title: Neuroprotective Effects of Temsirolimus in Animal Models of Parkinson's Disease.
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.
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Siracusa
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Irene
authors.initials: I
authors.lastname: Paterniti
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Marika
authors.initials: M
authors.lastname: Cordaro
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Rosalia
authors.initials: R
authors.lastname: Crupi
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Bruschetta
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Campolo
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy.|Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, Saint Louis, MO, USA.
authors.forename: Salvatore
authors.initials: S
authors.lastname: Cuzzocrea
authors.affiliation: Department of Chemical, Biological, Pharmaceutical and Environmental Science, University of Messina, Viale Ferdinando Stagno D'Alcontres n, 31 98166, Messina, Italy. eesposito@unime.it.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Esposito
mesh_terms: D000818:Animals; D001343:Autophagy / Q000187:drug effects / Q000502:physiology; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism; D020267:MPTP Poisoning / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018696:Neuroprotective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D016896:Treatment Outcome
chemical_list: D018836:Inflammation Mediators; D018696:Neuroprotective Agents; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D020123:Sirolimus
keywords: Autophagy; Neurodegenerative disease; Neuroinflammation; Neuroprotection; Rapamycin