Conduritol B epoxide

Conduritol B epoxide is an irreversible covalently bound acid β-glucosidase (GCase) inhibitor. In Vitro: Treating N2a and Conduritol B epoxide-N2a cells with G6 gave GC reductions to 7% and 26% of untreated levels, respectively. G6 treated Conduritol B epoxide-N2a also has significantly decreased GS. Co-treatment of G6 and dantrolene of Conduritol B epoxide-N2a cells lead to a similar degree of GC and GS reduction as G6 alone, indicating a specific effect of G6 on inhibition of substrate accumulation, Conduritol B epoxide-N2a cells have higher calcium levels than in N2a cells without caffeine at baseline. Conduritol B epoxide-N2a cells show a significant increase in cytosolic calcium levels compared to N2a cells. Conduritol B epoxide-N2a cells show a significant reduction in OCR as evidenced by approximately 50% in all the parameters, including rate of ATP production, basal respiration, and maximal respiration, compared to N2a cells, indicating reduced mitochondrial function in this nGD cell model. In dantrolene-treated Conduritol B epoxide-N2a cells, levels of Ryr3 are increased to 76% of WT level^[1]. In Vivo: Conduritol B epoxide treatment of 4L, 9H, 9V and WT mice (100 mg/kg/day, i.p.) from postnatal day 5 to 11 does not induce α-synuclein aggregates. Long-term daily Conduritol B epoxide treatment of 4L mice (100 mg/kg/day of Conduritol B epoxide from postnatal day 15 for 24 or 36 doses) leads to hind limb paralysis and small amounts of α-synuclein accumulation in the olfactory bulb, brainstem, and PVP near D3V (dorsal 3rd ventricle)^[2].