A Nurr1 Agonist Causes Neuroprotection in a Parkinson’s Disease Lesion Model Primed with the Toll-Like Receptor 3 dsRNA Inflammatory Stimulant Poly(I:C)

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.

Parkinson's disease, aging and adult neurogenesis: Wnt/β‐catenin signalling as the key to unlock the mystery of endogenous brain repair

“…Moreover, they further enhanced transrepression of neurotoxic proinflammatory gene expression in microglia (Kim et al, ). Of specific interest, pharmacological stimulation of Nurr1 causes both neuroprotection and anti‐inflammatory effects in the 6‐OHDA lesion model of PD (Kim et al, ; Smith et al, ). Additionally, these compounds significantly improved behavioral deficits in 6‐OHDA lesioned rat model of PD without any detectable signs of dyskinesia‐like behavior (Kim et al, ), underscoring the potential of small molecules targeting Nurr1 as neuroprotective strategy for PD (Kim et al, ).…”

“…Moreover, they further enhanced transrepression of neurotoxic proinflammatory gene expression in microglia (Kim et al, 2015). Of specific interest, pharmacological stimulation of Nurr1 causes both neuroprotection and anti-inflammatory effects in the 6-OHDA lesion model of PD (Kim et al, 2015;Smith et al, 2015). Additionally,…”

Nurr1‐Based Therapies for Parkinson's Disease

“…In addition, SA00025, another novel Nurr1 agonist (EC 50 : 2.5nM), shows a partial neuroprotective effect in PD models induced by inflammatory stimulant poly (I:C) and 6-hydroxydopamine (6-OHDA). It can modulate several DA target genes and display anti-inflammatory activity by reducing the activation of microglia and astrocytes [59]. …”

4-amino-7-chloroquinoline derivatives for treating Parkinson’s disease: implications for drug discovery

“…[25-31] In addition, SA00025, developed by Sanofi, showed a partial neuroprotective effect in a PD animal model induced by injection of poly(I:C) and 6-OHDA. [32] While these small molecules represent promising candidate drugs, none of them were shown to influence NR4A2 activity by directly binding to its LBD. In order to identify putative agonists that directly bind NR4A2's LBD and activate it, our laboratory established high-throughput assay systems and screened a chemical library composed of 960 FDA-approved drugs (MicroSource Discovery Systems, Inc., Gaylordsville, CT).…”