Objective: To examine the impact of Nurr1 agonists on regulation of striatal Nurr1 and levodopa (LD)-induced dyskinesias (LIDs) in a rat model of Parkinson’s disease (PD).

Background: A recent series of investigations have shown that ‘Nuclear receptor related 1 protein’ (Nurr1) agonist drugs or vector-mediated overexpression within nigral dopamine (DA) neurons can protect against alpha-synuclein and toxin induced death. These reports have sparked international enthusiasm that Nurr1 agonists may offer new promise for clinical neuroprotection. However, data from our labs and others demonstrate that dyskinogenic LD results in ectopic induction of striatal Nurr1, with levels correlating with LIDs severity. Whether systemic drugs that induce Nurr1 will exacerbate LIDs in parkinsonian subjects treated with LD remains unanswered.

Methods: We used the highly specific Nurr1 agonist amodiaquine (AQ) at the previously documented neuroprotective dose (20mg/kg; Kim et al., 2015). In Experiment 1 (Exp 1) intact rats received daily AQ or saline (Sal) for 28 days. In Exp 2, rats were lesioned with 6OHDA; 3 wks after lesion, rats received 1 day of AQ or Sal pretreatment prior to receiving a single acute injection of LD (12mg/kg, sc) +/- AQ on day of sacrifice. All rats were sacrificed 60-180 mins after final AQ; brains were processed for Nurr1 RNAscope® in situ hybridization.

Results: Exp 1: Densitometry revealed widespread upregulation of Nurr1 transcript in brain including dentate gyrus (p=0.014), VTA (p=0.021), CA1 (p=0.09), anterior cingulate (p=0.046); AQ vs Sal, N=4/group. However, in the absence of DA depletion or LD, AQ had no effect on striatal Nurr1. Exp 2: When rats were rendered parkinsonian, acute pretreatment with AQ and a single dose of LD resulted in a 22-fold induction of striatal Nurr1 compared to intact striatum; LD+Sal resulted in 9-fold induction (ANOVA p=0.0034, Intact vs LD+Sal vs LD+AQ; LD+Sal vs LD+AQ, p<0.05; N=4/grp). We are currently analyzing the impact of chronic LD +/- AQ on LIDs and motor behaviors.

Conclusions: The highly specific Nurr1 agonist AQ results in robust elevation of Nurr1 in multiple brain regions including striatum where it has been linked to induction of LIDs. Aberrant Nurr1 activation in striatum and regions associated with addiction and memory following systemic agonist treatment has the potential for significant off-target side-effects in PD patients.

References: Kim CH, Han BS, Moon J, Kim DJ, Shin J, Rajan S, Nguyen QT, Sohn M, Kim WG, Han M, Jeong I, Kim KS, Lee EH, Tu Y, Naffin-Olivos JL, Park CH, Ringe D, Yoon HS, Petsko GA, Kim KS, Nuclear receptor Nurr1 agonists enhance its dual functions and improve behavioral deficits in an animal model of Parkinson’s disease. Proc Natl Acad Sci U S A, 2015. 112(28): p. 8756-61.

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MDS Abstracts - https://www.mdsabstracts.org/abstract/off-target-implications-of-nurr1-agonist-therapy-in-parkinsons-disease/