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.
Highlights
Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment
We have reported significant differences in NDEL1 enzyme activity between antipsychotic naïve first-episode psychosis (FEP) patients compared to healthy controls (HCs) after treatment with risperidone, with a progressive decrease in NDEL1 activity observed during 2 months and/or 1 year of treatment with risperidone, during which a significant improvement of symptoms was observed in all patients, with significant positive correlation observed between NDEL1 activity decrease and these symptoms amelioration, as assessed by P ANSS31
The mean values for NDEL1 enzyme activity in the serum of 5 months-old drug-naïve normotensive Wistar rats (NWR) and spontaneously hypertensive rats (SHRs) were determined as 4.2 ± 0.7 and 7.1 ± 1.3 nM/min, respectively, showing a significantly higher NDEL1 activity in the blood of untreated SHR compared to normotensive counterpart strain Wistar rats (NWRs) animals (Student’s t test (t = 3.09, df = 15, p = 0.014) (Supplemental Fig. 1)
Summary
Nuclear distribution element-like 1 (NDEL1) enzyme activity is important for neuritogenesis, neuronal migration, and neurodevelopment. 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. We have demonstrated that NDEL1 knockout C. elegans had an important imbalance in the serotonin pathway with significant deficits in their response to typical antipsychotic haloperidol compared to the atypical antipsychotic clozapine, reinforcing the impaired serotonin pathway with NDEL1 e xpression[24] Together, these lines of evidence supported evaluating the involvement of NDEL1 enzyme activity in SCZ. These studies implicate NDEL1 activity in SCZ and, necessitate the use of in vivo models to delineate the role of NDEL1 in the potential effects of these antipsychotics on NDEL1 enzyme activity
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