Inhibition of mitochondria pyruvate carrier- an approach to attenuating neurodegeneration

ABSTRACT

Neurodegeneration is defined as the progressive loss of structure or function of neurons in the body. Different forms of neurodegenerative disease include Parkinson disease, Alzheimer disease, multiple sclerosis, Huntington’s disease, and they are caused by different mechanism such as inflammation, mitochondria dysfunction, excitotoxicity etc. Insulin sensitizers have been discovered by researchers in managing Neurodegeneration and the main one used are the thiazolidinedione. Due to the activation of Peroxisome proliferator- activated gamma by the old thiazolidinedione, more researches were carried out to discover insulin sensitizers that bypass the PPAR-gamma and that leads to the development of MSDC-1060- A drug that bypass the PPAR-gamma and inhibit the mitochondria pyruvate carrier.  The Mitochondria pyruvate carrier is a transport protein responsible for the movement of pyruvate from the cytosol into the mitochondria matrix. MSDC-1060 makes the mitochondria to use other substrates to balance its metabolism and hence attenuate neurodegeneration using autophagy augmentation, inflammation reduction and excitotoxicity reduction.

TABLE OF CONTENT

TITLE                                                                                                                        PAGES

TITLE                                                                                                                         i

CERTIFICATION                                                                                                     ii

DEDICATION                                                                                                           iii

ACKNOWLEDGEMENT                                                                                         iv        

TABLE OF CONTENT                                                                                             v

LIST OF FIGURES                                                                                                  vii

ABSTRACT                                                                                                              viii

CHAPTER ONE

1.1       INTRODUCTION                                                                                           1

CHAPTER TWO

2.1       NEURODEGENERATION                                                                            3

2.1.1    NEURODEGENERATIVE DISEASES AND TYPES                    3

                        2.1.1.1   ALZHEIMER DISEASE                                                     4

2.1.1.2   HUNTINGTON’S DISEASE                                               7

2.1.1.3   PARKINSON DISEASE                                                       9

2.2       MITOCHONDRIA PYRUVATE CARRIER                                                12

2.3       THIAZOLIDINEDIONES (TZDs) AND NEURODEGENERATION       14

            2.3.1    OLD GENERATION VERSUS NEW GENERATION TZDs            15

CHAPTER THREE

3.1       MECHANISMS OF ATTENUATING NEURODEGENERATION BY

MSDC-1060                                                                                                               18

            3.1.1    AUTOPHAGY AUGMENTATION                                                             19

3.1.2    INFLAMMATION REDUCTION                                                                21

3.1.3    EXCITOTOXICITY REDUCTION                                                              23

3.2       FUTURE PERCEPTIVE AND CLINICAL IMPLICATION OF MSDC-1060       25

CHAPTER 4

4.0       CONCLUSION                                                                                                           28

REFERENCES                                                                                                                       29