#Excitotoxicity is the pathological process by which nerve cells are damaged and killed by glutamate and similar substances. This occurs when receptors for the excitatory neurotransmitter glutamate such as the NMDA receptor and AMPA receptor are overactivated. Excitotoxins like NMDA and kainic acid which bind to these receptors, as well as pathologically high levels of glutamate, can cause excitotoxicity by allowing high levels of calcium ions (Ca2+) to enter the cell. Ca2+ influx into cells activates a number of enzymes, including phospholipases, endonucleases, and proteases such as calpain. These enzymes go on to damage cell structures such as components of the cytoskeleton, membrane, and DNA.
Excitotoxicity may be involved in spinal cord injury, stroke, traumatic brain injury and neurodegenerative diseases of the central nervous system (CNS) such as Multiple sclerosis, Alzheimer's disease, Amyotrophic lateral sclerosis (ALS), Parkinson's disease, Alcoholism or alcohol withdrawal and Huntington's disease. Other common conditions that cause excessive glutamate concentrations around neurons are hypoglycemia and status epilepticus.
#Mitochondrial dysfunction describes a loss of function of the mitochondria. Mitochondria are the power plants in our body. They are energy producing organelles existing in almost every cell of our body. They are very important to the functions and survival of our body cells and organs. As part of the energy production process in our cells the mitochondria produce Reactive oxygen species (ROS) as normal byproducts. ROS concentration is tightly controlled by antioxidant enzymes in the mitochondria (such as manganese superoxide dismutase (SOD2) and glutathione peroxidase). Over production of ROS (oxidative stress - see below) is a central feature of all neurodegenerative disorders. In addition to the generation of ROS, mitochondria are also involved with life-sustaining functions including calcium homeostasis, PCD, mitochondrial fission and fusion, lipid concentration of the mitochondrial membranes, and the mitochondrial permeability transition. In mitochondrial dysfunction some or all of these functions are impaired which leads to the activation of a programmed suicide pathway in the mitochondria and the cell that the dysfunctional mitochondrial belong to. This programmed pathway, called apoptosis, is the most common form of cell death in neurodegeneration (the intrinsic mitochondrial apoptotic pathway).
There is strong evidence that mitochondrial dysfunction and oxidative stress play a causal role in neurodegenerative disease pathogenesis, including in four of the more well known diseases Alzheimer's, Parkinson's, Huntington's, and Amyotrophic lateral sclerosis.
#Oxidative stress results when reactive oxygen species (ROS, see below) production exceeds the cells abilities to detoxify the ROS. ROS are very reactive oxygen containing free radicals and molecules that easily react with, and thereby cause damage to, other molecules including lipids (fats), proteins and DNA in the cells. This free radical oxidative damage to the different biomolecules in the body causes loss of cellular functions and often leads to cell death. Large amounts of this type of oxidative damage can lead to tissue damage and is involved in many different diseases.
#Reactive oxygen species (ROS) are small molecules that include oxygen ions, oxygen free radicals, and peroxides, both inorganic and organic. These molecules are highly reactive due to the presence of unpaired electrons. ROS form as a natural byproduct of the normal metabolism of oxygen and have important roles in cell signaling. However, during times of disease, exercise, or environmental stress (e.g. smoking, UV or heat exposure) ROS levels can increase dramatically, which can result in significant damage to cell structures. This cumulates into a situation known as oxidative stress (see above). ROS are also generated by exogenous sources such as ionizing radiation.
Cells are normally able to defend themselves against ROS damage through antioxidant enzymes (superoxide dismutases, catalases, glutathione peroxidases), and small molecule antioxidants such as vitamin C and E, uric acid, and glutathione. Similarly, polyphenol antioxidants, the major class of antioxidants in Enzogenol, assist in preventing ROS damage by scavenging free radicals.
ROS have positive and negative effects on cell metabolism. Positive effects where ROS mediate functions of normal cell metabolism include the induction of host defence genes and mobilisation of ion transport systems, and roles in redox signaling. Negative effects of overproduction of ROS are implicated in many cardiovascular, inflammatory and neurological diseases. Generally, harmful effects of reactive oxygen species on the cell are most often:
1. damage of DNA
2. oxidations of polydesaturated fatty acids in lipids (lipid peroxidation)
3. oxidations of amino acids in proteins
4. oxidatively inactivate specific enzymes by oxidation of co-factors