EVALUATION OF REGENERATIVE EFFICACY OF 4-PHENYL BUTYRIC ACID ON ENDOPLASMIC RETICULUM STRESS VIA PERK PATHWAY IN EXPERIMENTAL MULTIPLE SCLEROSIS (MS) MODEL

Project no. 22399 · Status: Kapanmış (Yayın bekleniyor) · 2020

Summary

Multiple Sclerosis (MS) is a chronic autoimmune inflammatory disease that results in demyelination, neurodegeneration and axonal loss in the central nervous system (CNS). While current treatments for MS can slow the progression, they are not completely successful. In addition, these treatments are associated with CNS and cardiovascular adverse events, and long-term use of these treatments can lead to life-threatening conditions. Recent research has shown that cellular therapies have the potential for CNS repair and may protect against post-injury inflammatory damage. In this context, the discovery of new therapeutic agents is very important. The causes of MS are largely unknown, but there are environmental and genetic factors known to play a crucial role in the development of the disease. However, Endoplasmic Reticulum (ER) stress, which is observed in all four known clinical forms of MS, plays the same role at the molecular level when the disease progresses clinically. ER stress is defined as a chronic disturbance in the homeostasis of the ER and is mainly characterized by disturbances in the protein folding mechanism and the accumulation of abnormal proteins that cause effects at the cellular level. Although ER stress occurs with the aim of protecting the cell, if stress management cannot be performed and becomes permanent in the cell, this may lead to the death of the cell. Suggested mechanisms to associate ER stress with cell death include the activation of proteases, kinases, transcription factors, and Bcl-2 proteins. Although IRE1 and ATF6 of the three pathways involved in the pathogenesis of MS have been elucidated, although the existence of the PERK pathway is known, how it affects the disease and its effects on the molecular mechanism of the disease in this pathway have not been investigated yet. With this project, the regenerative capacity of 4-phenylbutyric acid (4-PBA), which is used as a drug against ER stress in an experimental MS model, in various cancers and neurodegenerative diseases such as Parkinson’s, and which is a drug active ingredient in the phase 2 stage of Amyotrophic Lateral Sclerosis (ALS) disease. This study aims to evaluate the regenerative capacity of 4-PBA at the molecular and histochemical level via the PERK pathway.Although it has been shown that 4-PBA is used in various cancers and is effective in neurodegenerative diseases such as Parkinson's, the absence of any studies on the use of this substance in MS disease reveals the originality of this study. Glatiramer Acetate (GA), which was used within the scope of the thesis, is used as an anti-inflammatory drug in the treatment of MS disease, approved by the FDA. ER stress is known to play a role in the development and progression of neurodegenerative diseases, including MS. While GA helps to reduce ER stress, relieve the burden on the ER and improve protein folding and cellular function, GA treatment also reduces mitochondrial dysfunction in EAE. In our study, after the in vitro safety evaluation of 4-PBA and GA, in vivo efficacy studies were started. To generate MS disease, EAE was induced in experimental animal model C57BL/6 laboratory mice by administering pertussis toxin after injection of MOG35-55 peptide and FCA emulsion. After the model was induced, treatment applications were carried out in the form of 4-PBA, GA, ADMSC and their combinations with 4-PBA. At the end of our study, the weights of all animals were taken and biochemical, histochemical and immunohistochemical analyzes were performed from the tissues taken from the experimental animals after sacrification.In line with the data obtained, 4-PBA’s ability to alleviate inflammation and reduce ER stress proves that 4-PBA is an agent with high therapeutic potential for MS disease. In this study, both the therapeutic effect of 4-PBA in MS disease was revealed, and the therapeutic efficacy of 4-PBA against MS disease was determined by trying the combined treatments of 4-PBA with GA and ADMSCs. In the light of this information, this thesis is the first study to investigate target agents and their effects on a neurodegenerative disease.

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