Antipsychotic drugs increase N‐acetylaspartate and N‐acetylaspartylglutamate in SH‐SY5Y human neuroblastoma cells

Abstract

N‐Acetylaspartate (NAA) and N‐acetylaspartylglutamate (NAAG) are related neuronal metabolites associated with the diagnosis and treatment of schizophrenia. NAA is a valuable marker of neuronal viability in magnetic resonance spectroscopy, a technique which has consistently shown NAA levels to be modestly decreased in the brains of schizophrenia patients. However, there are conflicting reports on the changes in brain NAA levels after treatment with antipsychotic drugs, which exert their therapeutic effects in part by blocking dopamine D2 receptors. NAAG is reported to be an agonist of the metabotropic glutamate 2/3 receptor, which is linked to neurotransmitter release modulation, including glutamate release. Alterations in NAAG metabolism have been implicated in the development of schizophrenia possibly via dysregulation of glutamate neurotransmission. In the present study we have used high performance liquid chromatography to determine the effects of the antipsychotic drugs haloperidol and clozapine on NAA and NAAG levels in SH‐SY5Y human neuroblastoma cells, a model system used to test the responses of dopaminergic neurons in vitro. The results indicate that the antipsychotic drugs haloperidol and clozapine increase both NAA and NAAG levels in SH‐SY5Y cells in a dose and time dependant manner, providing evidence that NAA and NAAG metabolism in neurons is responsive to antipsychotic drug treatment.

Proton Magnetic Resonance Spectroscopy Changes After Antipsychotic Treatment

“…NAAG modulates the glutamatergic system through a presynaptic metabotropic glutamate receptor (mGluR2/3) [73][74][75] or NMDA receptors [76]. Arun et al (2008) found that antipsychotic drugs increased the NAA and NAAG levels in dopaminergic-like human neuroblastoma cells and hypothesized, that D2 blockade may modulate the NAAG and NAA expression. NAAG is also reported to reduce glutamate excitotoxicity via its mGluR2/3 receptor agonism.…”

“…On the other hand, changes in NAA may affect the glutamatergic system, via NAAG (N-acetylaspartylglutamate), which is believed to be formed biosynthetically from NAA and its concentration may be NAA-dependent [71] (Fig. 2).…”

Effects of N-Acetylaspartylglutamate (NAAG) Peptidase Inhibition on Release of Glutamate and Dopamine in Prefrontal Cortex and Nucleus Accumbens in Phencyclidine Model of Schizophrenia

“…Given the differences in their targets from those of the typical and atypical antipsychotic drugs, the discovery of the efficacy of group II mGluR agonists and NAAG peptidase inhibitors in these animal models of schizophrenia and in clinical trials using the agonists represents a potentially important breakthrough in antipsychotic drug design. Interestingly, it may turn out that current antipsychotic treatments may already achieve some of their effects via NAAG in as much as clozapine and haloperidol increase NAAG synthesis in a neuroblastoma cell line (23).…”

Metabolic Acetate Therapy for the Treatment of Traumatic Brain Injury

“…Brains were removed rapidly (within approximately 1 min) and the left injured hemispheres were isolated and homogenized immediately in ice-cold PBS (10% wt=vol) to be used for the estimation of NAA and ATP. NAA concentrations were determined using methods described earlier (Arun et al, 2008). Briefly, 50 ml of the 10% homogenate made above was mixed with 500 ml of 90% methanol in water, mixed vigorously, and centrifuged at 10,000g for 10 min at 48C.…”