**2.2 PON1 and dementias**

Erstwhile dementia is now termed as major neuro-cognitive disorder (MND). It describes an overall decline in memory and cognitive skills severe enough to reduce person's ability to perform everyday activities. Previously thought to affect elderly only now it is affecting the younger age group too. It is characterized by significant decline in any of the cognitive domain including, executive function, complex attention, language, learning, memory, and perceptual-motor or social cognition. Major neuro-cognitive disorder is diagnose by the decline in patient's previous cognitive ability without delirium, which should be persistent and progressive over the time. At present disease burden supposed to be 43 million worldwide which is expected to escalate to 131 million by 2050. Alzheimer disease (AD) which is responsible for nearly 70–80% cases of dementia worldwide, is one of the important cause of death over the age of 65 years [31].

One of the characteristic neuro-pathological features of AD is the presence of amyloid plaques which comprise aggregates of β-amyloid derived from the amyloid precursor protein [32]. Increasing evidence suggests that cholesterol plays a role in the pathophysiology of Alzheimer's disease, and elevated serum total-cholesterol level has been shown to be a risk factor for AD [33]. Abnormal phosphorylation of tau proteins is thought to be responsible for pathogenesis of AD. In addition to phosphorylation, neuronal degeneration is caused by a combination of beta amyloid production, oxygen deficiency. Lipid peroxidation too plays role in pathogenesis of AD. Amyloid is responsible for oxidative stress through free radicals. This oxidative stress is responsible for conversion of soluble amyloid proteins to insoluble fibrils and further in to polymerization of tau proteins [34, 35]. Some researchers report that deficient serum paraoxonase activity is a significant risk factor for AD and that paraoxonase activity is governed in part by at least 2 distinct variants, one located in the PON1 region and another in PON2 [36]. Some reports suggest that low PON1 activity is associated with cognitive decline, especially in AD [37]. There are many opposite results regarding polymorphism In MND. Some says there is definite correlation between the Q192R and L55M polymorphism and risk of AD and MND while others differ in their views as they found no correlation [38, 39].

### **2.3 PON1 and Parkinson's disease**

Parkinson's disease (PD) is an idiopathic disease of the nervous system characterized by both motor and non-motor system manifestations. It is a chronic progressive neurodegenerative disorder that occurs mostly in older persons but that can appear in much younger patients. It is the second most common neurodegenerative disease. Sometimes called "paralysis agitans", PD is uncommon in young people, especially those under 40 years of age [40, 41]. The pathological definition of PD is loss or degeneration of the dopaminergic neurons in the substantia nigra and development of Lewy Bodies in dopaminergic neurons. Pathologic changes may precede obvious symptoms by two decades or more. This preferential loss of dopamine producing neurons and simultaneous lack of cholinesterase inhibition results in marked imbalance acetylcholine and dopamine along with impairment of motor control. Lewy Bodies, or abnormal intracellular aggregates, contain various proteins including α-synuclein and ubiquitin that impair optimal neuron functioning [42, 43].

While the exact pathogenesis of the disease has not been completely elucidated, several theories implicating the association of genetic and environmental toxic elements such as exposure to pesticides or an oxidative cell environment conspire to trigger the neuron degeneration. Recent reports suggest that the chronic low-grade inflammation due to various sources like pesticides, drugs, aging process etc. is responsible for the cellular senescence in nervous tissue [44, 45]. From a pathologic

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

perspective, the brain's substantia nigra pars compacta and pontine locus ceruleus are affected by typical abnormalities of PD including depigmentation, neuronal loss and gliosis. Nearly 60–70% neurons are lost by the time symptoms appears [46, 47].

Pesticides have been implicated in the development of PD by inhibition of ubiquitine proteosome system. Probably upon exposure to pesticides, mitochondrial dysfunction and α-synuclein, which is a neuronal protein, undergo conformational change which leads to symptoms of PD. One hypothesis states that as a result of mitochondrial dysfunction, there is release of cytochrome-c in the cytosol which binds to apaf1 and starts apoptosis. This results into neuronal degeneration and ultimately to PD [48].

As PON1 has antioxidant capacity and is capable of hydrolyzing toxic substances, literature links PON1 polymorphism with PD. PON1 polymorphism as Met54 may be an independent risk factor for PD. This mutation could possibly be responsible for decreased PON1 activity which results in lessened metabolism of environmental neurotoxins and could play a role in neuro-degeneration. Researchers have found that there is an association between L55M polymorphism of PON1 and PD, whereas Q192R polymorphism was unlikely to be a major risk factor for susceptibility to PD [49]. Recently a researcher found MM PON1–55 genotype exhibit greater than 2-fold increase in PD risk when exposed to organophosphates, compared with subjects who had the wild type or heterozygous genotype and no exposure [50].

#### **2.4 PON1 and multiple sclerosis**

Multiple sclerosis (MS) is one of the most common neurological disorders, occurring mainly in young adults in age 20–40 years and more commonly in women. MS is a chronic inflammatory disease characterized by demyelinating lesions in the brain, spinal cord, and optic nerve [51, 52]. Some studies have suggested a role of the oxidative stress and lipid peroxidation in the pathogenesis of MS. Due to the pathogenetic role of reactive oxygen species and the oxidation of lipoproteins in MS pathology, antioxidants prevent free-radical mediated tissue destruction [53]. PON1 is shown to play an important antioxidant role in the blood. Variability of PON1 activity depends on polymorphism in the coding region. There are only a few studies that describe the relationship between PON1 polymorphism and the risk for MS [54]. The relationship between MS and oxidative stress due to oxidized lipoproteins in cholesterol transport has been discussed. It has been proposed that increased number of oxidized HDL particles due to decreased PON activity may be unable to protect LDL against oxidation increasing the risk of atherogenesis which may lead to MS [55].

Oxidative stress is a critical factor in pathogenesis of MS as it promotes leukocyte migration, participates in oligodendrocyte damage and axonal injury. Reactive oxygen species and reactive nitrogen species are produced in the CNS of MS patients chiefly by activated macrophages and microglia could account for demyelination and axonal disruption, the hallmarks of the disease [56, 57].

#### **2.5 PON1 and amyotrophic lateral sclerosis**

Amyotrophic lateral sclerosis (ALS) is a dangerous neurodegenerative disease, characterized by progressive motor neurons loss, paralysis, and inflammation with an average survival of 3–5years after diagnosis. 5–10% of cases are familial, and70% of the familial cases can be explained by identified gene mutations, e.g. the *C9orf72* repeat expansion [58]. ALS is a degenerative disease of adult-onset

and fatal outcome characterized by the simultaneous loss of motor neurons in the cerebral cortex, brainstem and spinal cord. In the familial cases, a large number of mutations have been found, most prominent of which is the mutation in the gene that encodes for the cytosolic enzyme superoxide dismutase [59, 60]. It was found in recent studies that PON1 gene is down-regulated in the central nervous system and peripheral cell like lymphocytes and fibroblasts. Some genetic mutations also are identified in the patients of ALS [61, 62]. It is well established fact that the oxidative stress is responsible for degeneration of the motor neurons in ALS. The CNS as a whole is particularly susceptible to oxidative stress because the neuronal membrane contains a high abundance of polyunsaturated fatty acids, especially arachidonic and docosahexaenoic acids; it consumes oxygen at a high rate; and it contains high concentrations of redox-active transition metals but a relatively low concentration of antioxidants. In ALS, at the cellular level, genetic factors, excitotoxicity, apoptosis, inflammation, mitochondrial dysfunction, protein aggregates, and oxidative stress are among the primary hypotheses put forth to explain motor neuron degeneration. Among these factors, oxidative stress appears intimately linked to a series of cellular events in motor neurons that contribute to neuronal degeneration and death [63, 64]. Individuals that had the homozygous genotypes RR and heterozygous GQ had a lower survival rate when compared to the homozygote genotype QQ. Moreover, the allele R was associated with bulbar onset. Some authors have mentioned the increased chance of ALS following the exposure to pesticides and the susceptibility increases two folds with single nucleotide polymorphisms (SNPs) like G-832A, G-162A and C-108 T [65, 66].
