台大心理系

N-methyl-D-aspartate receptor (NMDAR) is an essential glutamate receptor and be considered as a potential therapeutic target for neuropsychiatric disorders, including schizophrenia and multiple system atrophy (MSA). Schizophrenia is a devastating mental disorder with positive, negative, and cognitive symptoms. Accumulating evidence suggested that NMDAR hypofunction contributes to the pathogenesis of schizophrenia. On the other hand, MSA is a fatal and rapidly progressive neurodegenerative disease presenting autonomic dysfunction with atypical parkinsonism and cerebellar deficits. The accumulation of α-synuclein and promotion of NMDAR internalization are proposed as a potential hypothesis underlying the pathogenesis of MSA. Unfortunately, effective pharmacological treatments for negative and cognitive symptoms of schizophrenia and MSA are still unmet medical needs. Our research team developed a novel NMDAR modulator, RS-D7, with good safety profile. It is urgent to evaluate the therapeutic potentials of RS-D7 from preclinical models to patients. To investigate the efficacy of RS-D7, a series of preclinical experiments and proof-of-concept clinical trials were conducted. Taking advantage of enzymatic inhibition assay, RS-D7 is a potent D-amino acid oxidase inhibitor. Next, primary neurons study confirmed that RS-D7 significantly alleviated MK-801 (NMDAR antagonist) induced NMDAR dysfunctions. To further characterize efficacy of RS-D7, pharmacological and genetic mouse models were applied to mimic NMDAR hypofunction in schizophrenia and MSA. All schizophrenia-related and MSA-related behavioral deficits observed in these mouse models were significantly alleviated by the RS-D7 treatment. Furthermore, two open-label, proof-of-concept clinical trials were conducted at NTU Hospital in schizophrenia and MSA patients with RS-D7 prodrug (RS-D7pro). Schizophrenic patients treated with 8 weeks of RS-D7pro showed improvement in PANSS and SANS. Similarly, the ataxic scores were significantly improved 12 weeks after the RS-D7pro treatment in MSA patients. Collectively, these solid evidence and promising results supported the therapeutic potential of RS-D7 for the treatment of negative and cognitive symptoms in schizophrenia as well as MSA.