Why Should Psychiatrists and Neuroscientists Worry about Paraoxonase 1?

Abstract

Background: Nitro-oxidative stress (NOS) has been implicated in the pathophysiology of psychiatric disorders. The activity of the polymorphic antioxidant enzyme paraoxonase 1 (PON1) is altered in diseases where NOS is involved. PON1 activity may be estimated using different substrates some of which are influenced by PON1 polymorphisms. Objectives: 1) to review the association between PON1 activities and psychiatric diseases using a standardized PON1 substrate terminology in order to offer a state-of-the-art review; and 2) to review the efficacy of different strategies (nutrition, drugs, lifestyle) to enhance PON1 activities. Methods: The PubMed database was searched using the terms paraoxonase 1 and psychiatric diseases. Moreover, the database was also searched for clinical trials investigating strategies to enhance PON1 activity. Results: The studies support decreased PON1 activity as determined using phenylacetate (i.e., arylesterase or AREase) as a substrate, in depression, bipolar disorder, generalized anxiety disorder (GAD) and schizophrenia, especially in antipsychotic-free patients. PON1 activity as determined with paraoxon (i.e., POase activity) yields more controversial results, which can be explained by the lack of adjustment for the Q192R polymorphism. The few clinical trials investigating the influence of nutritional, lifestyle and drugs on PON1 activities in the general population suggest that some polyphenols, oleic acid, Mediterranean diet, no smoking, being physically active and statins may be effective strategies that increase PON1 activity. Conclusion: Lowered PON1 activities appear to be a key component in the ongoing NOS processes that accompany affective disorders, GAD and schizophrenia. Treatments increasing attenuated PON1 activity could possibly be new drug targets for treating these disorders.

Schizophrenia Phenomenology Comprises a Bifactorial General Severity and a Single-group Factor, Which Are Differently Associated with Neurotoxic Immune and Immune-regulatory Pathways

“…By inference, lowered natural IgM may be accompanied by a greater inflammatory potential and greater impact of gut commensal Gram-negative bacteria once they are translocated from the gut lumen through loosened gut barriers [20]. PON1 is an enzyme with strong antioxidant and anti-inflammatory properties [25] and lowered levels in schizophrenia are accompanied by increased immune responses [53,44]. Moreover, PON1 has quorum quenching properties thereby attenuating quorum sensing of Gram-negative bacteria (including P. aeruginosa) through the enzymatic impact on Nacyl homoserine lactones [55,56].…”

“…All in all, increased products of activated M1, Th-1, Th-2 and Th-17 cells may impact OSOS through neurotoxic effects exerted by increased levels of cytokines/chemokines such as CCL-11, CCL-2, IL-1β, IL-6, TNF-α, IL-4 and IL-13 [14], and neurotoxic TRYCATs such as PA, XA and 3HK [16]. Moreover, lowered innate immune protection against Gram-negative bacteria and inflammatory processes through lowered natural IgM [18] and PON1 activity [25,53,54] together with upregulated gut paracellular pathways [17,19] may explain the greater impact of gut commensal bacteria on the SGF. Furthermore, as explained previously, increased production of some neurotoxic products in schizophrenia (including CCL-11 and neurotoxic TRYCATs) may be associated with damage to the tight junctions of the BBB [17] thereby allowing the entrance of greater amounts of neurotoxic substances into the brain [17].…”

“…These IgM antibodies are produced by innate-like B1 and marginal zone B cells and have immune-regulatory, housekeeping, and anti-oxidant properties thereby protecting against an overzealous IRS and bacterial infections [21,22,23,24]. Finally, deficit schizophrenia is also accompanied by lowered activity levels of paraoxonase 1 (PON1) [Matsumoto et al, in preparation], a detoxifying and antioxidant enzyme that is strongly associated with high-density lipoproteins (HDLs) [25]. Interestingly, lowered natural IgM and PON1 activity are highly significantly associated with negative symptoms, but not with psychosis, hostility or mannerism [18,Matsumoto et al,in preparation).…”

Early Life Trauma Predicts Affective Phenomenology and the Effects are Partly Mediated by Staging Coupled with Lowered Lipid-Associated Antioxidant Defences

“…Recently, we have reviewed different strategies which may enhance PON1 activity, including administration of polyphenols, vitamin E/C and oleic acid, while also a Mediterranean diet and physical exercise and statins and fibrates may enhance PON1 activity [105]. Future research should (a) discover new treatments targeting PON1 binding to HDL to improve protection against activated neuro-oxidative and neuro-immune pathways and to remove consequent oxidative injuries from the body; and (b) examine the association between staging and antioxidant defences in prospective studies as well as the effects of ELT on these factors.…”

In Schizophrenia, PON1 Q192R Genotypes and/or Lowered Paraoxonase 1 (PON1) Enzymatic Activity are Significantly Associated with the Deficit Syndrome, Negative Symptoms, Formal Thought Disorders, Psychomotor Retardation, Excitation and Increased IgA Levels to Gram-Negative Microbiota

“…Moreover, activated O&NS pathways may affect signal transduction, structural plasticity and cellular resilience and, therefore, may be associated with neuroprogressive disorders including SCZ Brinholi et al, 2015). High density lipoprotein (HDL) is an important antioxidant and its protective role is attributed mainly to the enzyme paraoxonase 1 (PON1) that has antioxidant and anti-inflammatory activities (Moreira et al, 2018;. Genetic and epigenetic factors may cause significant differences among individuals in terms of PON1 levels and enzymatic activity.…”