Lowered Paraoxonase 1 Activities May Explain the Comorbidities Between Temporal Lobe Epilepsy or Mesial Temporal Sclerosis and Comorbid Depression, Anxiety and Psychosis

Abstract

Background: Temporal lobe epilepsy (TLE) is the most common focal epilepsy subtype in adults and is frequently accompanied by depression, anxiety and psychosis. Aberrations in total paraoxonase (PON)1 status may occur in TLE and those psychiatric conditions. Methods: We examined paraoxonase (PON)1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in 40 normal controls and 104 TLE patients, 27 without comorbidities, and 77 with comorbidities including mood disorders (n=25), anxiety disorders (n=27) and psychosis (n=25). Outcomes: CMPAase and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than in normal controls. The areas under the ROC curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (±0.037) for MTS. Partial Least Squares (PLS) path analysis showed that there were specific indirect effects of PON1 genotype on TLE severity (p<0.0001) and psychopathology (p<0.0001), which were both mediated by lowered CMPAase activity, while arylesterase activity was not significant. The severity of TLE was significantly associated with psychopathology scores. Furthermore, PON1 CMPAase activity was inversely associated with Mini Mental State Examination scores. Interpretation: The severity of TLE and comorbidities are to a large extent explained by lowered PON1 enzyme activities and by effects of the Q192R genotype which are mediated by lowered CMPAase activity. Total PON1 status plays a key role in the pathophysiology of TLE, MTS and psychiatric comorbidities by increasing the risk of oxidative toxicity. PON1 enzyme activities are new drug targets in TLE to treat seizure frequency and psychiatric comorbidities.

A novel pathway phenotype of temporal lobe epilepsy and comorbid psychiatric disorders: results of precision nomothetic medicine

“…Both oxidative stress toxicity (OSTOX) and a deficiency in antioxidant (ANTIOX) defenses contribute to TLE [10-14]. In TLE, increased ROS production and lipid peroxidation, as well as hippocampal neurodegeneration and reconfiguration of neuronal networks with reactive gliosis contribute to epiloptogenesis and greater sensitivity to subsequent seizures [15].…”

“…In individuals with TLE, reduced levels of antioxidants including superoxide dismutase, paraoxonase 1 (PON1), catalase, glutathione peroxidase, vitamin E, total reactive antioxidant potential (TRAP), and sulfhydryl (-SH) groups may be observed [13,14;18;19]. Both lowered levels of -SH groups and PON1 activity are highly specific for TLE resulting in areas under the ROC curves of 0.899 and 0.893, respectively [13,14].…”

“…In individuals with TLE, reduced levels of antioxidants including superoxide dismutase, paraoxonase 1 (PON1), catalase, glutathione peroxidase, vitamin E, total reactive antioxidant potential (TRAP), and sulfhydryl (-SH) groups may be observed [13,14;18;19]. Both lowered levels of -SH groups and PON1 activity are highly specific for TLE resulting in areas under the ROC curves of 0.899 and 0.893, respectively [13,14]. A healthy antioxidant system is critical for preventing lipid peroxidation and protein oxidation, and situations linked with decreased PON1 activity, such as TLE, are associated with an increased risk of developing lipid peroxidation [13,14].…”

“…Both lowered levels of -SH groups and PON1 activity are highly specific for TLE resulting in areas under the ROC curves of 0.899 and 0.893, respectively [13,14]. A healthy antioxidant system is critical for preventing lipid peroxidation and protein oxidation, and situations linked with decreased PON1 activity, such as TLE, are associated with an increased risk of developing lipid peroxidation [13,14]. Moreover, PON1 enzymatic activity, which is partly determined by the PON1 Q192R genotype, mediates the effects of this genetic variant on the phenome of TLE [13,20].…”

“…There is now also evidence that major depression, anxiety disorders such as generalized anxiety disorder (GAD), and schizophrenia are characterized by activated nitro-oxidative stress pathways, including increased lipid peroxidation, as assessed with lipid hydroperoxides (LOOH), MDA, and protein oxidation (increased AOPP), and by lowered antioxidant defenses including lowered PON1 activity, and -SH, TRAP, and glutathione levels [20,21, 22, 23, 24]. Moreover, the depressive, anxiety, and psychotic symptoms due to TLE are strongly associated with the same oxidative stress biomarkers (MDA and AOPP) and antioxidant levels (PON1 activity, -SH groups ad TRAP) [13,14]. These results indicate that lower PON1 activity, which is affected in part by the Q192R genetic variant, and the ensuing damage due to oxidative stress contribute to the pathophysiology of TLE and the psychiatric comorbidities.…”