Anti-Parkinsonian Effects of Nurr1 Activator in Ubiquitin-Proteasome System Impairment Induced Animal Model of Parkinson’s Disease

Abstract

Nurr1 is a member of the nuclear receptor superfamily and is a potential susceptibility gene for Parkinson's disease (PD). Several lines of studies in vitro and in vivo reported that defects in the Nurr1 gene cause nigrostriatal neuronal deficiency as seen in PD. In the present study, we used a a synthetic low molecular weight Nurr1 activator which increases the transcription of Nurr1 to investigate whether it has anti-parkinsonian effects against nigrostriatal neuronal degeneration induced by proteasome inhibitor lactacystin. Adult C57BL/6 mice were treated orally with the Nurr1 activator and an inactive structural analog as a control at a dose of 10mg/kg per day, starting 3 days before microinjection of proteasome inhibitor lactacystin into the medial forebrain bundle and the treatment continued for a total of 4 weeks. Animal behavior tests, and pathological and biochemical examinations were performed to determine the anti-parkinsonian effects of the Nurr1 activator. We found that treatment with the Nurr1 activator significantly improved rotarod performance, attenuated dopamine neuron loss and nigrostriatal dopamine reduction, increased expression of Nurr1, dopamine transporter and vesicular monoamine transporter 2, and alleviated microglial activation in the substantia nigra of lactacystin-lesioned mice. These results suggest that the Nurr1 activator may become an innovative strategy for the treatment of PD.

Animal Models of Parkinson's Disease: A Gateway to Therapeutics?

“…Chronic use of SH1 in a UPS-impaired mouse model can significantly improve locomotion and coordination, attenuate nigro-striatal DA neuron loss and DA content reduction, increase DAT and VAMT2 levels, and alleviate microglial activation [60]. These results suggest that the Nurr1 activator may be able to modify the disease course of PD [60].…”

“…Inhibition of 26/ 20S proteasomal degradation by lactacystin, PSI, and MG-132 via microinjection in the nigro-striatal pathway of rodents can lead to the accumulation of α-synuclein in the SN neurons, and the rodent models display a progressive course and pathological changes reminiscent of PD [57,58]. In a lactacystin-injected mouse model, DA neurons degenerate preferentially in the SN, accompanied by apoptosis and ubiquitin, and/or α-synuclein-positive aggregates, and focal inflammation [59,60]. Thus, this model recapitulates several features of PD, rendering it suitable for the study of nigral DA neuron degeneration and for the investigation of potential anti-PD medications [59,60].…”

“…In a lactacystin-injected mouse model, DA neurons degenerate preferentially in the SN, accompanied by apoptosis and ubiquitin, and/or α-synuclein-positive aggregates, and focal inflammation [59,60]. Thus, this model recapitulates several features of PD, rendering it suitable for the study of nigral DA neuron degeneration and for the investigation of potential anti-PD medications [59,60].…”

“…All these observations led to the hypothesis that activating Nurr1 in degenerating DA neurons might delay or modify the disease progression [167]. A synthetic low molecular weight Nurr1 activator named SH1, which increases the transcription of Nurr1, has been tested in a lactacystin-induced nigro-striatal degeneration model in mice [60]. Chronic use of SH1 in a UPS-impaired mouse model can significantly improve locomotion and coordination, attenuate nigro-striatal DA neuron loss and DA content reduction, increase DAT and VAMT2 levels, and alleviate microglial activation [60].…”

“…A synthetic low molecular weight Nurr1 activator named SH1, which increases the transcription of Nurr1, has been tested in a lactacystin-induced nigro-striatal degeneration model in mice [60]. Chronic use of SH1 in a UPS-impaired mouse model can significantly improve locomotion and coordination, attenuate nigro-striatal DA neuron loss and DA content reduction, increase DAT and VAMT2 levels, and alleviate microglial activation [60]. These results suggest that the Nurr1 activator may be able to modify the disease course of PD [60].…”