ABSTRACT
AIMS: The aim of the study is to evaluate the neuroprotective effects of olfactory ensheathing cells (OECs) with the overexpression of nuclear receptor-related factor 1 (Nurr1) and neurogenin 2 (Ngn2) in experimental models of Parkinson's disease (PD) and to elucidate the potential mechanism underlying the neuroprotective effects of OECs-Nurr1-Ngn2. MATERIALS AND METHODS: In vitro study, OECs-Nurr1-Ngn2 conditioned medium (CM) was added to MPP+-treated PC12 cells for 24h, and then the viability of PC12 cells, oxidative stress and apoptosis were detected. In vivo study, 48 male Sprague-Dawley (SD) rats were randomly divided into four groups. OECs/VMCs and OECs-Nurr1-Ngn2/VMCs groups were transplanted with 2×105 cells each of OECs or OECs-Nurr1-Ngn2 and VMCs into the right striatum one week after a unilateral 6-OHDA lesion. Control and PD groups were injected with 0.9% NaCl and 0.2% ascorbic acid into the same region. Rotational behavior was determined at 2, 4, 6 and 8weeks after injection or implantation in all groups. Neuronal differentiation markers, oxidative stress- and apoptosis-related indicators were detected at 8weeks post-grafting. KEY FINDINGS: OECs-Nurr1-Ngn2 increased the viability of PC12 cells, inhibited oxidative stress and apoptosis, and these effects could be reversed by pre-treatment of k252a, a TrkB receptor inhibitor. The behavioral deficits of PD rat were ameliorated by the transplantation of OECs-Nurr1-Ngn2/VMCs. SIGNIFICANCE: These results suggest that OECs-Nurr1-Ngn2 exhibits substantial neuroprotective, anti-oxidant, and anti-apoptotic effects against PD via the up-regulation of the neurotrophic factor-TrkB pathway.
Subject(s)
Basic Helix-Loop-Helix Transcription Factors/genetics , Nerve Tissue Proteins/genetics , Neuroglia/transplantation , Nuclear Receptor Subfamily 4, Group A, Member 2/genetics , Olfactory Bulb/cytology , Parkinson Disease/metabolism , Parkinson Disease/therapy , Transfection , Animals , Basic Helix-Loop-Helix Transcription Factors/therapeutic use , Cells, Cultured , Disease Models, Animal , Genetic Therapy/methods , Male , Nerve Tissue Proteins/therapeutic use , Neuroglia/metabolism , Neuroprotection , Nuclear Receptor Subfamily 4, Group A, Member 2/therapeutic use , PC12 Cells , Parkinson Disease/genetics , Parkinson Disease/pathology , Rats , Rats, Sprague-Dawley , Transfection/methods , Up-RegulationABSTRACT
Previous studies have documented that orphan nuclear receptor Nurr1 (also known as NR4A2) plays important roles in the midbrain dopamine (DA) neuron development, differentiation, and survival. Furthermore, it has been reported that the defects in Nurr1 are associated with Parkinson's disease (PD). Thus, Nurr1 might be a potential therapeutic target for PD. Emerging evidence from in vitro and in vivo studies has recently demonstrated that Nurr1-activating compounds and Nurr1 gene therapy are able not only to enhance DA neurotransmission but also to protect DA neurons from cell injury induced by environmental toxin or microglia-mediated neuroinflammation. Moreover, modulators that interact with Nurr1 or regulate its function, such as retinoid X receptor, cyclic AMP-responsive element-binding protein, glial cell line-derived neurotrophic factor, and Wnt/ß-catenin pathway, have the potential to enhance the effects of Nurr1-based therapies in PD. This review highlights the recent progress in preclinical studies of Nurr1-based therapies and discusses the outlook of this emerging therapy as a promising new generation of PD medication.
