A Novel Neuronal Cell Protecting Substance,Halxazone,Produced by Streptomyces halstedii.

The Journal of Antibiotics
2002.0

Abstract

Parkinson's disease (PD) is characterized by selective degeneration of dopaminergic neurons in the substantia nigra. Although the accurate etiology of PD is not clear, one of the hypothetical factors is oxidative stress. The excess administration of L-DOPA, which is an effective drug in PD therapy, results in the worsening of Parkinson's disease by generating reactive oxygen species (ROS). Thus, the advance of PD may be expected to be overcome by substances which suppress L-DOPA toxicity. In the course of our screening program for substances which protect rat pheochromocytoma PC12 cells from L-DOPA toxicity, we isolated a novel compound designated as halxazone (8-hydoroxymethyl-1-methoxy-3H phenoxazin-3-one) (1) from an actinomycete identified as Streptomyces halstedii 4029-SVS1. We report herein the isolation, structure elucidation, and biological activities of 1. The producing microorganism was cultivated, and the compound was extracted and purified via silica gel column chromatography, Toyopearl HW-40F, MPLC, and HPLC. Structure elucidation using IR, UV, HRFAB-MS, and NMR (1H, 13C, HMQC, HMBC) revealed the structure of 1. Biological activities showed that 1, michigazone (2), and 4-demethoxymichigazone (3) potentially protected PC12 cells from L-DOPA (50μM) toxicity with EC50 values of 15.4, 10.7, and 30.0nM, respectively. Additionally, 1 protected N18-RE-105 cells from L-glutamate toxicity with an EC50 value of 19.1nM, which was almost identical to that of 2. Since L-glutamate toxicity in N18-RE-105 cells is considered to be induced by the accumulation of ROS, 1 was deduced to protect PC12 cells from L-DOPA toxicity by exhibiting anti-ROS activity.

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