Deubiquitinating enzymes (DUBs) function to remove covalently attached ubiquitin from proteins, thereby controlling substrate activity and/or abundance. The DUB ubiquitin carboxyl-terminal hydrolase L1 (UCH-L1) is a component of the ubiquitin proteasome system (UPS), it is abundantly expressed in neuronal brain cells and has been connected to Parkinson’s disease (PD)[3]. LDN-57444 is a specific inhibitor of UCH-L1 with IC50 value of 0.88 μM[4]. In vitro, LDH-57444 treatment significantly inhibited proteasome activity in a concentration-dependent manner at 25 μM and above, and treatment with 50 μM LDH-5744 for 24h led to 70% inhibition of the proteasome activity in human neuroblastoma SK-N-SH cells. LDN-57444 greatly reduced the cell viability and induced apoptosis of SK-N-SH cells at concentration ranging in 25 – 100 μM[5]. In vivo, LDN-57444 had an inhibitory effect on UCHL1 in the hippocampus at systemic doses of 0.5 mg/kg. Administration LDN-57444 at dose of 1 mg/kg for 4h significantly inhibited levels of free monomeric ubiquitin in mice. However, high dose LDN-57444 (2.5 mg/kg) increased UCHL1 expression, possibly as a compensatory mechanism. In addition, both 1 mg/kg and 2.5 mg/kg doses of LDN57444 depleted the hippocampus of postsynaptic density protein PSD95[4].
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