Evaluation of NDEL1 oligopeptidase activity in blood and brain in an animal model of schizophrenia: effects of psychostimulants and antipsychotics

Abstract

Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. We reported previously lower NDEL1 enzyme activity in blood of treated first episode psychosis and chronic schizophrenia (SCZ) compared to healthy control subjects, with even lower activity in treatment resistant chronic SCZ patients, implicating NDEL1 activity in SCZ. Herein, higher NDEL1 activity was observed in the blood and several brain regions of a validated animal model for SCZ at baseline. In addition, long-term treatment with typical or atypical antipsychotics, under conditions in which SCZ-like phenotypes were reported to be reversed in this animal model for SCZ, showed a significant NDEL1 activity reduction in blood and brain regions which is in line with clinical data. Importantly, these results support measuring NDEL1 enzyme activity in the peripheral blood to predict changes in NDEL1 activity in the CNS. Also, acute administration of psychostimulants, at levels reported to induce SCZ-like phenotype in normal rat strains, increased NDEL1 enzyme activity in blood. Therefore, alterations in NDEL1 activity after treatment with antipsychotics or psychostimulants may suggest a possible modulation of NDEL1 activity secondary to neurotransmission homeostasis and provide new insights into the role of NDEL1 in SCZ pathophysiology.

Decreased nuclear distribution nudE-like 1 enzyme activity in an animal model with dysfunctional disrupted-in-schizophrenia 1 signaling featuring aberrant neurodevelopment and amphetamine-supersensitivity

“…In this context, the measurements of the Ndel1 enzyme activity were demonstrated here and elsewhere to be a strong biomarker to assess the possible influence of these changes in the CNS and the response to dopamine manipulations with stimulants and/or antipsychotics (Nani et al, 2019a). Interestingly, Ndel1 activity was also increased in line with the increased locomotion behavior observed in tg DISC1 but not in WT animals, at least for the employed dose, confirming the supersensitivity of tg DISC1 rats to AMPH stimulation and possible Ndel1 enzyme activity modulation due to increased sensitivity to released dopamine, and with a consequent increase of Ndel1 activity.…”

“…The homogenates were prepared as previously described (Nani et al, 2019a). Protein concentration of these samples was determined by employing the Bradford method (Bradford Protein Assay, BioRad, California, USA), and bovine serum albumin for the control calibration curve preparation, and measurements were performed at 595 nm.…”

“…Ndel1 enzyme activity was measured essentially as previously described (Dal Mas et al, 2019; Nani et al, 2019a), employing the fluorescence resonance energy transfer (FRET) substrate (Abz-GFSPFRQ-EDDnp) measured in F-7000 fluorimeter (Hitachi Ltd.). The Ndel1 activity was calculated using the formula (arbitrary units of fluorescence (AUF): μM/min=AUF/s×60 and μM/min/mg=AUF/s×60/mg of total protein added to the reaction, for serum and tissue homogenates, respectively.…”

“…NT in the nucleus accumbens was shown to reverse dopamine supersensitivity evoked by antipsychotic treatment (Servonnet et al, 2017), and therefore confirming its close association with the dopamine system, which includes its dual role in the stimulant and antipsychotic responses (Cáceda et al, 2012; Chastain et al, 2015; Fawaz et al, 2009; Kinkead et al, 2005; Servonnet et al, 2017). In addition, NT can induce a persistent synaptic depression by decreasing dopamine release (Piccart et al, 2015), while conversely, the activity of Ndel1, which has the potential to inactivate NT and BK, seems to be augmented by increased dopamine release (Bradshaw and Hayashi, 2017; Hayashi et al, 2000; Nani et al, 2019a).…”

“…Analysis of the Ndel1 enzyme activity in the blood-brain axis of another animal model of SCZ, namely the spontaneously hypertensive rat (SHR), allowed us to show a good correlation of Ndel1 activity measurements in peripheral blood and several brain regions. Therefore, allowing us to confirm the validation of peripheral measurements of Ndel1 activity to infer changes in the central nervous system (CNS), at baseline, or after the administration of stimulants or after a long-term treatment with antipsychotics (Nani et al, 2019a). In addition, long-term treatment with antipsychotics under conditions that reversed the SCZ-like behaviors in this specific animal model for SCZ studies diminished the Ndel1 activity, but this was not observed in the control normal strain with no SCZ-like phenotype (Nani et al, 2019a).…”