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Objectives: Angiotensin I-converting enzyme (ACE) was initially correlated with schizophrenia (SCZ) in studies showing a correlation of ACE increased enzyme activity with memory impairments. Possible role for ACE in SCZ was also suggested by ACE activity interaction with dopaminergic mechanisms to modulate abnormalities of sensorimotor gating. In addition, we have demonstrated higher ACE activity in blood of SCZ subjects, its implication in cognitive performance in SCZ and its power as a predictor for SCZ diagnosis. Methods: ACE activity was determined in the serum and in selected brain regions of an animal model presenting SCZ-like behaviour, before and after the treatment with typical and atypical antipsychotics, and also in the serum of animals receiving the psychostimulants amphetamine/lisdexamphetamine. Results: Dopaminergic manipulations with antipsychotics and psychostimulants influenced the ACE activity, but with no correlation with the animal blood pressure. Conclusions: The validity of measuring ACE activity in animal blood to predict activity in the CNS, as well as the lack of correlation between the activity and blood pressure, before and after the treatment with antipsychotics, were confirmed here. Correlations of the present findings with data from clinical studies also strengthen the value of this animal model for studying several aspects of SCZ.

Background: Abnormal activity of two enzymes relevant to neurodevelopment, namely nuclear-distribution element-like 1 (Ndel1) and angiotensin I-converting enzyme (ACE), was reported in individuals with schizophrenia; to our knowledge, these oligopeptidases were never measured in bipolar disorder (BD)., Aims: Evaluate the enzyme activity of Ndel1 and ACE in euthymic individuals with BD type 1 which was compare to healthy control (HC) group., Methods: Ndel1 and ACE activities were assessed in the serum of individuals with BD type 1 according to DSM-IV criteria (n = 70) and a HC group (n = 34). The possible differences between BD type 1 and HC groups were evaluated using Analysis of Covariance (ANCOVA), and the results were adjusted for age, gender and body mass index., Results: We observed a positive correlation between Ndel1 activity and the total YMRS score in BD group (p = 0.030) and a positive correlation between ACE activity and Ham-D score (p = 0.047). ANCOVA analysis showed lower Ndel1 activity in BDs compared to HCs. Interestingly, we did not observe between-groups differences in ACE activity, despite the recognized correlation of ACE activity levels with cognitive functions, also described to be worsened in psychiatric patients., Conclusion: Oligopeptidases, especially Ndel1, which has been strongly correlated with neurodevelopment and brain formation, are potentially a good new target in the study of the neurobiology of BD., Limitations: The relatively small sample size did not permit to examine the cause-effect relationship of clinical dimensions of BD and the enzymatic activity., (Copyright © 2018. Published by Elsevier B.V.)

In schizophrenia (SCZ), higher angiotensin I-converting enzyme (ACE) levels have been reported in patient's blood and cerebrospinal fluid (CSF). Hereby, we propose to explore whether the ACE activity levels are associated to cognitive performance in SCZ. Seventy-two patients with SCZ or schizoaffective disorder diagnosis, and 69 healthy controls (HCs) underwent a cognitive battery with parallel collection of peripheral blood samples to measure ACE activity. Significant higher ACE activity levels were confirmed in the plasma of SCZ patients compared with HCs (Student's t=-5.216; P<0.001). ACE activity significantly correlated to Hopkins delayed recall measures (r=-0.247; P=0.004) and Hopkins total (r=-0.214; P=0.012). Subjects grouped as high ACE activity (above average) had worse performance compared with low ACE activity level group for Hopkins delayed recall measure, even after correction for clinical condition, age, gender and years of education (P=0.029). The adjusted R squared for this final model was 0.343. This result was evident only comparing extreme groups for ACE activity, when splitting the sample in three groups with similar number of subjects. To clarify this finding, we performed an evaluation of the cognitive performance of transgenic mice with three copies of ACE gene in novel object recognition (NOR) test, which showed that such animals presented impairment in NOR (P<0.05) compared with two copies of wild-type animals. The results observed in SCZ patients and animal model suggest both the association of ACE to cognitive deficits in SCZ. This finding may support the evaluation of novel treatment protocols and/or of innovative drugs for specific intervention of cognitive deficits in SCZ envisioning concomitant ACE activity and behavior evaluations., Competing Interests: AG received PhD fellowship from CAPES (Coordenação de Aperfeiçoamento de Pessoal de Nível Superior), while AMV was a recipient of a fellowship from CNPq. MAS and CMY are recipients of a fellowship from FAPESP (Fundação de Amparo à Pesquisa do Estado de São Paulo). VO, VA, RAB and MAFH are all supported by FAPESP, CAPES and CNPq. MAFH is also the recipient of a fellowship from CNPq (311815/2012-0). RAB has also received lecture fees from Astra Zeneca, Bristol, Janssen and Lundbeck, with research grants from private companies such as Janssen, Eli Lilly, Lundbeck, Novartis and Roche, and Fundação Safra and Fundação ABADS. RAB is also a shareholder of Radiopharmacus Ltda and Biomolecular Technology Ltda. The remaining authors declare no conflict of interest.

Previous studies of our group showed increased plasmatic Angiotensin-I Converting Enzyme (ACE) activity in schizophrenia (SCZ) patients compared to healthy controls, which was also associated to poor cognitive functioning. The ACE main product angiotensin II (Ang-II) has pro-inflammatory properties. Activated immune-inflammatory responses in SCZ and their association with disease progression and cognitive impairments are also well-described. Therefore, we examined here the association of plasma ACE activity and inflammatory mediators in 33 SCZ patients and 92 healthy controls. Non-parametric correlations were used to investigate the association of the enzyme activity and the peripheral levels of immune inflammatory markers as interleukins, tumor necrosis factor (TNF-α), and interferon (IFN-γ). Although no significant correlations could be observed for ACE activity and measured cytokines levels in healthy controls, a significant positive correlation for ACE enzymatic activity and IL-17a levels was observed in SCZ patients. Correcting for gender did not change these results. Moreover, a significant association for ACE activity and IFN-γ levels was also observed. To our knowledge, this is the first study to show a significant association between higher ACE activity and the levels of cytokines, namely IL-17a and IFN-γ, in patients with SCZ., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

Background: Angiotensin-I converting enzyme (ACE) is a key component of the renin-angiotensin system (RAS). Although the several contradictory data, ACE has been associated with schizophrenia (SCZ) pathophysiology. Here the ACE activity of SCZ patients and healthy controls (HCs), and its possible correlations with the ACE polymorphism genotype and symptomatic dimensions, was investigated., Methodology: ACE activity of 86 SCZ patients and 100 HCs paired by age, gender and educational level was measured, using the FRET peptide substrate and the specific inhibitor lisinopril. The ACE insertion/deletion (I/D) genotypes were assessed by the restriction fragment length polymorphism (RFLP) technique., Results: Significantly higher ACE activity was observed in SCZ patients compared to HCs (t=-5.09; p<0.001). The area under the receiver operating characteristic (ROC) curve was 0.701. Mean ACE activity levels were higher for the D-allele carriers (F=5.570; p=0.005), but no significant difference was found among SCZ patients and HCs for genotypes frequencies (Chi-squared=2.08; df=2; p=0.35). Interestingly, we found that the difference between the measured ACE activity for each SCZ patient and the expected average mean value for each respective genotype group (for control subjects) was a better predictor of SCZ than the ACE dichotomized values (high/low) or ACE I/D., Conclusion: Our results suggest that higher levels of ACE activity are associated with SCZ with stronger impact when the genetic background of each individual is considered. This may explain the heterogeneity of the results on ACE previously reported., (Copyright © 2015 Elsevier B.V. All rights reserved.)