Neuronopathic Gaucher disease is caused by mutations in GBA1 that encodes lysosomal acid β-glucosidase (GCase) that has glucosylceramide (GC) and its un-acylated form, glucosylsphingosine (GS) as substrates. Conduritol B epoxide (CBE) is an irreversible covalently bound GCase inhibitor. Differentiated N2a cells treated with CBE resulted in significant GC and GS accumulation in CBE-N2a cells, thereby creating a nGD model. CBE-N2a cells had higher calcium levels than in N2a cells without caffeine at baseline and higher cytosolic calcium levels compared to N2a cells. CBE-N2a cells showed a significant reduction in OCR (oxygen consumption rate) as evidenced by rate of ATP production, basal respiration and maximal respiration, compared to N2a cells, indicating reduced mitochondrial function in this nGD cell model[2]. In vivo, long-term daily CBE treatment (100 mg/kg) of 4L mice led to hind limb paralysis and small amounts of α-synuclein accumulation in the olfactory bulb and brainstem[3].
Conduritol B epoxide/环己烯四醇β环氧化物 细胞实验
Cell Line
Concentration
Treated Time
Description
References
recombinant human GBA (rGBA, Cerezyme)
4.28 μM
3 h
Evaluate the inhibitory effect of CBE on GBA, results showed IC50 of CBE for GBA was 4.28 μM
J Am Chem Soc. 2019 Mar 13;141(10):4214-4218
primary murine microglia
200 µM
48 h
To investigate the effects of GCase inhibition on microglial morphology and function, results showed CBE treatment altered microglial morphology and motility
Cells. 2023 Jan 17;12(3):343
Oli-neu cells
10 μM
3 days
To evaluate the impact of β-glucocerebrosidase inactivation on myelination, lysosomal degradation, and α-synuclein accumulation. Results showed that CBE treatment significantly reduced β-glucocerebrosidase activity, increased accumulation of GlcCer and HexSph, impaired lysosomal function, increased α-synuclein aggregation, and decreased levels of myelin-related proteins such as MAG and CNP.
Mol Neurodegener. 2024 Mar 7;19(1):22
Conduritol B epoxide/环己烯四醇β环氧化物 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
Mice
MyTrMaSt null mice
Intraperitoneal injection
25, 32, 37.5, or 100 mg/kg
Daily injection until the end of the experiment
To study the role of Conduritol B epoxide in a mouse model of neuronal forms of Gaucher disease, finding that the IFN signaling pathway is not related to mouse viability but attenuates neuroinflammation
J Neuroinflammation. 2020 Sep 7;17(1):265
Mice
Wild-type mice
Intraperitoneal injection
100 mg/kg
Once daily for 3 days
To study the effects of in vivo GCase inhibition on microglial function, results showed CBE treatment impaired the neuroprotective function of microglia
Cells. 2023 Jan 17;12(3):343
Mice
Wild-type and Tmem106b /C0//C0 mice
Intraperitoneal injection
50 mg/kg and 100 mg/kg
Once daily for 30 days (50 mg/kg) and 15 days (100 mg/kg)
To study the role of TMEM106B in the Gaucher disease model. TMEM106B depletion ameliorates neuronal degeneration and some behavioural abnormalities.
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