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The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease.

Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS - Sci Rep (2014)

Bottom Line: Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication.On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib.This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.

ABSTRACT
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.

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c-Abl inhibitor, nilotinib protects against MPTP-induced dopamine depletion.Nilotinib or vehicle administered mice were subjected to acute MPTP injections (20 mg/kg, MPTP free base X 4, every 2 h). Striatal dopamine (DA) and metabolites levels were analysed 7 days after the last MPTP injection by HPLC-ECD analysis. (a) Nilotinib rescues DA loss and (b) DOPAC in the striatum of MPTP mice. (c) Striatal levels of HVA and (d) 3MT were restored in mice treated with nilotinib. (e) There is a significant decrease in DA turnover [(DOPAC+HVA/DA) and (f) (DOPAC+3MT/DA)] in the striatum of nilotinib treated mice. Error bars represent the mean ± SEM, n = 5 mice per group. Two-way ANOVA was used to test significant and followed with post-hoc Bonferroni test to compare with the multiple group. **p<0.0002, *** p<0.0001 for MPTP with compare control group, #p<0.05, ### p<0.001 for Nil+ MPTP compared MPTP group. (ns: not significant).
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f3: c-Abl inhibitor, nilotinib protects against MPTP-induced dopamine depletion.Nilotinib or vehicle administered mice were subjected to acute MPTP injections (20 mg/kg, MPTP free base X 4, every 2 h). Striatal dopamine (DA) and metabolites levels were analysed 7 days after the last MPTP injection by HPLC-ECD analysis. (a) Nilotinib rescues DA loss and (b) DOPAC in the striatum of MPTP mice. (c) Striatal levels of HVA and (d) 3MT were restored in mice treated with nilotinib. (e) There is a significant decrease in DA turnover [(DOPAC+HVA/DA) and (f) (DOPAC+3MT/DA)] in the striatum of nilotinib treated mice. Error bars represent the mean ± SEM, n = 5 mice per group. Two-way ANOVA was used to test significant and followed with post-hoc Bonferroni test to compare with the multiple group. **p<0.0002, *** p<0.0001 for MPTP with compare control group, #p<0.05, ### p<0.001 for Nil+ MPTP compared MPTP group. (ns: not significant).

Mentions: The levels of DA and its metabolites in the striatum were measured by employing reverse-phase HPLC-electrochemical detection (ECD) to determine whether nilotinib can prevent the MPTP-induced reductions in DA and its metabolites. MPTP induces a significant reduction in DA levels in MPTP injected mice (Fig. 3a). Oral administration of nilotinib rescues the MPTP-induced DA loss in the striatum compared to MPTP treated mice (Fig. 3a). MPTP also causes a significant reduction in 3,4-dihydroxyphenylacetic acid (DOPAC) (Fig. 3b), homovanillic acid (HVA) (Fig. 3c) and 3-methoxytyramine (3MT) (Fig. 3d). Notably, administration of nilotinib significantly restores the reductions in DOPAC in MPTP injected mice (Fig. 3b). To analyse whether the catabolism of DA is altered by nilotinib treatment, we assessed the DA turnover ratio. In the MPTP group, the DA turnover ratio is increased significantly, whereas these effects are significantly attenuated by nilotinib (Fig. 3e and f). Nilotinib alone has no effect on the levels of dopamine and its metabolites and turnover.


The c-Abl inhibitor, nilotinib, protects dopaminergic neurons in a preclinical animal model of Parkinson's disease.

Karuppagounder SS, Brahmachari S, Lee Y, Dawson VL, Dawson TM, Ko HS - Sci Rep (2014)

c-Abl inhibitor, nilotinib protects against MPTP-induced dopamine depletion.Nilotinib or vehicle administered mice were subjected to acute MPTP injections (20 mg/kg, MPTP free base X 4, every 2 h). Striatal dopamine (DA) and metabolites levels were analysed 7 days after the last MPTP injection by HPLC-ECD analysis. (a) Nilotinib rescues DA loss and (b) DOPAC in the striatum of MPTP mice. (c) Striatal levels of HVA and (d) 3MT were restored in mice treated with nilotinib. (e) There is a significant decrease in DA turnover [(DOPAC+HVA/DA) and (f) (DOPAC+3MT/DA)] in the striatum of nilotinib treated mice. Error bars represent the mean ± SEM, n = 5 mice per group. Two-way ANOVA was used to test significant and followed with post-hoc Bonferroni test to compare with the multiple group. **p<0.0002, *** p<0.0001 for MPTP with compare control group, #p<0.05, ### p<0.001 for Nil+ MPTP compared MPTP group. (ns: not significant).
© Copyright Policy - open-access
Related In: Results  -  Collection

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f3: c-Abl inhibitor, nilotinib protects against MPTP-induced dopamine depletion.Nilotinib or vehicle administered mice were subjected to acute MPTP injections (20 mg/kg, MPTP free base X 4, every 2 h). Striatal dopamine (DA) and metabolites levels were analysed 7 days after the last MPTP injection by HPLC-ECD analysis. (a) Nilotinib rescues DA loss and (b) DOPAC in the striatum of MPTP mice. (c) Striatal levels of HVA and (d) 3MT were restored in mice treated with nilotinib. (e) There is a significant decrease in DA turnover [(DOPAC+HVA/DA) and (f) (DOPAC+3MT/DA)] in the striatum of nilotinib treated mice. Error bars represent the mean ± SEM, n = 5 mice per group. Two-way ANOVA was used to test significant and followed with post-hoc Bonferroni test to compare with the multiple group. **p<0.0002, *** p<0.0001 for MPTP with compare control group, #p<0.05, ### p<0.001 for Nil+ MPTP compared MPTP group. (ns: not significant).
Mentions: The levels of DA and its metabolites in the striatum were measured by employing reverse-phase HPLC-electrochemical detection (ECD) to determine whether nilotinib can prevent the MPTP-induced reductions in DA and its metabolites. MPTP induces a significant reduction in DA levels in MPTP injected mice (Fig. 3a). Oral administration of nilotinib rescues the MPTP-induced DA loss in the striatum compared to MPTP treated mice (Fig. 3a). MPTP also causes a significant reduction in 3,4-dihydroxyphenylacetic acid (DOPAC) (Fig. 3b), homovanillic acid (HVA) (Fig. 3c) and 3-methoxytyramine (3MT) (Fig. 3d). Notably, administration of nilotinib significantly restores the reductions in DOPAC in MPTP injected mice (Fig. 3b). To analyse whether the catabolism of DA is altered by nilotinib treatment, we assessed the DA turnover ratio. In the MPTP group, the DA turnover ratio is increased significantly, whereas these effects are significantly attenuated by nilotinib (Fig. 3e and f). Nilotinib alone has no effect on the levels of dopamine and its metabolites and turnover.

Bottom Line: Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication.On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib.This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.

View Article: PubMed Central - PubMed

Affiliation: 1] Neuroregeneration and Stem Cell Programs, Institute for Cell Engineering, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [2] Department of Neurology, The Johns Hopkins University School of Medicine, Baltimore, MD 21205. USA [3] Adrienne Helis Malvin Medical Research Foundation, New Orleans, LA 70130-2685, USA.

ABSTRACT
c-Abl is activated in the brain of Parkinson's disease (PD) patients and in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-intoxicated mice where it inhibits parkin through tyrosine phosphorylation leading to the accumulation of parkin substrates, and neuronal cell death. In the present study, we evaluated the in vivo efficacy of nilotinib, a brain penetrant c-Abl inhibitor, in the acute MPTP-induced model of PD. Our results show that administration of nilotinib reduces c-Abl activation and the levels of the parkin substrate, PARIS, resulting in prevention of dopamine (DA) neuron loss and behavioral deficits following MPTP intoxication. On the other hand, we observe no reduction in the tyrosine phosphorylation of parkin and the parkin substrate, AIMP2 suggesting that the protective effect of nilotinib may, in part, be parkin-independent or to the pharmacodynamics properties of nilotinib. This study provides a strong rationale for testing other brain permeable c-Abl inhibitors as potential therapeutic agents for the treatment of PD.

Show MeSH
Related in: MedlinePlus