Reduced paraoxonase 1 activities may explain the comorbidities between temporal lobe epilepsy and 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 1 (PON1) status may occur in TLE and these psychiatric conditions.

Aim: To examine PON1 status, namely Q192R PON1 genotypes and PON1 enzymatic activities, in TLE.

Methods: We recruited 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).

Results: Four-(chloromethyl)phenyl acetate hydrolysis (CMPAase) and arylesterase activities were significantly lower in TLE and mesial temporal sclerosis (MTS) with and without psychiatric comorbidities than those in normal controls. The areas under the receiver operating characteristic curve of CMPAase were 0.893 (0.037) for TLE and 0.895 (± 0.037) for MTS. Partial least squares 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 score.

Conclusion: The severity of TLE and comorbidities are to a large extent explained by reduced PON1 enzyme activities and by effects of the Q192R genotype, which are mediated by reduced 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.

Keywords: Affective disorders; Antioxidants; Major depression; Mood disorders; Neuroimmune; Oxidative stress.

Figure 1

Box plot of 4-(chloromethyl) phenyl acetate hydrolysis activity in controls (0), pure temporal lobe epilepsy (temporal lobe epilepsy: No comorbidities are present) and temporal lobe epilepsy with psychiatric comorbidities. TLE: Temporal lobe epilepsy; CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis.

Figure 2

The Brief Psychiatric Rating Scale score and total Hamilton Depression Rating Scale score on 4-(chloromethyl) phenyl acetate hydrolysis activity in 104 patients with temporal lobe epilepsy with and without comorbidities and 40 healthy controls. A: Inverse association between the Brief Psychiatric Rating Scale score and 4-(chloromethyl) phenyl acetate hydrolysis activity in 104 patients with temporal lobe epilepsy with and without comorbidities and 40 healthy controls; B: The partial regression of the total Hamilton Depression Rating Scale score on 4-(chloromethyl) phenyl acetate hydrolysis activity in 104 patients with temporal lobe epilepsy with and without comorbidities and 40 healthy controls. BPRS: Brief Psychiatric Rating Scale; CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis; HAM-D: Hamilton Depression Rating Scale.

Figure 3

Results of partial least squares path analysis with a latent vector extracted from three psychopathology dimensions as outcome variable and a latent vector extracted from temporal lobe epilepsy features, paraoxonase 1 activity and the Q19R paraoxonase 1 genotype (additive model) as input variables. Shown are path coefficient with P value (between brackets). Frequency: Seizure frequency; Aura: Aura present or not; Controlled: Seizure free and fairly and poorly controlled seizures; PI confusion: History of post-ictal confusion; BPRS: Brief Psychiatric Rating Scale; HAM-D/HAM-A: Hamilton Depression and Anxiety Rating Scale scores; TLE: Temporal lobe epilepsy; CMPAase: 4-(chloromethyl)phenyl acetate hydrolysis.