**4. Paraoxonase 3**

PON3 is an antioxidant hydrolase enzyme with approximately 40-kDa, synthesized in the liver. In plasma PON3 is bound to HDL and apolipoprotein—A1 and possesses strong anti-oxidant properties but its concentration is about two orders of magnitude less abundant than PON1. PON3 is also expressed at low levels in the kidney. PON3 was the last enzyme in the paraoxonase family genetic cluster to be described. Currently, very little is known about its function and physiological characteristics in humans. The enzymes PON3 and PON1 show some similarities in structure and hydrolase activity. Regarding the structure, both enzymes have three highly conserved cysteine (Cys) residues in positions -41; -283 and -351 in the protein chain. As for enzyme activity, PON3 can hydrolyze cyclic carbonate esters and lactones rapidly, mainly drugs such as statin lactones. The arylesterase activity of PON3 is almost undetectable when compared to PON1 [79, 80].

PON3 protein expression in the white-matter brain areas of healthy C57BL/6J mice. One study reports that there is strong evidence of PON1 and PON3 expression surrounding Aβ plaques, and intense positive staining in star-shaped cells that resembled glial cells in areas with an abundance of Aβ plaques [81]. It was suggested in the study that localization of PON1 and PON3 in astrocytes or oligodendrocytes, at the same time there is colocalization of PON3 in microglia which indicates a potential antioxidant role of PON1 and PON3 in decreasing levels of ROS and/or preventing lipid peroxidation in these cells in Alzheimer disease pathology.

Although there is no documented *PON1* or *PON3* gene expression in any of the mouse- or human-brain regions, one of the study indicated that PON1 and PON3 proteins are expressed in myelinated fibers in the brain tissue of healthy C57BL/6 mice. This suggests that PON1 and PON3 are somehow transferred from blood circulation to the brain [82]. Overall the PON3 is much less studied as compared to PON1 & PON2. So much less information is available in the literature than others.

#### **4.1 Paraoxonases and acetylcholine esterase**

PON1 and Acetylcholine esterase are both serum ester hydrolases. Genes for both are located on the same chromosome—7q1-22—near to each other [83]. At the genetic level, due to the proximity in their locations, it is thought that the genes for both would be regulated by a locus control region. It has been shown that PON1 and acetylcholinesterase share an inverse relationship. This relationship is not shown by pseudocholinesterase. It is thought that the same locus control region may control their interactions. Acetylcholine esterase is especially susceptible to oxidative stress, and paraoxonase is an antioxidant. This also contributes to their interactions.

Organophosphates are inhibitors of acetylcholine esterase (AChE). They are metabolized in liver to form oxones, which irreversibly inhibit AChE. The usual form of AChE is oligomeric and it is this form which is inhibited by organophosphate compounds (OPCs). On inhibition, up-regulation at genetic level causes increase in synthesis of AChE; however, this AChE is unable to oligomerize. This form of AChE, also called AChER, is thought to act in inflammatory processes, contributing to the disease pathobiology. PON1 is a key detoxifier of organophosphates and organophosphate exposure has been linked to the development of neurological disorders where acetylcholine plays a significant role [84].

#### *Paraoxonase in Nervous System DOI: http://dx.doi.org/10.5772/intechopen.110843*

PON1 is thought to protect AChE through its antioxidant action by neutralizing superoxide radicals. They also spare AChE from organophosphates by lysis of organophosphate compounds. Exposure to OPCs usually results from chronic domestic pesticide exposure. PON1 polymorphisms result in hypofunction of PON1. In such states, OPCs irreversibly inactivate circulating AChE. PON1 usually is not a vital enzyme, but in case of a person with PON1 polymorphism, exposure to OPCs may trigger detrimental effects of the polymorphism present. In absence of functional PON1, the organophosphate exposure results in irreversible inhibition of the circulating oligomeric AChE and up-regulation of AChER. Thus, presence of PON1 is thought to prevent this by its antioxidant and paraoxonase activities, and genetic variations in PON1 affect the individual's susceptibility to OPC exposure [85].

The nigrostriatal pathway of dopamine secretion degenerates with increasing age. This leads to minor DA depletion. In people with intact and functional AChE and PON1, this minor depletion does not cause any significant detrimental alteration in health, even in presence of OPCs exposure. However, in presence of polymorphisms in either of AChE or PON1, this can predispose to Parkinson disease. In Parkinson disease, the acetylcholine and dopamine levels are imbalanced with respect to each other due to damage to the substantia nigra. Chronic exposure to OPCs aggravates this imbalance by the means explained above. PON1 counters this imbalance through its antioxidant and paraoxonase activities [84].

Alzheimer disease, on the other hand, is linked to cholinergic deficiency. Hence, AChE inhibitors (AChEIs) are used to treat it. However, the response of patients to these AChEIs is not uniform—many patients have been found not to respond to the same. It was discovered that the AChEI activity was inversely related to PON2 esterase activity. Further investigations [85] revealed that this was most likely because the esterase activity of PON2 lead to the lysis of the AChEIs. While PON1 mutations did not have this esterase effect on these drugs, the PON2 polymorphic forms, 311C and 148G, showed increased esterase activity. Thus, PON2 analysis in patients with Alzheimer disease may indicate whether the AChEI therapy would be successful or not [86].

We can conclude that the paraoxonase is the molecule which has implications in the neurodegenerative disease and other aspects of nervous system. Mostly the role of paraoxonase is protective one by the virtue of prevention of oxidative stress which arises due to the imbalance in the redox system. But this is only the tip off the iceberg as more research is required in this aspect.
