Inhibition of transcription factor SP1 produces neuroprotective effects through decreasing MAO B activity in MPTP/MPP+ Parkinson's disease models. Issue 10 (13th July 2018)

• Record Type: Journal Article
• Authors: Yao, Lu; Dai, Xing; Sun, Yina; Wang, Yong; Yang, Qian; Chen, Xinlin; Liu, Yong; Zhang, Li; Xie, Wen; Liu, Jian
• Is Part Of: Journal of neuroscience research. Volume 96:Issue 10(2018)
• Page Start: 1663
• Page End: 1676
• Publication Date: 2018-07-13
• Subjects: monoamine oxidase B -- neuroprotection -- Parkinson's disease -- research resource identifiers -- specificity protein 1; Neurobiology -- Periodicals; 612
• DOI: 10.1002/jnr.24266
• Languages: English
• ISSNs: 0360-4012

Abstract

Abstract: Monoamine oxidase B (MAO B) inhibitors, which inhibit dopamine decomposition by antagonizing MAO B activity, are approved and widely used for clinical treatment of Parkinson's disease (PD). Nonetheless, the mechanism of the abnormally increased MAO B activity in PD is still unclear. Previous research showed transcription factor specificity protein 1 (SP1) directly regulates MAO B activity by binding the SP1 binding sequence in MAO B promoter. In our study, we first observed that the SP1 protein level and SP1 binding activity in the MAO B promoter were increased in 1‐methyl‐4‐phenylpyridinium (MPP + ) neurotoxin‐induced SH‐SY5Y cells. Inhibition of SP1 by pretreatment with SP1 inhibitor mithramycin A (MMA) attenuated the abnormal increase in SP1 binding activity and the MAO B protein level to basal levels. Then, we investigated the neuroprotective effects of SP1 inhibition. In SH‐SY5Y cell models of PD, preincubation with MMA or knockdown by SP1‐specific small interfering RNA showed potent protection against MPP + ‐induced apoptosis via SP1. In a male C57BL/6 mouse model of PD, MAO B activity and MPP + concentrations in mouse brain following injection of 1‐methyl‐4‐phenyl‐1, 2, 3, 6‐tetrahydropyridine (MPTP) were increased, whereas the elevated MAO B activity was decreased after pre‐injection of MMA. Moreover, MMA ameliorated MPTP‐induced loss of dopaminergic neurons in the substantia nigra pars compacta and mouse behavioral impairments. Altogether, our study suggests that SP1 is a principal factor regulating increases in MAO B activity, and SP1 inhibition produces neuroprotective effects in PD models through decreases in MAO B activity, which may be a new neuroprotective therapeutic strategy for PD treatment.