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

Zhen      Zhang; Xuping      Li; Wen-jie      Xie; Houzhen      Tuo; Samuel      Hintermann; Joseph      Jankovic; Weidong      Le

doi:10.2174/187152712803581155

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.

Keywords: Lactacystin; Inflammation; Neuroprotection; Nurr1 gene activator; Parkinson’s disease; ubiquitin-proteasome system, Dopamine, Dopamine transporter, 4-dihydroxy-phenylacetic acid, RT-PCR,

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