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OBJECTIVE: Schizophrenia (SCZ) is a disabling disorder that continues to defy clinicians and researchers. We investigated the effects of sodium nitroprusside (sNP) in an animal model of SCZ and as an add-on therapy in patients and the relationship between treatment with sNP and activity of the nDel1 enzyme, whose involvement in the pathophysiology of the disorder has been suggested earlier. METHODS: Ndel1 activity was measured following sNP infusions in spontaneously hypertensive rats (SHR; 2.5 or 5.0 mg/kg) and in a double-blind trial with SCZ patients (0.5 µg/kg/min). RESULTS: Ndel1 activity was significantly reduced after sNP infusion in blood of SHR compared to controls, and in patients receiving sNP (t = 7.756, df = 97, p < 0.0001, dcohen = 1.44) compared to placebo. Reduced Ndel1 activity between baseline and the end of the infusion was only seen in patients after treatment with sNP. CONCLUSION: Our findings suggest that SCZ patients may benefit from adjunctive therapy with sNP and that the Ndel1 enzyme is a candidate biomarker of psychopathology in the disorder. Future research should look into the role of Ndel1 in SCZ and the potential effects of sNP and drugs with similar profiles of action in both animals and patients.

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Ndel1 oligopeptidase activity shows promise as a potential biomarker for diagnosing schizophrenia (SCZ) and monitoring early-stage pharmacotherapy. Ndel1 plays a pivotal role in critical aspects of brain development, such as neurite outgrowth, neuronal migration, and embryonic brain formation, making it particularly relevant to neurodevelopmental disorders like SCZ. Currently, the most specific inhibitor for Ndel1 is the polyclonal anti-Ndel1 antibody (NOAb), known for its high specificity and efficient anti-catalytic activity. NOAb has been vital in measuring Ndel1 activity in humans and animal models, enabling the prediction of pharmacological responses to antipsychotics in studies with patients and animals. To advance our understanding of in vivo Ndel1 function and develop drugs for mental disorders, identifying small chemical compounds capable of specifically inhibiting Ndel1 oligopeptidase is crucial, including within living cells. Due to challenges in obtaining Ndel1's three-dimensional structure and its promiscuous substrate recognition, we conducted a high-throughput screening (HTS) of 2,400 small molecules. Nine compounds with IC50-values ranging from 7 to 56 µM were identified as potent Ndel1 inhibitors. Notably, one compound showed similar efficacy to NOAb and inhibited Ndel1 within living cells, although its in vivo use may pose toxicity concerns. Despite this, all identified compounds hold promise as candidates for further refinement through rational drug design, aiming to enhance their inhibitory efficacy, specificity, stability, and biodistribution. Our ultimate goal is to develop druggable Ndel1 inhibitors that can improve the treatment and support the diagnosis of psychiatric disorders like SCZ.

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Maternal infections are among the main risk factors for cognitive impairments in the offspring. Zika virus (ZIKV) can be transmitted vertically, causing a set of heterogeneous birth defects, such as microcephaly, ventriculomegaly and corpus callosum dysgenesis. Nuclear distribution element like-1 (Ndel1) oligopeptidase controls crucial aspects of cerebral cortex development underlying cortical malformations. Here, we examine Ndel1 activity in an animal model for ZIKV infection, which was associated with deregulated corticogenesis. We observed here a reduction in Ndel1 activity in the forebrain associated with the congenital syndrome induced by ZIKV isolates, in an in utero and postnatal injections of different inoculum doses in mice models. In addition, we observed a strong correlation between Ndel1 activity and brain size of animals infected by ZIKV, suggesting the potential of this measure as a biomarker for microcephaly. More importantly, the increase of interferon (IFN)-beta signaling, which was used to rescue the ZIKV infection outcomes, also recovered Ndel1 activity to levels similar to those of uninfected healthy control mice, but with no influence on Ndel1 activity in uninfected healthy control animals. Taken together, we demonstrate for the first time here an association of corticogenesis impairments determined by ZIKV infection and the modulation of Ndel1 activity. Although further studies are still necessary to clarify the possible role(s) of Ndel1 activity in the molecular mechanism(s) underlying the congenital syndrome induced by ZIKV, we suggest here the potential of monitoring the Ndel1 activity to predict this pathological condition at early stages of embryos or offspring development, during while the currently employed methods are unable to detect impaired corticogenesis leading to microcephaly. Ndel1 activity may also be possibly used to follow up the positive response to the treatment, such as that employing the IFN-beta that is able to rescue the ZIKV-induced brain injury.

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Schizophrenia (SCZ) is a complex psychiatric disorder with severe impact on patient's livelihood. In the last years, the importance of neuropeptides in SCZ and other CNS disorders has been recognized, mainly due to their ability to modulate the signaling of classical monoaminergic neurotransmitters as dopamine. In addition, a class of enzymes coined as oligopeptidases are able to cleave several of these neuropeptides, and their potential implication in SCZ was also demonstrated. Interestingly, these enzymes are able to play roles as modulators of neuropeptidergic systems, and they were also implicated in neurogenesis, neurite outgrowth, neuron migration, and therefore, in neurodevelopment and brain formation. Altered activity of oligopeptidases in SCZ was described only more recently, suggesting their possible utility as biomarkers for mental disorders diagnosis or treatment response. We provide here an updated and comprehensive review on neuropeptides and oligopeptidases involved in mental disorders, aiming to attract the attention of physicians to the potential of targeting this system for improving the therapy and for understanding the neurobiology underlying mental disorders as SCZ.

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Our previous studies showed reduced Ndel1 enzyme activity in patients with chronic schizophrenia (SCZ), and only a subtle NDEL1 mRNA increases in antipsychotic-naïve first-episode psychosis (FEP) individuals compared to matched healthy controls (HC). Aiming to refine the evaluation of Ndel1 enzyme activity in early stages of psychosis, we compared 3 groups composed by (1) subjects at ultra-high-risk (UHR) for psychosis, (2) a cohort comprising antipsychotic-naïve FEP individuals (assessed in three moments, at baseline (FEP-0), and after 2 months (FEP-2 M) and one year (FEP-1Y) of treatment with risperidone), and (3) a HC group. There was no significant difference in Ndel1 enzyme activity between UHR and HC, but this activity was significantly lower in FEP compared to HC. Conversely, Ndel1 activity in HC groups was higher than in FEP even before (FEP-0) or after the treatment with risperidone (FEP-2 M and FEP-1Y), and with progressive decrease of Ndel1 activity and significant improvement of symptoms observed after this treatment. In addition, a positive correlation was observed for Ndel1 activity with clinical symptoms as assessed by PANSS, while a negative correlation was seen for GAF scores. Our results suggest that reductions in Ndel1 activity in FEP may be possibly related to responses to the illness, rather than to the pharmacological effects of antipsychotics, which might be acting essentially in the symptoms suppression. This hypothesis might be further evaluated in prospective long-term follow-up studies with a larger sample cohort.

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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.

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