Browsing by Subject "neuroinflammation"
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(2021)Mild traumatic brain injury (TBI) is defined as an injury that disrupts the normal functioning of the brain and is the result of external force to the head. It is the most common type of traumatic head injury, and it is common especially in contact sports and within military personnel. Mild TBI typically causes no clear structural changes to the head, but it can induce persistent clinical symptoms, as well as microscopic pathological changes to the brain that may eventually lead to neurodegeneration and increase the risk for several diseases. Mild TBI is a risk factor for several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and chronic traumatic encephalopathy. The primary objective of this study was to develop a repetitive mild TBI mouse model for future research purposes in the field of head trauma and neurodegeneration. The injury was induced as a closed head injury with an electromagnetic impactor. Literature and pilot experiments were used to define the parameters of the impactor required to induce a brain injury of desired severity. The characterization criteria of the mild TBI model considered the criteria used to define human mild TBI, as well as long term effects often reported after repetitive mild TBI: neurodegeneration as tau protein related pathology, neuroinflammation, and memory deficits. The secondary objective of this study was to tentatively test a prolyl oligopeptidase (PREP) inhibitor on the behavioral and histological effects of mild TBI. The functioning of the mild TBI model was studied by histopathological and behavioral assessments. After baseline behavioral assessment and repetitive (1 injury every 24 hours altogether 5 times) mild TBI inductions, the mice were monitored for approximately 3 months, during which several rounds of behavioral tests were performed. Barnes maze and novel object recognition tests were used to assess memory functions, and locomotor activity test was used to assess general locomotor activity. After euthanasia, brain histopathology was performed to study the amount of tau protein and the level of neuroinflammation. Due to the low number of animals in the study, the results are directional and need to be confirmed in subsequent studies. The histopathology showed greater amount of neuroinflammation and tau protein in the brains of injured mice, but statistical evaluations could not be made. Memory functions were slightly worse in the injured mice compared to controls, but significance of the results is unclear. Locomotor activity was not influenced by the mild TBIs. PREP inhibition treatment increased the locomotor activity of the mice, but the significance is unclear. The mild TBI model seems promising and the characterization criteria were partially met. The results of the study need to be verified in subsequent studies with a greater amount of animals. The model developed here can be used to study the involvement of head trauma in neurodegeneration, as well as treatment alternatives to changes caused by mild TBIs. As there currently are no curative treatments to neurodegenerative diseases, research regarding neurodegeneration and its risk factors is highly important.
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(2024)Multiple sclerosis (MS) is an inflammatory neurodegenerative disease of the central nervous system, that affects over 2 million people worldwide. In MS, there is an autoimmune reaction against the myelin surrounding axons, causing neurological deficits and progressive neurological deterioration over time. Currently, there is no curative treatment for MS; only disease-modifying treatments are available. In this study, the effect of C-MANF (C-terminal mesencephalic astrocyte-derived neurotrophic factor) on unfolded protein response (UPR), neuroinflammation and myelination was investigated in different models of myelination by analyzing gene expression with quantitative polymerase chain reaction (qPCR). C-MANF is a C-terminal fragment of endoplasmic reticulum (ER) located protein MANF, which has been shown to protect cells against ER-stress induced apoptosis. UPR is a cellular defense mechanism against ER stress, but when prolonged, it can direct cells into apoptosis. The effect of C-MANF was investigated in ER-stressed Oli-neu cell cultures, both undifferentiated and differentiated. Cells were treated for 5 hours with thapsigargin to induce ER stress and simultaneously with C-MANF. In differentiated cells, a longer 24 hour exposure to ER stress and C-MANF was also investigated. Organotypic cerebellar brain slices from C57BL/6 P10 mice were demyelinated with lysophosphatidylcholine (LPC) for 17 hours, after which C-MANF was given during 5 day remyelination period. After the experiments were conducted, RNA was isolated and converted to cDNA for quantitative polymerase chain reaction (qPCR) using SYBR green. In addition, spinal cords from experimental autoimmune encephalomyelitis (EAE) animal experiment, where mice were given C-MANF subcutaneously, were included in this study, and qPCR was performed on them. This study showed significant changes in UPR gene expression in differentiated Oli-neu cells and EAE mice, indicating that C-MANF could alleviate UPR signaling and thus protect cells. Neuroinflammation was assessed with cerebellar brain slices and EAE mice; both models showed significant changes in gene expression related to neuroinflammation, indicating reduced neuroinflammation in response to C-MANF treatment. C-MANF did not seem to have an effect on myelination in this study. Large variation in between different groups in cerebellar brain slices may be due to challenges in RNA isolation an may have affected the results. However, these findings suggest the potential of C-MANF as a therapeutic for diseases associated with upregulated UPR signaling and a high degree neuroinflammation, such as MS. Further research and additional methodologies are needed to confirm these findings.
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