d-609 and Central-Nervous-System-Diseases

Tricyclodecan-9-yl-xanthogenate (D609) is known for its antiviral and antitumor properties. D609 actions are widely attributed to inhibiting phosphatidylcholine (PC)-specific phospholipase C (PC-PLC). D609 also inhibits sphingomyelin synthase (SMS). PC-PLC and/or SMS inhibition will affect lipid second messengers 1,2-diacylglycerol (DAG) and/or ceramide. Evidence indicates either PC-PLC and/or SMS inhibition affected the cell cycle and arrested proliferation, and stimulated differentiation in various in vitro and in vivo studies. Xanthogenate compounds are also potent antioxidants and D609 reduced Aß-induced toxicity, attributed to its antioxidant properties. Zn²⁺ is necessary for PC-PLC enzymatic activity; inhibition by D609 might be attributed to its Zn²⁺ chelation. D609 has also been proposed to inhibit acidic sphingomyelinase or down-regulate hypoxia inducible factor-1α; however these are down-stream events related to PC-PLC inhibition. Characterization of the mammalian PC-PLC is limited to inhibition of enzymatic activity (frequently measured using Amplex red assay with bacterial PC-PLC as a standard). The mammalian PC-PLC has not been cloned; sequenced and structural information is unavailable. D609 showed promise in cancer studies, reduced atherosclerotic plaques (inhibition of PC-PLC) and cerebral infarction after stroke (PC-PLC or SMS). D609 actions as an antagonist to pro-inflammatory cytokines have been attributed to PC-PLC. The purpose of this review is to comprehensively evaluate the literature and summarize the findings and relevance to cell cycle and CNS pathologies.

Topics: Animals; Antioxidants; Bridged-Ring Compounds; Cell Cycle; Central Nervous System Diseases; Humans; Norbornanes; Sphingomyelin Phosphodiesterase; Thiocarbamates; Thiones; Type C Phospholipases