Temsirolimus promotes autophagic clearance of α-synuclein and provides protective effects in animal models of Parkinson's disease.

Parkinson's disease (PD) is a disorder resulted by degeneration of dopaminergic neurons. The most common symptoms of the disease are: resting tremor, rigidity, and hypokinesia, with onset asymmetrical. Now there is no cure. Recent studies have shown that autophagy may have a protective role against the development of a number of neurodegenerative diseases, including PD. The aim of the present study was to evaluate the effect of temsirolimus, an analog of rapamycin, on the neuroinflammation process and on the neuronal death associated with PD. In in vivo model of PD, mice received four injections of the dopaminergic neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine . Starting 24 h after the first administration of MPTP, we treated animals with temsirolimus (5 mg/kg intraperitoneal) daily for 7 days. On the 8th days, brains were processed for western blotting and immunohistochemical analysis. Treatment with temsirolimus significantly reduced the expression of specific markers of PD such as tyrosine hydroxylase, dopamine transporter and α-synuclein. Furthermore, western blot analysis and immunohistochemical staining showed that temsirolimus administration increased autophagy process. In fact, treatment with temsirolimus maintained high Beclin-1, p62 and microtubule-associated protein 1A/1B-light chain 3 expression and continued to inhibit the p70S6K expression. Moreover, 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, p38 and p-ERK. Base on these evidence we 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.