University of Groningen
Pre-clinical investigation of brain mechanisms associated with Parkinson’s disease: The impact of diet
Reali Nazario, Luiza
DOI:
10.33612/diss.130756082
IMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite from it. Please check the document version below.
Document Version
Publisher's PDF, also known as Version of record
Publication date: 2020
Link to publication in University of Groningen/UMCG research database
Citation for published version (APA):
Reali Nazario, L. (2020). Pre-clinical investigation of brain mechanisms associated with Parkinson’s disease: The impact of diet. University of Groningen. https://doi.org/10.33612/diss.130756082
Copyright
Other than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of the author(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).
Take-down policy
If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons the number of authors shown on this cover page is limited to 10 maximum.
English Summary
| Chapter 9
178
Parkinson’s disease (PD) is the second most prevalent neurodegenerative disease and, with the increasing life expectancy of the population, the number of patients with this pathology is growing. Attempts are being made to find a cure or at least a better treatment, but so far, no intervention that can slow down the progression of the disease has been discovered. A better understanding of the basic mechanisms that underlie this disease is of great importance for the development of new drugs. One of the factors that can affect disease progression or onset is lifestyle. Lifestyle can influence different factors that are involved in PD, such as the purinergic system, the dopaminergic system, neuroinflammation and microbiota. In this thesis, these factors will be explored in different ways.
Chapter 2 provides an overview of the interaction of the purinergic and
dopaminergic system in the context of PD. It also addresses the effect of adenosine receptor antagonists in combination with dopaminergic drugs like L-DOPA, the drug most frequently used to suppress the symptoms of this disease. Also, non-dopaminergic therapies to decrease the main adverse effects of long-term use of L-DOPA, the motor side effects, are discussed. Treatment with multiple targeted drugs, such as adenosine receptor antagonists and drugs targeting other neurotransmitter systems than the dopaminergic system, has received significant attention lately, since PD is associated with complex biological interactions. While pharmacological approaches to cure or ameliorate the symptoms of PD are still the leading strategy in this area, positive effects of emerging non-pharmacological approaches have been observed as well and inhibition of the function of adenosine appears to be involved in both strategies.
In Chapter 3, we investigated the interaction of purinergic and dopaminergic receptors in an animal model of PD. For this purpose, we investigated behavioural parameters, dopamine levels and expression levels of adenosine and dopamine receptors in the brain of adult zebrafish injected with 6-OHDA in the right telencephalon (8 µg/µL). The animals were evaluated 3, 7 and 28 days after injection of 6-OHDA. The locomotor parameter ‘turn angle’ and the anxiety parameter ‘time spent in the superior zone’ were decreased on day 28 and 7, respectively. Dopamine levels in the whole brain were not altered, but D2 receptor expression was higher on
day 3, while expression levels of A2A1 receptors were increased on day 7, but had
normalized again on day 28. Thus, after intra-encephalic injection of 6-OHDA, zebrafish presented behavioral changes, in particular in the turn angle and the time spent in the superior zone, despite the slight effect on the dopaminergic system. Further studies involving pharmacological and genetic manipulation are necessary to investigate the interaction of purinergic and dopaminergic neurotransmission in this PD model.
Considering the importance of zebrafish for studying different disease process, in Chapter 4 we performed a translational project to investigate the feasibility of in vivo PET imaging in living healthy adult zebrafish and in a zebrafish model of inflammation. To optimize imaging conditions, the optimal dose of the anesthetic tricaine was determined and the distribution of the PET tracers 18F-FDG and 18F-NaF in control
zebrafish was measured at various time points. We have shown that PET imaging in living zebrafish is feasible and that a concentration 0.1 g/L of tricaine for anesthesia and a distribution time of 30 min for 18F-FDG and 150 min for 18F-NaF provided optimal
conditions. After the standardization, whole-body PET imaging with 18F-FDG was able
to reveal LPS-induced inflammation, as a significant difference in tracer uptake in the head region between control and LPS-injected animals was observed. In summary, this study demonstrated that in vivo PET imaging with 18F-FDG and 18F-NaF in living
zebrafish is feasible and differences in uptake can be seen in an inflammation model. The incidence of PD has been associated with lifestyle factors like diet. In the last part of this thesis, we therefore investigated the effect of diet in a rodent model for PD. In Chapter 5, however, we first analyzed the impact of a cafeteria diet (high caloric diet) on the reward system. Dopamine and its D2 receptors are involved in the reward
system. Consumption of a diet high in fat and sugar might lead to a change in D2
receptors expression and dopamine turnover. The compulsive eating behavior that is seen in obese patients might be related to a decreased activation of the reward system or a low number of D2 receptors. The main objective of the study described in chapter
5 was to investigate the effect of highly palatable food on the availability of dopamine D2 receptors in rats. Male Wistar rats were divided in two groups: control diet (chow
| Chapter 9
180
of dopamine D2 receptor availability: baseline (before the start of diet); after four weeks
on the diet (day 28), and immediately after consuming highly palatable sweetened condensed milk (day 30). From day four onward, the body weight gain and caloric intake was significantly higher in the cafeteria diet group than in the control diet group. The animals in the standard diet group did not show any significant difference in 11
C-raclopride uptake in striatum between the baseline PET scan and the either of the follow-up scans. The cafeteria diet decreased the tracer binding on both follow-up time points, which is indicative of a reduction in the availability of the D2 receptors. Our
study suggests that D2 receptors play a role in obesity and consumption of a high
caloric diet. It also showed that the challenge with condensed milk was not able to change the dopaminergic response as observed by PET. More studies should be done to confirm if there are any changes in the levels of dopamine and related molecules.
To elucidate the influence of a high fat diet on PD progression, we investigated the effect of a high-fat diet (HFD) on the availability of D2 receptors and behavioral
parameters in rats (Chapter 6). Wistar rats were fed with either an HFD (60% fat) or a standard diet (STD; 10% fat) for three months. After two months of diet the animals were submitted to stereotactic administration of a low dose of 6-OHDA (2x 3µg) in the
right striatum. 11C-Raclopride PET scans were performed two days before and one
month after the surgery. After three months, animals on the HFD had a higher bodyweight gain and caloric intake than those on the STD. The surgery caused a temporary decrease in bodyweight in both groups. No difference in the glucose tolerance test between the STD and HFD groups were found. 11C-Raclopride PET
showed a significantly decreased ipsilateral/contralateral tracer uptake ratio in the striatum in the HFD group one month after 6-OHDA injection, when compared to the STD and HFD groups before stereotactic surgery, however no significant difference was found between groups one month after 6-OHDA administration. This pattern was also found in the cylinder test, but no differences between groups and time points were found in other behavior analyses. Postmortem analysis of 11C-raclopride uptake in the
gut showed significantly lower tracer uptake in duodenum of animals in the HFD group than in the SD group. Concluding, the HFD aggravated the damage in the PD model in this study, as was demonstrated by a lower D2 receptor availability and a reduced
use of the contralateral paw. Both observations suggest a detrimental role of the HFD on the onset or progression of Parkinson’s disease.
In Chapter 7, the impact of a high fat diet on inflammatory parameters in the PD model was investigated. In particular, the composition of the microbiota, development of neuroinflammation and clinical symptoms were evaluated in a validated rodent model (6-OHDA unilateral injection). The rats were fed with either a high-fat diet (HFD) or a standard diet (SD) for three months. After two months of diet, the rats were submitted to stereotactic surgery injecting a low dose of 6-OHDA. 11
C-PBR28 PET scans were performed before and one month after the 6-OHDA injection. Stool was collected before the start of the diet (baseline), after two months of the diet and one month after the 6-OHDA injection. Microbiome analysis was performed on stool samples. An increase in body weight, a decrease in the use of the ipsilateral paw, as assessed by the cylinder test, and increased uptake of the neuroinflammatory marker 11C-PBR28 was shown in animals on a high fat diet one month after injection
of 6-OHDA, as compared to the assessment before stereotactic surgery. No differences between time points were found in the SD group. The increased accumulation of 11C-PBR28 in the HFD group after 6-OHDA administration was
accompanied with alterations in the microbiota profile and no effect in the cytokine levels in plasma. This study suggests the documented impact of an HFD on neuroinflammation may be mediated by the gut microbiome in the 6-OHDA rat model of Parkinson’s disease and suggest it is independent of peripheral inflammation.
Knowledge of the basic mechanisms underlying PD and their relation with changes in lifestyle can help scientists to better understand the factors that trigger the onset of the disease and aid the development of new treatments and diagnostic tools. My small contribution to this field is the possibility to investigate the interaction of two diseases (obesity and PD) in the same animal using the PET for longitudinal monitoring. These studies can help reveal the complicity of the interaction between behavior, microbiota, dopaminergic and purinergic response, and inflammation in the gut and the brain.
| Chapter 9
