tailieunhanh - Báo cáo sinh học: "Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies"

Tuyển tập báo cáo các nghiên cứu khoa học quốc tế ngành hóa học dành cho các bạn yêu hóa học tham khảo đề tài: Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies | Rojas et al. Journal of Translational Medicine 2011 9 27 http content 9 1 27 TRANSLATIONAL MEDICINE RESEARCH Open Access Glutamate carboxypeptidase activity in human skin biopsies as a pharmacodynamic marker for clinical studies 11 2 3 3 2 Camilo Rojas Marigo Stathis Michael Polydefkis Michelle A Rudek Ming Zhao Gigi J Ebenezer Barbara S Slusher1 2 Abstract Background Glutamate excitotoxicity is thought to be involved in the pathogenesis of neurodegenerative disease. One potential source of glutamate is N-acetyl-aspartyl-glutamate NAAG which is hydrolyzed to glutamate and N-acetyl-aspartate NAA in a reaction catalyzed by glutamate carboxypeptidase GCP . As a result GCP inhibition is thought to be beneficial for the treatment of neurodegenerative diseases where excess glutamate is presumed pathogenic. Both pharmacological and genetic inhibition of GCP has shown therapeutic utility in preclinical models and this has led to GCP inhibitors being pursued for the treatment of nervous system disorders in human clinical trials. Specifically GCP inhibitors are currently being developed for peripheral neuropathy and neuropathic pain. The purpose of this study was to develop a pharmacodynamic PD marker assay to use in clinical development. The PD marker will determine the effect of GCP inhibitors on GCP enzymatic activity in human skin as measure of inhibition in peripheral nerve and help predict drug doses required to elicit pharmacologic responses. Methods GCP activity was first characterized in both human skin and rat paw pads. GCP activity was then monitored in both rodent paw pads and sciatic nerve from the same animals following peripheral administration of various doses of GCP inhibitor. Significant differences among measurements were determined using two-tailed distribution equal variance student s t test. Results We describe for the first time a direct and quantifiable assay to evaluate GCP enzymatic activity in human skin biopsy .