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. 2016 Sep 15;25(18):3975-3987.
doi: 10.1093/hmg/ddw238. Epub 2016 Jul 27.

Pridopidine activates neuroprotective pathways impaired in Huntington Disease

Michal Geva  1 , Rebecca Kusko  2 , Holly Soares  1 , Kevin D Fowler  2 , Tal Birnberg  1 , Steve Barash  1 , Avia Merenlender -Wagner  1 , Tania Fine  1 , Andrew Lysaght  2 , Brian Weiner  2 , Yoonjeong Cha  2 , Sarah Kolitz  2 , Fadi Towfic  2 , Aric Orbach  1 , Ralph Laufer  1 , Ben Zeskind  2 , Iris Grossman  1 , Michael R Hayden  3
Affiliations

Pridopidine activates neuroprotective pathways impaired in Huntington Disease

Michal Geva et al. Hum Mol Genet. .

Abstract

Pridopidine has demonstrated improvement in Huntington Disease (HD) motor symptoms as measured by secondary endpoints in clinical trials. Originally described as a dopamine stabilizer, this mechanism is insufficient to explain the clinical and preclinical effects of pridopidine. This study therefore explored pridopidine's potential mechanisms of action. The effect of pridopidine versus sham treatment on genome-wide expression profiling in the rat striatum was analysed and compared to the pathological expression profile in Q175 knock-in (Q175 KI) vs Q25 WT mouse models. A broad, unbiased pathway analysis was conducted, followed by testing the enrichment of relevant pathways. Pridopidine upregulated the BDNF pathway (P = 1.73E-10), and its effect on BDNF secretion was sigma 1 receptor (S1R) dependent. Many of the same genes were independently found to be downregulated in Q175 KI mice compared to WT (5.2e-7 < P < 0.04). In addition, pridopidine treatment upregulated the glucocorticoid receptor (GR) response, D1R-associated genes and the AKT/PI3K pathway (P = 1E-10, P = 0.001, P = 0.004, respectively). Pridopidine upregulates expression of BDNF, D1R, GR and AKT/PI3K pathways, known to promote neuronal plasticity and survival, as well as reported to demonstrate therapeutic benefit in HD animal models. Activation of S1R, necessary for its effect on the BDNF pathway, represents a core component of the mode of action of pridopidine. Since the newly identified pathways are downregulated in neurodegenerative diseases, including HD, these findings suggest that pridopidine may exert neuroprotective effects beyond its role in alleviating some symptoms of HD.

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Figures

Figure 1.
Figure 1.
BDNF pathway genes modulated in HD CAG KI mice compared to WT and oppositely regulated by pridopidine treatment in rats. Shown are six selected genes. qPCR was performed in the same samples as the microarray experiment, unless otherwise noted. KLF5: RNAseq (ENSMUSG00000005148) FC = -0.17 P = 3.41E-02 adj P = 7.23E-02; microarray (1368363_at) FC = 2.29 P = 1.06E-04 adj P = 9.32E-02; PCR P <  0.004 EGR2: RNAseq (ENSMUSG00000037868) FC = -2.09 P = 6.54E-07 adj P = 3.15E-05; microarray (1387306_a_at) FC = 2.26 P = 9.91E-06 adj P = 2.09E-02; PCR P <  0.001 HOMER1A: RNAseq (ENSMUSG00000007617) FC = -0.75 P = 9.41E-06 adj P = 2.46E-04; microarray (1370997_at) FC = 2.25 P = 7.70E-06 adj P = 2.00E-02; PCR (result is from Table 2 dose response study 60mg treatment) P <  0.001 ARC: RNAseq (ENSMUSG00000022602) FC = -0.90 P = 4.04E-05 adj P = 7.79E-04; microarray (1387068_at) FC = 1.38 P = 7.55E-03 adj P = 4.79E-01; PCR P <  0.0002 EGR1: RNAseq (ENSMUSG00000038418) FC = -0.93 P = 3.88E-06 adj P = 1.26E-04; microarray (1368321_at) FC = 1.35 P = 6.44E-05 adj P = 6.47E-02; PCR P <  0.0007 CDKN1A: RNAseq (ENSMUSG00000023067) FC = -0.53 P = 4.28E-03 adj P = 1.71E-02; microarray (1388674_at) FC = 1.29 P = 7.81E-03 adj P = 4.86E-01; PCR P <  0.02.
Figure 2.
Figure 2.
Effect of pridopidine treatment on BDNF release (pg/ml) as measured by in situ ELISA. Data is expressed in pg/ml (mean ± SEM; *P <  0.05; **P <  0.01; ***P <  0.001; one way ANOVA followed by Dunnett’s test). SA4503 (1µM) was used as positive control. NE100, sigma-1 receptor antagonist (1µM).
Figure 3.
Figure 3.
PI3K/AKT pathway genes modulated in HD CAG KI mice compared to WT and oppositely regulated by pridopidine treatment in rats. CDKN1A is also part of the PI3K/AKT pathway lading edge and is shown in Figure 1. PCR is of same samples as microarray. NR4A1: RNAseq (ENSMUSG00000023034) FC= -0.94 P = 8.06E-05, adj P = 1.36E-03; microarray (1386935_at) FC = 1.79 P = 1.18E-06, adj P = 4.25E-03; PCR P <  0.000001 PIK3R2: RNAseq (ENSMUSG00000031834) FC= -0.10 P = 1.40E-02 adj P = 3.25E-02; microarray (1370100_at) FC = 1.08 P = 2.57E-02 adj P = 6.30E-01; PCR not tested
Figure 4.
Figure 4.
D1R pathway genes modulated in HD CAG KI mice compared to WT and oppositely regulated by pridopidine treatment in rats. EGR1, EGR2, and KLF5 are also part of D1R leading edge and presented in Figure 1. REM2: RNAseq (ENSMUSG00000022176) FC = -0.55 P = 2.99E-07, adj P = 1.71E-05; microarray (1374035_at) FC: 1.58, P = 2.63E-02, adj P = 6.30E-01; PCR not tested PER1: RNAseq (ENSMUSG00000020893) FC = -0.67 P = 4.23E-06, adj P = 1.34E-04; microarray (1374855_at) FC: 1.31 P = 2.2E-05, adj P = 0.03; PCR not tested
Fig 5.
Fig 5.
GR pathway genes modulated in HD CAG KI mice compared to WT and oppositely regulated by pridopidine treatment in rats. pPCR was performed in the same samples as the microarray experiment. SGK1: RNAseq not significant; microarray (1367802_at) FC = 1.98 P = 2.28E-05 adj P = 2.95E-02; PCR P <  0.002 NFKBIA: RNAseq not significant; microarray (1389538_at) FC = 1.69 P = 7.40E-07 adj P = 3.84E-03; PCR P <  0.0004 DDIT4: RNAseq not significant; microarray (1368025_at) FC = 1.46 P = 1.01E-05 adj P = 2.09E-02; PCR P <  0.001 TIPARP: RNAseq (ENSMUSG00000034640) FC = -0.52 P = 4.66E-04 adj P = 5.58E-03; microarray (1374446_at) FC = 1.46 P = 2.90E-07 adj P = 2.16E-03; PCR not tested DUSP1: RNAseq (ENSMUSG00000024190) FC = -0.63 P = 8.71E-06 adj P = 2.31E-04 0.000231857; microarray (1368146_at) FC = 1.42 P = 1.98E-03 adj P = 3.09E-01; PCR P <  0.001 PDK4: RNAseq not significant; microarray (1369150_at) FC = 1.35 P = 1.63E-03 adj P = 2.86E-01; PCR P <  0.002
Figure 6.
Figure 6.
Impact of pridopidine treatment on BDNF signalling, AKT activation, and the glucocorticoid pathway.
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