Therapeutic effects of rapamycin on MPTP-induced Parkinsonism in mice

Neurochem Res. 2013 Jan;38(1):201-7. doi: 10.1007/s11064-012-0909-8. Epub 2012 Nov 2.

Abstract

In neurodegenerative disorders such as Parkinson's disease (PD), autophagy is implicated in the process of dopaminergic neuron cell death. The α-synuclein protein is a major component of Lewy bodies and Lewy neurites, and mutations in α-synuclein have been implicated in the etiology of familial PD. The current work investigates the mechanisms underlying the therapeutic effects of the autophagy-stimulating antibiotic rapamycin in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD. Male C57BL/6 mice were treated with intravenous rapamycin or saline control for 7 days following MPTP administration. Immunohistochemistry and western blotting were used to detect alterations in the expression of PD biomarkers, including tyrosine hydroxylase (TH), and the level of autophagy was evaluated by the detection of both microtubule-associated protein light chain 3 (LC3) and α-Synuclein cleavage. In addition, levels of monoamine neurotransmitters were measured in the striatum using high performance liquid chromatography (HPLC). Immunohistochemistry using antibodies against TH indicated that the number of dopaminergic neurons in the substantia nigra following MPTP treatment was significantly higher in rapamycin-treated mice compared with saline-treated controls (p < 0.01). Levels of TH expression in the striatum were similar between the groups. α-synuclein Immunoreactivity was significantly decreased in rapamycin-treated mice compared with controls (p < 0.01). Immunoreactivity for LC3, however, was significantly higher in the rapamycin-treated animals than controls (p < 0.01). The concentrations of both striatal dopamine, and the dopamine metabolite DOPAC, were significantly decreased in both MPTP-treated groups compared with untreated controls. The loss of DOPAC was less severe in rapamycin-treated mice compared with saline-treated mice (p < 0.01) following MPTP treatment. These results demonstrate that treatment with rapamycin is able to prevent the loss of TH-positive neurons and to ameliorate the loss of DOPAC following MPTP treatment, likely via activation of autophagy/lysosome pathways. Thus, further investigation into the effectiveness of rapamycin administration in the treatment of PD is warranted.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Anti-Bacterial Agents / therapeutic use*
  • Autophagy
  • Biogenic Monoamines / biosynthesis
  • Biomarkers / metabolism
  • Blotting, Western
  • Brain / pathology
  • Chromatography, High Pressure Liquid
  • Electrochemistry
  • Immunohistochemistry
  • MPTP Poisoning / drug therapy*
  • MPTP Poisoning / pathology
  • MPTP Poisoning / physiopathology
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Microscopy, Electron, Transmission
  • Microtubule-Associated Proteins / biosynthesis
  • Microtubule-Associated Proteins / genetics
  • Neostriatum / drug effects
  • Neostriatum / metabolism
  • Neurotransmitter Agents / metabolism
  • Parkinson Disease, Secondary / drug therapy*
  • Parkinson Disease, Secondary / pathology
  • Parkinson Disease, Secondary / physiopathology
  • Sirolimus / therapeutic use*
  • Tyrosine 3-Monooxygenase / biosynthesis
  • alpha-Synuclein / metabolism

Substances

  • Anti-Bacterial Agents
  • Biogenic Monoamines
  • Biomarkers
  • Map1lc3b protein, mouse
  • Microtubule-Associated Proteins
  • Neurotransmitter Agents
  • alpha-Synuclein
  • Tyrosine 3-Monooxygenase
  • Sirolimus