Abstract
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of genes required for dopamine synthesis, handling and reuptake and the expression of these genes is largely controlled by nuclear receptor related 1 (Nurr1). Nurr1 is also expressed in astrocytes and microglia where it functions to mitigate the release of proinflammatory cytokines and neurotoxic factors. Given that Parkinson’s disease (PD) pathogenesis has been linked to both loss of Nurr1 expression in the SNpc and inflammation, increasing levels of Nurr1 maybe a promising therapeutic strategy. In this study a novel Nurr1 agonist, SA00025, was tested for both its efficiency to induce the transcription of dopaminergic target genes in vivo and prevent dopaminergic neuron degeneration in an inflammation exacerbated 6-OHDA-lesion model of PD. SA00025 (30mg/kg p.o.) entered the brain and modulated the expression of the dopaminergic phenotype genes TH, VMAT, DAT, AADC and the GDNF receptor gene c-Ret in the SN of naive rats. Daily gavage treatment with SA00025 (30mg/kg) for 32 days also induced partial neuroprotection of dopaminergic neurons and fibers in rats administered a priming injection of polyinosinic-polycytidylic acid (poly(I:C) and subsequent injection of 6-OHDA. The neuroprotective effects of SA00025 in this dopamine neuron degeneration model were associated with changes in microglial morphology indicative of a resting state and a decrease in microglial specific IBA-1 staining intensity in the SNpc. Astrocyte specific GFAP staining intensity and IL-6 levels were also reduced. We conclude that Nurr1 agonist treatment causes neuroprotective and anti-inflammatory effects in an inflammation exacerbated 6-OHDA lesion model of PD.
Highlights
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of specific genes required for dopamine regulation and the expression of these genes is controlled by the nuclear receptor related 1 (Nurr1) protein [1,2,3]
SA00025 treatment significantly modulated the expression of Nurr1 and dopaminergic target genes from 1–48 hrs after oral administration for 7 days (F3,18 = 5.61, p
A normalization of Nurr1, tyrosine hydroxylase (TH) and vesicular monoamine transporter (VMAT) mRNA expression was observed at 4 hours post oral administration and an increase in c-Ret observed at 24 hrs (Fig. 1D)
Summary
Dopaminergic neurons in the substantia nigra pars compacta (SNpc) are characterized by the expression of specific genes required for dopamine regulation and the expression of these genes is controlled by the nuclear receptor related 1 (Nurr1) protein [1,2,3]. Nurr is required for the transcription of tyrosine hydroxylase (TH), vesicular monoamine transporter (VMAT), dopamine active transporter (DAT) and aromatic l-amino acid decarboxylase (AADC) and plays a fundamental role in both the differentiation of dopaminergic neurons in embryonic stages and the long-term maintenance of the dopaminergic phenotype throughout life [1,2,3]. The role of wild-type Nurr in the onset and progression of PD is not well established, there is a reduced expression in the SNpc with increased age [10], which is the major risk factor in the development of PD. Reduced Nurr expression is observed in PD patients compared to age matched controls [11,12]. Neurotrophic factors may act synergistically to promote dopaminergic neuron survival
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
