Neuroprotective Effects of Temsirolimus in Animal Models of Parkinson’s Disease

  • Rosalba Siracusa
  • Irene Paterniti
  • Marika Cordaro
  • Rosalia Crupi
  • Giuseppe Bruschetta
  • Michela Campolo
  • Salvatore Cuzzocrea
  • Emanuela Esposito
Article

Abstract

Parkinson’s disease (PD) is a disorder caused by degeneration of dopaminergic neurons. At the moment, there is no cure. Recent studies have shown that autophagy may have a protective function against the advance of a number of neurodegenerative diseases. Temsirolimus is an analogue of rapamycin that induces autophagy by inhibiting mammalian target of rapamycin complex 1. For this purpose, in the present study we investigated the neuroprotective effects of temsirolimus (5 mg/kg intraperitoneal) on 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced (MPTP) neurotoxicity in in vivo model of PD. At the end of the experiment, brain tissues were processed for histological, immunohistochemical, Western blot, and immunofluorescent analysis. Treatment with temsirolimus significantly ameliorated behavioral deficits, increased the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter, as well as decreased the upregulation of α-synuclein in the substantia nigra after MPTP induction. Furthermore, Western blot and immunohistochemistry analysis showed that temsirolimus administration significantly increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62, and microtubule-associated protein 1A/1B-light chain 3 expression and inhibited the p70S6K expression. In addition, we showed that temsirolimus has also anti-inflammatory properties as assessed by the significant inhibition of the expression of mitogen-activated protein kinases such as p-JNK, p-p38, and p-ERK, and the restored levels of neurotrophic factor expression such as BDNF and NT-3. On the basis of this evidence, we clearly demonstrate that temsirolimus is able to modulate both the autophagic process and the neuroinflammatory pathway involved in PD, actions which may underlie its neuroprotective effect.

Keywords

Neurodegenerative disease Autophagy Neuroinflammation Neuroprotection Rapamycin 

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Copyright information

© Springer Science+Business Media New York 2017

Authors and Affiliations

  • Rosalba Siracusa
    • 1
  • Irene Paterniti
    • 1
  • Marika Cordaro
    • 1
  • Rosalia Crupi
    • 1
  • Giuseppe Bruschetta
    • 1
  • Michela Campolo
    • 1
  • Salvatore Cuzzocrea
    • 1
    • 2
  • Emanuela Esposito
    • 1
  1. 1.Department of Chemical, Biological, Pharmaceutical and Environmental ScienceUniversity of MessinaMessinaItaly
  2. 2.Department of Pharmacological and Physiological ScienceSaint Louis University School of MedicineSaint LouisUSA

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