneficial effects of five weeks exercise training on the heart, were not reflected in changes in the brain nor in altered behavior., (© 2022. The Author(s).)

Whole body vibration (WBV) is a form of passive exercise by the stimulation of mechanical vibration platform. WBV has been extensively investigated through clinical studies with main focus on the musculoskeletal system. However, pre-clinical data in the context of behavior, memory and motor functions with aged rodents are limited. The aim of this experiment was to investigate the dose dependent effects of a five weeks long WBV intervention with an aged animal model including anxiety-related behavior, memory and motor functions, as well as markers of (neuro)inflammation. Male Wistar rats (18 months) underwent 5 or 20 min daily vibration exposure or pseudo-treatment (i.e.: being subjected to the same environmental stimuli for 5 or 20 min, but without exposure to vibrations) 5 times per week. After 5 weeks treatment, cognitive functions, anxiety-like behavior and motor performance were evaluated. Finally, brain tissue was collected for immunohistological purposes to evaluate hippocampal (neuro)inflammation. Animals with 20 min daily session of WBV showed a decrease in their anxiety-like behavior and improvement in their spatial memory. Muscle strength in the grip hanging test was only significantly improved by 5 min daily WBV treatments, whereas motor coordination in the balance beam test was not significantly altered. Microglia activation showed a significant decrease in the CA1 and Dentate gyrus subregions by both dose of WBV. In contrast, these effects were less pronounced in the CA3 and Hilus subregions, where only 5 min dose showed a significant effect on microglia activation. Our results indicate, that WBV seems to be a comparable strategy on age-related anxiety, cognitive and motor decline, as well as alleviating age-related (neuro)inflammation., (© 2022. The Author(s).)

Aging is a progressive process leading to functional decline in many domains. Recent studies have shown that physical exercise (PE) has a positive influence on the progression of age-related functional decline, including motor and brain functions. Whole body vibration (WBV) is a form of passive stimulation by mechanical vibration platforms, which offers an alternative for PE interventions, especially for aged individuals. WBV has been demonstrated to mimic the beneficial effects of PE on the musculoskeletal system, as well on the central nervous system. However, preclinical data with aged rodents are very limited. Hence, the purpose of this experiment was to investigate the effects of a 5-week WBV intervention with an aged animal model on memory functions, anxiety-related behavior, and motor performance. The 18-month old male ( N = 14) and female ( N = 14) Wistar rats were divided into two groups, namely, vibration and pseudo-vibration. Animals underwent a 5-week WBV intervention protocol with low intensity (frequency of 30 Hz and amplitude of 50-200 μm) stimulation. After 5 weeks, the following cognitive and motor tests were administered: open-field, novel and spatial object recognition, grip-hanging, and balance-beam. WBV-treated rats showed a decrease in their anxiety level in the open field test compared with those in the pseudo-treated controls. In addition, WBV-treated male animals showed significantly increased rearing in the open-field test compared to their pseudo controls. Spatial memory was significantly improved by WBV treatment, whereas WBV had no effect on object memory. Regarding motor performance, both grip strength and motor coordination were improved by WBV treatment. Our results indicate that WBV seems to have comparable beneficial effects on age-related emotional, cognitive, and motor decline as what has been reported for active PE. No striking differences were found between the sexes. As such, these findings further support the idea that WBV could be considered as a useful alternative for PE in case active PE cannot be performed due to physical or mental issues., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Oroszi, Geerts, de Boer, Schoemaker, van der Zee and Nyakas.)

Acute sympathetic stress can result in cardiac fibrosis, but may also lead to mental dysfunction. Exercise training after isoproterenol (ISO)-induced acute sympathetic stress was investigated regarding cardiac damage, neuroinflammation, brain function and behavior. Male Wistar rats (12 months) received ISO or saline. One week later, treadmill running or control handling (sedentary) started. After 4 weeks, cognitive- and exploratory behavior were evaluated, and heart and brain tissues were analyzed regarding cardiac damage, hippocampal neuroinflammation and neuronal function. ISO did not affect cognitive performance nor hippocampal function. However, ISO reduced anxiety, coinciding with locally reduced microglia (processes) size in the hippocampus. Exercise in ISO rats reversed anxiety, did not affect microglia morphology, but increased brain function. Thus, exercise after ISO did not affect cardiac damage, cognition or hippocampal neuroinflammation, but normalized anxiety. Increased localized BDNF expression may indicate improved brain function., (© 2021. The Author(s).)

Chronic (neuro)inflammation plays an important role in many age-related central nervous system (CNS) diseases, including Alzheimer's disease, Parkinson's disease and vascular dementia. Inflammation also characterizes many conditions that form a risk factor for these CNS disorders, such as physical inactivity, obesity and cardiovascular disease. Lipocalin 2 (Lcn2) is an inflammatory protein shown to be involved in different age-related CNS diseases, as well as risk factor conditions thereof. Lcn2 expression is increased in the periphery and the brain in different age-related CNS diseases and also their risk factor conditions. Experimental studies indicate that Lcn2 contributes to various neuropathophysiological processes of age-related CNS diseases, including exacerbated neuroinflammation, cell death and iron dysregulation, which may negatively impact cognitive function. We hypothesize that increased Lcn2 levels as a result of age-related risk factor conditions may sensitize the brain and increase the risk to develop age-related CNS diseases. In this review we first provide a comprehensive overview of the known functions of Lcn2, and its effects in the CNS. Subsequently, this review explores Lcn2 as a potential (neuro)inflammatory link between different risk factor conditions and the development of age-related CNS disorders. Altogether, evidence convincingly indicates Lcn2 as a key constituent in ageing and age-related brain diseases., (Copyright © 2021 The Author(s). Published by Elsevier B.V. All rights reserved.)

Policymakers aim to move toward animal-free alternatives for scientific research and have introduced very strict regulations for animal research. We argue that, for neuroscience research, until viable and translational alternatives become available and the value of these alternatives has been proven, the use of animals should not be compromised., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Inflammation plays an important role in postoperative cognitive dysfunction (POCD), particularly in elderly patients. Enteral enriched nutrition was shown to inhibit the response on inflammatory stimuli. Aim of the present study was to explore the therapeutic potential of enteral enriched nutrition in our rat model for POCD. The anticipated mechanism of action was examined in young rats, while responses in the target group of elderly patients were evaluated in old rats., Methods: Male 3 and 23 months old Wistar rats received a bolus of enteral fat/protein-enriched nutrition 2 ​h and 30 ​min before surgery. The inflammatory response was evaluated by systemic inflammation markers and brain microglia activity. Additionally, in old rats, the role of the gut-brain axis was studied by microbiome analyses of faecal samples. Days 9-14 after surgery, rats were subjected to cognitive testing. Day 16, rats were sacrificed and brains were collected for immunohistochemistry., Results: In young rats, enriched nutrition improved long-term spatial learning and memory in the Morris Water Maze, reduced plasma IL1-β and VEGF levels, but left microglia activity and neurogenesis unaffected. In contrast, in old rats, enriched nutrition improved short-term memory in the novel object- and novel location recognition tests, but impaired development of long-term memory in the Morris Water Maze. Systemic inflammation was not affected, but microglia activity seemed even increased. Gut integrity and microbiome were not affected., Conclusion: Enteral enriched nutrition before surgery in young rats indeed reduced systemic inflammation and improved cognitive performance after surgery, whereas old rats showed a mixed favorable/unfavorable cognitive response, without effect on systemic inflammation. Anti-inflammatory effects of enriched nutrition were not reflected in decreased microglia activity. Neither was an important role for the gut-brain axis observed. Since the relatively straight forward effects of enriched nutrition in young rats could not be shown in old rats, as indicated by a mixed beneficial/detrimental cognitive outcome in the latter, caution is advised by translating effects seen in younger patients to older ones., Competing Interests: The authors have no competing interests to declare., (© 2021 The Author(s).)

Background: Myocardial infarction (MI) coinciding with depression worsens prognosis. Although Tumor Necrosis Factor alpha (TNF) is recognized to play a role in both conditions, the therapeutic potential of TNF inhibition is disappointing. TNF activates two receptors, TNFR1 and TNFR2, associated with opposite effects. Therefore, anti-inflammatory treatment with specific TNF receptor interference was compared to non-specific TNF inhibition regarding effects on heart, (neuro)inflammation, brain and behavior in mice with MI., Methods: Male C57BL/6 mice were subjected to MI or sham surgery. One hour later, MI mice were randomized to either non-specific TNF inhibition by Enbrel, specific TNFR1 antagonist-, or specific TNFR2 agonist treatment until the end of the protocol. Control sham and MI mice received saline. Behavioral evaluation was obtained day 10-14 after surgery. Eighteen days post-surgery, cardiac function was measured and mice were sacrificed. Blood and tissue samples were collected for analyses of (neuro)inflammation., Results: MI mice displayed left ventricular dysfunction, without heart failure, (neuro) inflammation or depressive-like behavior. Both receptor-specific interventions, but not Enbrel, doubled early post-MI mortality. TNFR2 agonist treatment improved left ventricular function and caused hyper-ramification of microglia, with no effect on depressive-like behavior. In contrast, TNFR1 antagonist treatment was associated with enhanced (neuro)inflammation: more plasma eosinophils and monocytes; increased plasma Lcn2 and hippocampal microglia and astrocyte activation. Moreover, increased baseline heart rate, with reduced beta-adrenergic responsiveness indicated sympathetic activation, and coincided with reduced exploratory behavior in the open field. Enbrel did not affect neuroinflammation nor behavior., Conclusion: Early receptor interventions, but not non-specific TNF inhibition, increased mortality. Apart from this undesired effect, the general beneficial profile after TNFR2 stimulation, rather than the unfavourable effects of TNFR1 inhibition, would render TNFR2 stimulation preferable over non-specific TNF inhibition in MI with comorbid depression. However, follow-up studies regarding optimal timing and dosing are needed., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Soluble oligomeric amyloid-β (Aβ), rather than Aβ plaques, seems to be the culprit in Alzheimer's disease (AD). Accordingly, a new concept vaccine of small cyclic peptide conjugates, selectively targeting oligomeric Aβ, has been developed., Objective: Study the therapeutic potential of this new vaccine in a mouse model for AD., Methods: J20 mice, overexpressing human amyloid precursor protein, were validated for an AD-like phenotype. Then, J20 mice were vaccinated at 2, 3, and 4 months of age and AD phenotype was evaluated at 6, 9, and 12 months of age; or at 9, 10, and 11 months with evaluation at 12 months. Effects on Aβ pathology were studied by plaque load (immunohistochemistry; 6E10) and antibody titers against Aβ (ELISA). AD behavioral phenotype was evaluated by performance in a battery of cognitive tests., Results: J20 mice displayed age-related Aβ plaque development and an AD-like behavioral phenotype. A consistent antibody response to the cyclic peptides was, however, not extended to Aβ, leaving plaque load unaffected. Nevertheless, immunization at young ages prevented working- and short-term spatial memory loss, but deteriorated long-term spatial learning and memory, at 12 months of age. Immunization at later ages did not affect any measured parameter., Conclusion: J20 mice provide a relevant model for AD to study potential anti-Aβ treatment. Early vaccination prevented short-term memory loss at later ages, but deteriorated long-term spatial memory, however without affecting Aβ pathology. Later vaccination had no effects, but optimal timing may require further investigation., Competing Interests: The authors have no conflict of interest to report., (© 2020 – IOS Press and the authors. All rights reserved.)

Objective: The aim of this study was to examine gender differences of the associations between depressive symptoms and anxiety with inflammatory markers in patients with non-obstructive coronary artery disease (NOCAD)., Methods: Depressive symptoms and anxiety (Beck Depression Inventory BDI and Hospital Anxiety and Depression Scale HADS) were examined in 524 patients with NOCAD (52% women, mean age 64 ± 9 years) as part of the TweeSteden Mild Stenosis (TWIST) observational cohort study. Blood samples were analyzed for neutrophil gelatinase-associated lipocalin (NGAL) levels, high-sensitive C-reactive protein (hsCRP), and leukocyte differentiation. Multivariate analysis for the inflammatory markers with main effects of depressive symptoms or anxiety, gender, and their interactions were observed., Results: Women had elevated levels of hsCRP, and a lower monocyte and eosinophil count than men, with small to medium effect sizes (range η (p) 2  = 0.019-0.047). After Holm-Bonferroni correction depressive symptoms according to the BDI were associated with an overall elevated hsCRP level explaining 2.4% of the hsCRP variance. A significant positive association between BDI cognitive symptoms with elevated hsCRP level was observed in men (R 2  = 0.045), but not in women (R 2  < 0.001). Adjustment for age, body mass index, smoking, and physical activity attenuated this finding., Conclusion: Small associations of inflammatory markers with depressive symptoms and anxiety were confounded by lifestyle factors, predominantly smoking. The interacting roles of gender, smoking, and psychological factors on inflammatory markers may point toward different behavioral and inflammatory pathways for women and men with NOCAD, which remains to be further explored., Observational Cohort Registration: ClinicalTrials.gov identifier: NCT01788241., (Copyright © 2019 Elsevier Inc. All rights reserved.)

In anaesthetic practice the risk of cerebral ischemic/hypoxic damage is thought to be attenuated by deep anaesthesia. The rationale is that deeper anaesthesia reduces cerebral oxygen demand more than light anaesthesia, thereby increasing the tolerance to ischemia or hypoxia. However, evidence to support this is scarce. We thus investigated the influence of light versus deep anaesthesia on the responses of rat brains to a period of hypoxia. In the first experiment we exposed adult male Wistar rats to deep or light propofol anaesthesia and then performed [18F]- Fludeoxyglucose (FDG) Positron Emission Tomography (PET) scans to verify the extent of cerebral metabolic suppression. In subsequent experiments, rats were subjected to light/deep propofol anaesthesia and then exposed to a period of hypoxia or ongoing normoxia (n = 9-11 per group). A further 5 rats, not exposed to anaesthesia or hypoxia, served as controls. Four days later a Novel Object Recognition (NOR) test was performed to assess mood and cognition. After another 4 days, the animals were sacrificed for later immunohistochemical analyses of neurogenesis/neuroplasticity (Doublecortin; DCX), Brain Derived Neurotrophic Factor (BDNF) expression and neuroinflammation (Ionized calcium-binding adaptor protein-1; Iba-1) in hippocampal and piriform cortex slices. The hippocampi of rats subjected to hypoxia during light anaesthesia showed lower DCX positivity, and therefore lower neurogenesis, but higher BDNF levels and microglia hyper-ramification. Exploration was reduced, but no significant effect on NOR was observed. In the piriform cortex, higher DCX positivity was observed, associated with neuroplasticity. All these effects were attenuated by deep anaesthesia. Deepening anaesthesia attenuated the brain changes associated with hypoxia. Hypoxia during light anaesthesia had a prolonged effect on the brain, but no impairment in cognitive function was observed. Although reduced hippocampal neurogenesis may be considered unfavourable, higher BDNF expression, associated with microglia hyper-ramification may suggest activation of repair mechanisms. Increased neuroplasticity observed in the piriform cortex supports this, and might reflect a prolonged state of alertness rather than damage.

Background: Whole body vibration (WBV) is a form of physical stimulation via mechanical vibrations transmitted to a subject. It is assumed that WBV induces sensory stimulation in cortical brain regions through the activation of skin and muscle receptors responding to the vibration. The effects of WBV on muscle strength are well described. However, little is known about the impact of WBV on the brain. Recently, it was shown in humans that WBV improves attention in an acute WBV protocol. Preclinical research is needed to unravel the underlying brain mechanism. As a first step, we examined whether chronic WBV improves attention in mice., Material and Methods: A custom made vibrating platform for mice with low intensity vibrations was used. Male CD1 mice (3 months of age) received five weeks WBV (30 Hz; 1.9 G), five days a week with sessions of five (n=12) or 30 (n=10) minutes. Control mice (pseudo-WBV; n=12 and 10 for the five and 30 minute sessions, respectively) were treated in a similar way, but did not receive the actual vibration. Object recognition tasks were used as an attention test (novel and spatial object recognition - the primary outcome measure). A Balance beam was used for motor performance, serving as a secondary outcome measure., Results: WBV sessions of five (but not WBV sessions of 30 minutes) improved balance beam performance (mice gained 28% in time needed to cross the beam) and novel object recognition (mice paid significantly more attention to the novel object) as compared to pseudo WBV, but no change was found for spatial object performance (mice did not notice the relocation). Although 30 minutes WBV sessions were not beneficial, it did not impair either attention or motor performance., Conclusion: These results show that brief sessions of WBV improve, next to motor performance, attention for object recognition, but not spatial cues of the objects. The selective improvement of attention in mice opens the avenue to unravel the underlying brain mechanisms.

Delirium is a frequent outcome for aged and demented patients that suffer a systemic inflammatory insult. Animal models that reconstruct these etiological processes have potential to provide a better understanding of the pathophysiology of delirium. Therefore, we systematically reviewed animal studies in which systemic inflammation was superimposed on aged or diseased animal models. In total, 77 studies were identified. Aged animals were challenged with a bacterial endotoxin in 29 studies, 25 studies superimposed surgery on aged animals, and in 6 studies a bacterial infection, Escherichia coli (E. coli), was used. Diseased animals were challenged with a bacterial endotoxin in 15 studies, two studies examined effects of the cytokine IL-1β, and one study used polyinosinic:polycytidilic acid (poly I:C). This systematic review analyzed the impact of systemic inflammation on the production of inflammatory and neurotoxic mediators in peripheral blood, cerebrospinal fluid (CSF), and on the central nervous system (CNS). Moreover, concomitant behavioral and cognitive symptoms were also evaluated. Finally, outcomes of behavioral and cognitive tests from animal studies were compared to features and symptoms present in delirious patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Neutrophil gelatinase-associated lipocalin (NGAL) has recently gained interest as a marker for neuroinflammation and associated behavioral dysfunction. We aimed to explore the link between NGAL and behavior in a rat model of postoperative cognitive dysfunction (POCD). Material collected in two previous studies on POCD was analyzed and associated with outcomes for exploratory behavior and spatial learning. Plasma and hippocampal NGAL and microglial activity were analyzed. Pearson's correlations and backward linear regression were performed to study the associations between behavioral parameters, NGAL concentrations, and microglial activity. Plasma and hippocampal NGAL were increased following surgery. Plasma NGAL was associated with impaired spatial learning only, microglial activity was associated with exploratory behavior only, while hippocampal NGAL was associated with both behavioral aspects. Spatial learning was best predicted by a model containing plasma NGAL concentrations and hippocampal microglial activity. NGAL may serve as a sensitive marker in connecting the peripheral inflammatory state to POCD, while postoperative changes in exploratory behavior are better reflected by hippocampal neuroinflammation. These findings warrant further exploration in the role of NGAL in development of postoperative behavioral deficits., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Background: In patients with heart failure (HF) depressive symptoms have been associated with mortality, as well as biological risk factors, including inflammation, nitric oxide (NO) regulation, and oxidative stress. We investigated the joint predictive value of depressive symptoms, inflammation and NO regulation on all-cause mortality in patients with HF, adjusted for covariates., Methods: Serum levels of inflammation (TNFα, sTNFr1, sTNFr2, IL-6, hsCRP, NGAL), NO regulation (l-arginine, ADMA, and SDMA), and oxidative stress (isoprostane 8-Epi Prostaglandin F2 Alpha) were measured in 104 patients with HF (mean age 65.7±SD 8.4years, 28% women). Depressive symptoms (Beck Depression Inventory, BDI) were measured as continuous total, cognitive, and somatic symptoms, as well as categorized presence of mild/moderate depression (cut-off BDI ⩾10). In Cox proportional hazard models we adjusted for age, sex, poor exercise tolerance and comorbidity., Results: After on average 6.1years follow-up (SD=2.9, range 0.4-9.2), 49 patients died. Total and somatic depressive symptoms, mild/moderate depression, higher NGAL, sTNFr2, IL-6, hsCRP and SDMA serum levels were significantly associated with a higher all-cause mortality rate, adjusted for covariates. The findings were most consistent for CRP level and somatic depressive symptoms. When combined, both depressive symptoms and markers of inflammation and NO regulation remained significantly associated with all-cause mortality. These associations were not confounded by age, sex, poor exercise tolerance and comorbidity., Conclusion: Depressive symptoms and markers of inflammation and NO regulation are codominant risk factors for all-cause mortality in heart failure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Heart failure is associated with an increased risk of developing depression and cognitive dysfunction, which negatively affects prognosis. Plasma levels of neutrophil gelatinase associated lipocalin (NGAL) are increased in heart failure and depression. Moreover, NGAL levels are associated with depression in heart failure patients. Since women are at a higher risk of developing comorbid depression with heart failure, the aim of this study was to examine sex differences in the link between NGAL and behavior in a rat model of heart failure. In young adult male and female Wistar rats, myocardial infarction (MI) was induced by means of coronary artery ligation, while control rats received sham surgery. We analyzed aspects of cognition and depression/anxiety using various behavioral tests starting three weeks after surgery. Hemodynamic measurements were performed and hearts and lungs were weighed. NGAL levels in plasma, cerebrospinal fluid (CSF) and brain tissue were analyzed. MI induced impairment in cardiac contractility and relaxation, and an increase in lung weight. NGAL correlated with signs of heart failure in male, but not female rats. Male MI rats displayed cognitive problems, but not depressive-like or anxiety-like behavior. No behavioral effects of MI were observed in female rats. Plasma NGAL levels were higher in male than female rats with higher concentrations in MI compared to sham. CSF NGAL was higher in MI rats compared to sham and higher in males compared to females. The number of NGAL positive cells in the paraventricular nucleus of the hypothalamus (PVN) was only increased in male MI rats. In male, but not in female rats, NGAL levels correlated with depressive-like behavior and cognitive dysfunction. Data indicate that while MI increased NGAL levels in plasma, CSF and PVN, correlations of NGAL with behavior are sex-specific, but independent of whether sham or MI surgery was performed. This suggests that inflammatory processes related to thorax surgery and their potential effects on depressive-like behavior and cognition may be sex-specific., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Postoperative cognitive dysfunction (POCD) is a debilitating surgical complication, with cardiac surgery patients at particular risk. To gain insight in the mechanisms underlying the higher incidence of POCD after cardiac versus non-cardiac surgery, systemic and central inflammatory changes, alterations in intraneuronal pathways, and cognitive performance were studied after cardiac and abdominal surgery in rats. Male Wistar rats were subjected to ischemia reperfusion of the upper mesenteric artery (abdominal surgery) or the left coronary artery (cardiac surgery). Control rats remained naïve, received anesthesia only, or received thoracic sham surgery. Rats were subjected to affective and cognitive behavioral tests in postoperative week 2. Plasma concentrations of inflammatory factors, and markers for neuroinflammation (NGAL and microglial activity) and the BDNF pathway (BDNF, p38MAPK and DCX) were determined. Spatial memory was impaired after both abdominal and cardiac surgery, but only cardiac surgery impaired spatial learning and object recognition. While all surgical procedures elicited a pronounced acute systemic inflammatory response, NGAL and TNFα levels were particularly increased after abdominal surgery. Conversely, NGAL in plasma and the paraventricular nucleus of the hypothalamus and microglial activity in hippocampus and prefrontal cortex on postoperative day 14 were increased after cardiac, but not abdominal surgery. Both surgery types induced hippocampal alterations in BDNF signaling. These results suggest that POCD after cardiac surgery, compared to non-cardiac surgery, affects different cognitive domains and hence may be more extended rather than more severe. Moreover, while abdominal surgery effects seem limited to hippocampal brain regions, cardiac surgery seems associated with more wide spread alterations in the brain., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objectives: Neutrophil gelatinase-associated lipocalin (NGAL) is an inflammatory marker associated with the pathophysiology of heart failure (HF), the psychopathology of depression and the co-existing symptoms of depression in HF patients. The aim of this study is to determine whether the association of serum NGAL levels with depressive symptoms dimensions in HF is independent of well-known inflammatory markers., Methods: Serum NGAL, high sensitive C-reactive protein (hsCRP), tumour necrosis factor-α (TNF-α), its two soluble receptors; sTNFR1, sTNFR2, Interleukin-6 (IL-6) and leukocytes were measured in 104 patients with HF at baseline and 12 months. Depressive symptoms were evaluated using the Beck Depression Inventory (BDI) at both timepoints. Correlations between NGAL and inflammatory markers and depressive symptoms dimensions were determined. The effect of hsCRP, IL-6, TNF-α, sTNFR1, sTNFR2 and leukocytes on the association of NGAL with depressive symptoms was determined and adjusted for time, demographics, cardiac disease severity, and kidney function., Results: NGAL levels were significantly correlated with hsCRP, TNF-α, sTNFR1, sTNFR2 and leukocytes. NGAL was significantly associated with somatic depressive symptoms, independent of abovementioned markers., Conclusions: Serum NGAL is an independent inflammatory marker for somatic depressive symptoms in HF and may function as an immunopathogen linking somatic symptoms of depression to HF.

Older patients may experience persisting postoperative cognitive dysfunction (POCD), which is considered to largely depend on surgery-induced (neuro)inflammation. We hypothesize that inflammatory events before surgery could predispose patients to POCD. When part of our aged rats developed Mycoplasma pulmonis, this presented the unique opportunity to investigate whether a pulmonary infection before surgery influences surgery-induced neuroinflammation and POCD. Male 18-mo-old Wistar rats that had recovered from an active mycoplasma infection (infection) and control rats (healthy) were subjected to abdominal surgery and jugular vein catheterization under general anesthesia (surgery) or remained naïve (control). In postoperative week 2, behavioral tests were performed to assess cognitive performance and exploratory behavior. The acute systemic inflammatory response was investigated by measuring plasma IL-6 and IL-12. In the hippocampus, prefrontal cortex and striatum, microglial activity, neurogenesis, and concentrations of IL-6, IL-12, IL1B, and brain-derived neurotropic factor on postoperative day 14 were determined. Rats still showed signs of increased neuroinflammatory activity, as well as cognitive and behavioral changes, 3 wk after the symptoms of infection had subsided. Rats that had experienced infection before surgery exhibited a more generalized and exacerbated postoperative cognitive impairment compared with healthy surgery rats, as well as a prolonged increase in systemic cytokine levels and increased microglial activation in the hippocampus and prefrontal cortex. These findings support the hypothesis that an infection before surgery under general anesthesia exacerbates POCD. Future studies are necessary to determine whether the found effects are aging specific and to investigate the magnitude and time course of this effect in a controlled manner., (Copyright © 2015 the American Physiological Society.)

Depression is more common in patients with cardiovascular disease than in the general population. Conversely, depression is a risk factor for developing cardiovascular disease. Comorbidity of these two pathologies worsens prognosis. Several mechanisms have been indicated in the link between cardiovascular disease and depression, including inflammation. Systemic inflammation can have long-lasting effects on the central nervous system, which could be associated with depression. NGAL is an inflammatory marker and elevated plasma levels are associated with both cardiovascular disease and depression. While patients with depression show elevated NGAL levels, in patients with comorbid heart failure, NGAL levels are significantly higher and associated with depression scores. Systemic inflammation evokes NGAL expression in the brain. This is considered a proinflammatory effect as it is involved in microglia activation and reactive astrocytosis. Animal studies support a direct link between NGAL and depression/anxiety associated behavior. In this review we focus on the role of NGAL in linking depression and cardiovascular disease., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Objective: Nitric oxide (NO) regulation plays a critical role in cardiovascular diseases including heart failure (HF). Markers of NO dysregulation have been found in individuals with depression without cardiovascular disease. Because depression is associated with poor HF outcomes, the present study tested the hypothesis that depression is associated with a dysregulated NO pathway in patients with HF., Methods: Serum levels of NO regulation (L-arginine, asymmetric dimethylarginine [ADMA], and symmetric dimethylarginine [SDMA]) and oxidative stress (isoprostane 8-epi prostaglandin F2α) were measured in 104 patients with HF (mean [standard deviation] age = 65.7 [8.4] years, 28% women) at baseline and 12 months. Depressive symptoms were measured using the Beck Depression Inventory. The associations between depressive symptoms with markers of NO regulation were examined with mixed-model analysis, adjusted for age, sex, time of assessment, left ventricular ejection fraction, creatinine, and hypertension., Results: Depressive symptoms were correlated with a lower L-arginine/ADMA ratio (r = -0.22, p = .003) and higher SDMA levels (r = 0.28, p < .001). Associations were similar for somatic depressive symptoms and cognitive-affective symptoms (L-arginine/ADMA ratio: r = -0.20 [p = .009] versus r = -0.19 [p = .013]; ADMA: r = 0.16 [p = .043] versus r = 0.10 [p = .20]; SDMA: r = 0.27 [p < .001] versus r = 0.22 [p = .005], respectively). No associations were found between depressive symptoms and isoprostane. The association between depression and the L-arginine/ADMA ratio remained significant in multivariate adjusted models., Conclusions: Depressive symptoms were associated with markers of NO dysregulation, particularly the L-arginine/ADMA ratio and SDMA, in patients with HF. The lower L-arginine/ADMA ratio indicates less available NO, suggesting that NO-related endothelial dysfunction may play a role in the adverse risk of HF progression associated with depression.

Research indicates that neuroinflammation plays a major role in postoperative cognitive dysfunction (POCD) in older patients. However, studies have mainly focused on hippocampal neuroinflammation and hippocampal-dependent learning and memory, which does not cover the whole spectrum of POCD. We hypothesized that regional differences in postoperative neuroinflammation in the brain may underlie variation in postoperative cognitive impairment. We aimed to investigate this hypothesis in a rat-model for POCD, by analyzing postoperative impairment in behavioral task performance and microglial activation in related brain areas. We subjected 25 months old Wistar rats to surgery and assessed spatial learning and memory, object and location recognition, reversal learning and exploratory behavior in the second postoperative week. The number and morphology of microglia were analyzed in the hippocampus, prefrontal cortex, striatum and amygdala on postoperative day 14. Control groups consisted of 3 and 25 months old rats that did not undergo surgery. We observed age related impairment in learning, memory and behavior, which was aggravated following surgery. Additionally, in old rats surgery was associated with signs of classical microglial activation in brain areas related to the impaired cognitive functions. These outcomes suggest that indeed neuroinflammation may be involved in POCD. Moreover, effects of age and surgery on cognition and microglial morphology seem to be area specific and hence cannot be generalized to the whole brain. This underpins the importance for expanding the research of POCD beyond the hippocampus., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Postoperative cognitive dysfunction (POCD) has been hypothesized to be mediated by surgery-induced inflammatory processes, which may influence neuronal functioning either directly or through modulation of intraneuronal pathways, such as the brain derived neurotrophic factor (BDNF) mediated pathway. To study the time course of post-surgical (neuro)inflammation, changes in the BDNF-pathway and POCD, we subjected 3months old male Wistar rats to abdominal surgery and implanted a jugular vein catheter for timed blood sampling. Cognition, affective behavior and markers for (neuro)inflammation, BDNF and neurogenesis were assessed at 1, 2 and 3weeks following surgery. Rats displayed changes in exploratory activity shortly after surgery, associated with postoperatively elevated IL-6 plasma levels. Spatial learning and memory were temporarily impaired in the first 2weeks following surgery, whereas non-spatial cognitive functions seemed unaffected. Analysis of brain tissue revealed increased neuroinflammation (IL-1B and microgliosis) 7days following surgery, decreased BDNF levels on postoperative day 14 and 21, and decreased neurogenesis until at least 21days following surgery. These findings indicate that in young adult rats only spatial learning and memory is affected by surgery, suggesting hippocampal dependent cognition is especially vulnerable to surgery-induced impairment. The observed differences in time course following surgery and relation to plasma IL-6 suggest cognitive dysfunction and mood changes comprise distinct features of postoperative behavioral impairment. The postoperative changes in neuroinflammation, BDNF and neurogenesis may represent aspects of the underlying mechanism for POCD. Future research should be aimed to elucidate how these players interact., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Depression adversely affects prognosis in heart failure (HF) patients. Inflammation is indicated as potential biological pathway in this co-morbidity. Since increased levels of the cytokine Neutrophil Gelatinase-Associated Lipocalin (NGAL) are predictive for HF prognosis, and recently indicated in patients with major depression, this study examined the association of serum NGAL levels with symptoms of depression in patients with HF. Serum NGAL levels were measured in 104 patients with HF (left ventricular ejection fraction, LVEF⩽40). Depression, evaluated using the Beck Depression Inventory (BDI; total score, somatic and cognitive component), and the Hamilton Depression Rating scale (HAMD), at baseline and 12months follow-up, was associated with NGAL levels using mixed model analysis. Analyses were adjusted for demographics measures, disease severity indicators, inflammation, comorbidity and medication. Increased serum NGAL levels were significantly associated with depression measured by HAMD (baseline: r=0.25, p<.05) and BDI (baseline: r=0.22, p<.05; 12months: r=0.37, p<.01). This association remained significant after adjustment for covariates; age, sex, time, LVEF, and creatinine (HAMD, t=2.01, p=.047; BDI, t=2.28, p=.024). NGAL was significantly associated with somatic- (p=0.004), but not cognitive depressive symptoms (p=0.32). NGAL levels were associated with the experienced HF-related functional limitations (6min walk test), rather than the severity of cardiac dysfunction (LVEF). This study indicates that depression in patients with chronic HF is associated with elevated NGAL levels, independent of clinical severity of the underlying disease., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Elderly patients may experience impairments in cognition or mood following surgery. To study the development and underlying mechanisms of these postoperative behavioral changes, young (3 months) and aged (18-20 months) male rats were subjected to abdominal surgery followed by behavioral testing during a period of 6 weeks. Microglia activation (IBA-1) and neurogenesis (DCX) were immunohistochemically determined. In separate experiments, the effects of anesthesia and the cytokine response (IL-6) following surgery were evaluated. Increased age was associated with changes in affective behavior, decreased cognitive flexibility and increased microglia activation as well as increased weight loss and plasma IL-6 following surgery. No effects of surgery on cognition were observed at either age. However, aged rats displayed long-term changes in affective behavior and had increased microgliosis in the CA1 hippocampal region following surgery. Microglia activation following surgery was positively correlated to parameters of behavior and spatial learning. These findings support the hypothesis that elderly patients have an increased behavioral and (neuro)inflammatory response to surgery and these factors may be related., (© 2013.)

Objectives: Chronic renal dysfunction severely increases cardiovascular risk. Adverse cardiac remodeling is suggested to play a major role as predisposition for increased cardiac ischemic vulnerability. The aim of the present study was to examine the role of adverse cardiac remodeling in cardiac sensitivity to acute ischemia/reperfusion damage in a rat model for renal dysfunction., Methods: Munich Wistar Fromter (MWF) rats, developing spontaneous progressive renal dysfunction and mild hypertension, were compared to healthy Wistar rats, and to nonproteinuric spontaneously hypertensive rats (SHRs). In MWF rats, renal dysfunction and mild hypertension were confirmed. Hearts were analyzed for adverse cardiac remodeling, including myocyte hypertrophy, capillary density, and interstitial fibrosis, by histology. In parallel, sensitivity to cardiac ischemia/reperfusion damage was obtained from infarct size measured after 30-min coronary artery occlusion, followed by 24  h of reperfusion., Results: Infarcts were larger in MWF rats [56 ± 3% of risk area (P = 0.04)], but at a similar extent in SHRs [52 ± 4% (P = 0.16)], when compared to Wistar rats (45 ± 4%). However, whereas SHRs showed pronounced adverse cardiac remodeling, MWF rats did not: no left ventricular hypertrophy (myocyte size MWF rats +29%; SHRs +72%), no lower capillary density (MWF rats +34%; SHRs -13%), and no interstitial fibrosis (MWF rats -16%; SHRs +70%)., Conclusion: Data indicate that chronic renal dysfunction in MWF rats is associated with elevated cardiac sensitivity to acute ischemia/reperfusion damage, as reflected by larger infarcts. Comparing results to SHRs suggests that this higher susceptibility could not be attributed to hypertension or adverse cardiac remodeling.

Patients experiencing an acute myocardial infarction (AMI) have a three times higher chance to develop depression. Vice versa, depressive symptoms increase the risk of cardiovascular events. The co-existence of both conditions is associated with substantially worse prognosis. Although the underlying mechanism of the interaction is largely unknown, inflammation is thought to be of pivotal importance. AMI-induced peripheral cytokines release may cause cerebral endothelial leakage and hence induces a neuroinflammatory reaction. The neuroinflammation may persist even long after the initial peripheral inflammation has subsided. Among those selected brain regions that are prone to blood-brain barrier dysfunction, the paraventricular nucleus of the hypothalamus (PVN), a major center for cardiovascular autonomic regulation, is indicated to play a mediating role. Optimal cardiovascular therapy improves cardiovascular prognosis without major effects on depression. By the same token, antidepressant therapy in cardiovascular disease is associated with modest improvement in depressive symptoms, however without improvement in cardiac outcome. The failure of current antidepressants and the growing number of patients suffering from both conditions legitimize the search for better antidepressive therapies, from patients as well as society perspectives. Though we appreciate the mutual character of the interaction between depression and AMI, the present review focuses on the side of AMI induced depression and discusses the role of inflammation, represented by the proinflammatory cytokine TNF-α, as potential underlying mechanism. It is conceivable that inhibition of the inflammatory response post-AMI, through targeted anti-inflammatory pharmacotherapeutical agents may prevent the development of depressive symptoms and ultimately may improve cardiovascular outcomes., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Following surgery, patients may experience cognitive decline, which can seriously reduce quality of life. This postoperative cognitive dysfunction (POCD) is mainly seen in the elderly and is thought to be mediated by surgery-induced inflammatory reactions. Clinical studies tend to define POCD as a persisting, generalised decline in cognition, without specifying which cognitive functions are impaired. Pre-clinical research mainly describes early hippocampal dysfunction as a consequence of surgery-induced neuroinflammation. These different approaches to study POCD impede translation between clinical and pre-clinical research outcomes and may hamper the development of appropriate interventions. This article analyses which cognitive domains deteriorate after surgery and which brain areas might be involved. The most important outcomes are: (1) POCD encompasses a wide range of cognitive impairments; (2) POCD affects larger areas of the brain; and (3) individual variation in the vulnerability of neuronal networks to neuroinflammatory mechanisms may determine if and how POCD manifests itself. We argue that, for pre-clinical and clinical research of POCD to advance, the effects of surgery on various cognitive functions and brain areas should be studied. Moreover, in addition to general characteristics, research should take inter-relationships between cognitive complaints and physical and mental characteristics into account., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Primary chronic kidney disease is associated with high cardiovascular risk. However, the exact mechanisms behind this cardiorenal interaction remain unclear. We investigated the interaction between heart and kidneys in novel animal model for cardiorenal interaction. Normal Wistar rats and Munich Wistar Fromter rats, spontaneously developing renal dysfunction, were subjected to experimental myocardial infarction to induce cardiac dysfunction (CD) and combined cardiorenal dysfunction (CRD), respectively (N = 5-10). Twelve weeks later, cardiac- and renal parameters were evaluated. Cardiac, but not renal dysfunction was exaggerated in CRD. Accelerated cardiac dysfunction in CRD was indicated by decreased cardiac output (CD 109 ± 10 vs. CRD 79 ± 8 ml/min), diastolic dysfunction (E/e') (CD 26 ± 2 vs. CRD 50 ± 5) and left ventricular overload (LVEDP CD 10.8 ± 2.8 vs. CRD 21.6 ± 1.7 mmHg). Congestion in CRD was confirmed by increased lung and atrial weights, as well as exaggerated right ventricular hypertrophy. Absence of accelerated renal dysfunction, measured by increased proteinuria, was supported by absence of additional focal glomerulosclerosis or further decline of renal blood flow in CRD. Only advanced peripheral endothelial dysfunction, as found in CRD, appeared to correlate with both renal and cardiac dysfunction parameters. Thus, proteinuric rats with myocardial infarction showed accelerated cardiac but not renal dysfunction. As parameters mimic the cardiorenal syndrome, these rats may provide a clinically relevant model to study increased cardiovascular risk due to renal dysfunction. Peripheral endothelial dysfunction was the only parameter that correlated with both renal and cardiac dysfunction, which may indicate a mediating role in cardiorenal interaction.

Airway remodelling and emphysema are major structural abnormalities in chronic obstructive pulmonary disease (COPD). In addition, pulmonary vascular remodelling may occur and contribute to pulmonary hypertension, a comorbidity of COPD. Increased cholinergic activity in COPD contributes to airflow limitation and, possibly, to inflammation and airway remodelling. This study aimed to investigate the role of acetylcholine in pulmonary inflammation and remodelling using an animal model of COPD. To this aim, guinea pigs were instilled intranasally with lipopolysaccharide (LPS) twice weekly for 12 weeks and were treated, by inhalation, with the long-acting muscarinic receptor antagonist tiotropium. Repeated LPS exposure induced airway and parenchymal neutrophilia, and increased goblet cell numbers, lung hydroxyproline content, airway wall collagen and airspace size. Furthermore, LPS increased the number of muscularised microvessels in the adventitia of cartilaginous airways. Tiotropium abrogated the LPS-induced increase in neutrophils, goblet cells, collagen deposition and muscularised microvessels, but had no effect on emphysema. In conclusion, tiotropium inhibits remodelling of the airways as well as pulmonary inflammation in a guinea pig model of COPD, suggesting that endogenous acetylcholine plays a major role in the pathogenesis of this disease.