University of Groningen
Neuroinflammation as common denominator in heart failure associated mental dysfunction
Gouweleeuw, Leonie
DOI:
10.33612/diss.122192415
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Publication date:
2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Gouweleeuw, L. (2020). Neuroinflammation as common denominator in heart failure associated mental
dysfunction: Studies in animal models. University of Groningen. https://doi.org/10.33612/diss.122192415
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138 Summary
Summary
We’ve known for some time that there is a link between cardiovascular disease and mental dysfunction. Patients with cardiovascular disease have a higher probability of developing mental dysfunction like depression, anxiety and memory dysfunction. On the other hand, patients with mental dysfunction have a higher probability of developing cardiovascular disease like heart attack (myocardial infarction, MI) or high blood pressure. In this thesis we have focused on the development of mental dysfunction after MI.
Even though it is often thought that the development of mental problems after MI is an innocent side effect, patients with both conditions have a worse prognosis than cardiovascular patients without mental problems. The treatment is also problematic, since for instance the use of antidepressants does not lead to a better prognosis.
To come to a better treatment of mental problems in patients with cardiovascular disease, it is important to better understand the causes of this association. Some causes have been described in literature, including psychological factors, lack of oxygen in the brain (hypoxia), changes in the sympatic nervous system and inflammation. Especially the latter one is interesting to us. A certain degree of inflammation is necessary for wound healing and scar formation. However, the inflammatory reaction does not stay limited to the heart, inflammatory markers can remain elevated in the blood for weeks. This can lead to leakage of the blood brain barrier, with consequences for the functioning of the brain. In this thesis we used animal models to study inflammation and behavioural changes after myocardial infarction. We’ve paid special attention to microglia (immune cells in the brain), and the inflammatory markers tumour necrosis factor alpha (TNF-α) and neutrophil gelatinase associated lipocalin (NGAL). We specifically focussed on these factors because of previously found results regarding cardiovascular disease, neuroinflammation and mental dysfunction. We know that microglia are locally activated in the brain after MI and that activation of microglia is associated with conditions such as dementia and depression. It is well known for TNF-α that this marker is involved in inflammatory reactions after MI, and that locally in the brain of animal models of heart failure the concentration of TNF-α is increased. In depressed patients TNF-α levels in the blood are increased compared to subjects without depression. NGAL is an important prognostic marker in patients with heart failure. Previous studies from our group have also proven that NGAL can be linked to signs of depression in patients with heart failure. To find out whether the results found were specific for MI, we’ve compared the results with those after abdominal surgery. With abdominal surgery, an inflammatory
reaction also takes place, and this can also give rise to mental dysfunction. We were curious to know whether there is a difference in behavioural outcome and inflammatory factors between abdominal surgery and MI models.
MI and microglia
Microglia are immune cells in the brain. They can be activated by various circumstances, including infection or trauma. Activated microglia can secrete inflammatory factors, which can affect brain functioning. We have studied the effects of MI on microglia in chapters 3, 4 and 6. In chapter 3 microglia were studied in different brain regions 14 days after MI in a mouse model. Compared to the control group (without MI) there was an increased number of microglia and increased microglia activity in the hippocampus, a brain region important for memory and mood.
In chapter 4 we studied microglia in rats at 6 weeks after MI. Here we initially did not find any differences in microglia between the different groups. At closer examination we did find that there was an association between behaviour and microglia. In male rats a higher degree of microglia activity in the amygdala (important for fear and emotion) was associated with lower exploratory behaviour and lower motivation to explore a new environment. Higher microglia activity in the paraventricular nucleus of the hypothalamus (PVN, important in control of cardiac function and hormone balance) was also associated with lower motivation. In female rats we found an association between anxious behaviour and microglia activity in the hippocampus. Female rats with higher microglia activity in the hippocampus showed more anxious behaviour.
In chapter 6 we studied microglia activity in a model for abdominal surgery. Here it showed that microglia activity in the hippocampus was elevated after surgery. Higher microglia activity was also associated with lower degree of exploratory behaviour, but not with lower spatial memory.
Since changes in microglia activity usually are linked to inflammation, we have also measured the inflammatory factors TNF-α and NGAL, results of which are discussed in the paragraphs below.
140 Summary
MI and TNF-α
TNF-α is an inflammatory factor which owes its name due to the role it has in tumour cells. Besides that, TNF-α is an inflammatory factor that influences a number of processes in which inflammation plays a role. TNF-α is one of the inflammatory markers that is elevated shortly after MI and stays elevated for weeks hereafter. In chapter 3 we measured TNF-α in the blood and brain of mice 14 days after MI. TNF-α in the blood was not elevated 2 weeks after MI. In the brain we did find differences when we compared the MI group to the control group. TNF-α was elevated in the brain of mice with MI. Unfortunately, the group size was too small to say for sure that there were also differences in the expression of the different TNF-α receptors.
Furthermore, in chapter 4 we found TNF-α was elevated in the blood, but not the cerebrospinal fluid (CSF) of rats at 6 weeks after MI.
MI and NGAL
NGAL is an inflammatory marker that is mostly known for its role as a biomarker in kidney failure, patients show higher levels of this marker in their blood and urine. We know, however, that NGAL is involved in many processes in which inflammation plays a role. NGAL is one of the most important prognostic markers in heart failure, which means that higher NGAL levels in the blood are associated with higher risk of complications or death. We were especially interested in the role of NGAL in our animal models because we know NGAL is elevated in brain cells after stimulation with TNF-α and because in heart failure patients NGAL is associated with signs of depression.
We have studied NGAL in the context of heart failure in chapter 5 and in the context of abdominal surgery in chapter 6. In chapter 5 we found that NGAL is elevated after MI in the blood and CSF and locally in the brain (in part of the PVN). Furthermore, it appeared that in male rats the degree of heart failure (increase in heart and lung weight, infarct size) was associated with NGAL levels in the blood. In male rats we also found a link between increased NGAL in the blood and decreased exploration, motivation and spatial memory. Decreased exploration was also linked to increased NGAL levels in the hippocampus and PVN. In female rats we found no link between NGAL in the blood and disease markers or behaviour. In the brain increased NGAL in the hippocampus was associated with lower exploration.
In chapter 6 we studied NGAL in the context of abdominal surgery, to determine whether results found in chapter 5 are specific for cardiovascular disease. Here we found that
NGAL in both blood and hippocampus were elevated after surgery. We also found a link between increased NGAL in the blood and decreased spatial memory. Increased NGAL in the hippocampus was associated with both decreased spatial memory and decreased exploration. From this we can conclude, for now, that NGAL can be a link between physical damage and certain behavioural changes, but that this is not limited to one specific condition.
Concluding remarks
In this thesis we studied behavioural changes and markers of inflammation in animal models of MI. We have found that MI in animal models can lead to changes in microglia activity and changes in inflammatory markers TNF-α and NGAL. Furthermore, in male rats spatial memory is impaired after MI. Additionally, we found associations between changes in microglia and NGAL and the degree of behavioural changes. Our study in a model for abdominal surgery showed that the effects of NGAL and microglia may not be specific for MI, but can be seen as general markers of (neuro)inflammation in physical damage that needs wound healing. Placing these results in a clinical context is difficult. We know that in cardiovascular patients there is an increased risk of mental dysfunction including depression and memory impairment and that these are to some extend related to changes in inflammatory markers. In our animal models we studied behaviour and inflammatory markers after MI and made some interesting findings. Still it is difficult to translate these findings directly to the clinic. A healthy, young mouse or rat in which experimental MI is induced by ligation of a coronary artery, has a different history that a patient that develops an MI after years of high cholesterol, high blood pressure and atherosclerosis. The consequences of MI however, look similar to those in patients, and thus justify the use of these animals as models for patients. It is also difficult to interpret behavioural changes in animals as feelings of depression. Especially when we talk about behaviour that can be influenced by physical condition.
To eventually come to a better understanding of the relationship between cardiovascular disease and mental dysfunction, it is important to continue the execution of medical research. An important factor in this research should be to improve the animal models so they can be a better model for patients.
