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Effects of Macrophage Migration Inhibitory Factors’ (MIF) inhibition on chronic neuroinflammation
Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and the most common form of dementia. Considering the aging population, AD will be one of the challenging problems of the public health in the near future. Current medication used for AD can only alleviate the symptoms temporar...
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| Contributors: | |
| Format: | Doctoral Thesis |
| Language: | English |
| Published: |
Philipps-Universität Marburg
2016
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| Subjects: | |
| Online Access: | PDF Full Text |
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| Summary: | Alzheimer’s disease (AD) is a progressive neurodegenerative disorder
and the most common form of dementia. Considering the aging population,
AD will be one of the challenging problems of the public health in the near
future. Current medication used for AD can only alleviate the symptoms
temporarily; therefore it is imperative to identify new therapeutic targets to
prevent the progression of the disease. Being one of the early key events in
early AD pathology, chronic inflammation precedes the cognitive decline and
an increasing interest has been focused on identifying potential targets within
inflammatory cascades.
Macrophage Migration Inhibitory Factor (MIF) is a multi-potent proinflammatory
cytokine, which promotes production of other proinflammtory
mediators. MIF is synthesized by several cell types in the brain such as
microglia, astrocytes and hippocampal neurons, and is secreted in early
asymptomatic stage of the disease, which might contribute to the persistent
activation of glial cells and perpetuating neuroinflammatory responses leading
to neurodegeneration. In this project we hypothesized that inhibition of MIF
can attenuate the inflammatory milieu in the brain and improve the cognitive
deficits as a result of chronic cytokine production.
We used Intracerebroventricular Streptozotocin Injections (STZ-ICV) to test
our hypothesis.
In in vitro experiments, ISO-1 was used to inhibit the MIF molecule in primary
astrocyte, neuron and microglia treated with proper concentrations of STZ
molecule as stimulus. The cytokine response was documented in protein and
mRNA level. The collected in vitro data suggests that MIF inhibition can
alleviate inflammation by down-regulating production of proinflammtory
cytokines (such as IL-6 and IL-12p40).
In vitro experiments were followed up by in vivo behavioral assessment of
cognitive deficits and cytokine production in streptozotocin induced model of
neurodegeneration. For this purpose, MIF-KO and wild type mice were
intracerebroventricularly injected with streptozotocin (STZ-ICV) or vehicle
(Veh-ICV).
We confirmed that by triggering an ongoing and chronic immune response,
STZ interferes with learning via disrupting the spatial learning in C57BL/6 mice.
We observed significant relationships between cognitive improvement (in
terms of contextual memory) and MIF inhibition in STZ-ICV model for
neuroinflammation. The inhibition of MIF (by novel Intraperitoneal (IP)
application of ISO-1), tended to improve the spatial learning and memory in
the context of clockmaze and fear conditioning in wild type animal.
Similar trend as in vitro has been observed in down regulation of cytokines
(IL-6 and IL-12p40) as a result of MIF inhibition.
In contrast to wild type STZ-ICV, we observed no significant upregulation in
inflammatory mediator or glial cell markers in mRNA levels of MIF-KO
animals.
In conclusion, the results from my thesis confirms the role of MIF as an
upstream cytokine in regulating secretion of other inflammatory mediators and
shows the potential of this molecule as a therapeutic target to attenuate
cytokine induced cognitive deficits. |
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| Physical Description: | 165 Pages |
| DOI: | 10.17192/z2017.0151 |