Файл: Extracellular and Intracellular Signaling (книга).pdf

DNA repair enzymes.69 PARP uses NAD as an energy source and as a substrate to poly(ADP-ribosylate) itself and several nuclear enzymes. This poly(ADP-ribosylation) alters the activities of many enzymes.

Neuronal DNA is much more than just an archive of genetic information. It is very actively involved in producing proteins for neurotransmitter synthesis, release, reuptake and other neuronal functions. Damage to neuronal DNA very extensively a ects the ability of neurons to function normally, including maintaining neurotransmitters.70

PARP may ADP-ribosylate various transcription factors that regulate gene transcription.71,72 PARP is a component of positive cofactor 1 activity that regulates class II gene transcription.70 When DNA is damaged, PARP is activated, which inhibits class II gene transcription regulated by RNA polymerase II.73 PARP is also important in the action of p53, the tumor suppressor protein. Both PARP and p53 bind to DNA breaks. PARP can form complexes with p53 that may alter the activity of p53.74 Interestingly, p53 is involved in the inhibition of RNA polymerase III dependent gene transcription.75

It is important to recognize that the PARP referred to above is PARP-1. There are several enzymes with PARP activity.76 It is not known if the other enzymes, PARP-2, PARP-3, tankyrase and V-PARP, can fill in for PARP-1 when PARP inhibitors are used. Clearly, in PARP-1 knockout mice, the other PARP enzymes are still functional and can protect DNA and synthesize poly(ADP-ribose). It is also not known if PARP inhibitors are specific for PARP-1 or can inhibit all forms of PARP.

The energetic consequences of DNA damage and PARP activation are

enormous (Figure 10.2). PARP activation rapidly depletes NAD and ATP levels in the cell, leaving the cell depleted of energy sources.69,77 NADPH

depletion also occurs.77 Glutathione oxidizes. Glycolysis, the pentose phosphate pathway and mitochondrial energetics are a ected.

Recent research indicates that the secondary brain injury associated with stroke is induced by inflammatory processes. Nicotinamide can decrease the recruitment of neutrophils to potential sites of inflammation by inhibiting PARP in neutrophils and other cells.78 In fact, nicotinamide has been recommended for the treatment of arthritic patients since the 1940s. It was found in pilot trails that nicotinamide improved joint mobility and decreased the need for anti-inflammatory medication in arthritic cases.79 In the process of inflammation, the genes for intercellular adhesion molecule 1 and collagenase in neutrophils are activated. Neutrophils are recruited to sites of inflammation. Nitric oxide synthase is activated and oxygen radicals, hydrogen peroxide and nitric oxide are released. These reactive species can damage cellular DNA in the area of inflammation, resulting in apoptosis, necrosis and more serious inflammation.80 PARP has a number of functions in inflammation due to its ability to regulate gene expression.80 Inhibition by nicotinamide of PARP leads to decreased expression of these genes and decreases the extent and severity of inflammation. Nicotinamide also decreases the induction of iNOS, thereby decreasing damage to the blood-brain barrier.81

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Figure 10.2 The energetic consequences of DNA damage caused by oxidative stress. PARP is poly(ADP-ribose) polymerase. NAM is nicotinamide. NMN is nicotinamide mononucleotide. Na is niacin. Na-MN is niacin mononucleotide. Na-AD is niacin adenine dinucleotide. 1 is nicotinamide phosphoribosyl transferase, which requires ATP. 2 is NMN adenyl transferase, which requires ATP. PPP is the pentose phosphate pathway. G-6-P is glucose-6-phosphate. R-5-P is ribose-5-phosphate. G-3-P is 3-phosphoglycerate.

DNA damage leads to cell death. A large amount of DNA fragmentation causes rapid necrosis, with cell swelling and rupture, nuclear swelling and rupture and cytoplasmic vacuole formation. A smaller amount of DNA fragmentation causes apoptosis with cell shrinkage, nuclear condensation and fragmentation, large vacuole formation in the cytoplasm and cell fragmentation forming apoptotic bodies.82 Necrosis is a rapid process that does not require energy. Apoptosis is a delayed process that requires ATP. The center of a brain infarction is typically made up of necrotic cell debris.83 The limit area surrounding the core contains necrotic, apoptotic and normal cells.83

disease and Parkinson’s disease. Neovascularization can produce arterioles that leak until they become well established and form tight junctions between endothelial cells. Leaky arterioles may produce more damage in stroke, Alzheimer’s disease and Parkinson’s disease.

10.5 Conclusions

Neurodegeneration may be caused by or increased by toxic lifestyles. Diet and exercise improvements could be encouraged to prevent or perhaps control neurodegenerative diseases. Toxic lifestyles lead to adipokine elevations in the blood and oxygen radical formation, possibly through visfatin, CD38 and NADH oxidase mechanisms. Hydrogen peroxide formed during this process crosses cell membranes and damages DNA. The cells first damaged in this process are probably the endothelial cells of the blood-brain barrier. Adipokines cause white blood cells and platelets to stick to the damaged blood-brain barrier. This sets up an inflammatory process that produces more damage. The leaky blood-brain barrier allows the infiltration of inflammatory cells into the brain parenchyma. These inflammatory cells produce oxygen radicals that damage the DNA in neurons and other brain cells leading to brain lesions. In Alzheimer’s disease these lesions are most important in the hippocampus, cerebral cortex and other areas. In Parkinson’s disease these lesions are critical in the dopaminergic neurons of the substantia nigra, dopaminergic neuronal projections in the basal ganglia and other regions.

Stroke is a rapid process that also involves toxic lifestyles. Adipokines damage arteries in the body. Clots and thrombi are produced that lodge in the middle cerebral artery and other locations to produce ischemia, followed later by reperfusion as the clot or thrombus is removed or resolves. Ischemia and reperfusion produce oxygen radicals and hydrogen peroxide that damage cellular DNA leading to cell death through apoptosis and necrosis. Brain lesions are typically seen in the basal ganglia, hippocampus, cerebral cortex and other regions.

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