Therapeutic Effects of Rapamycin on MPTP-Induced Parkinsonism in Mice

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.

The Neuroprotective Effect and Probable Mechanism of <smlcap>DL</smlcap>-3-n-Butylphthalide in Brain Diseases

“…NBP can protect against MPP + -induced neurotoxicity via activation of an autophagic process [1,15]. This report strongly suggests that NBP promotes intracellular autophagic activity and subsequently enhances the degradation of α-synuclein.…”

“…Motor symptoms of PD are mainly due to the selective degeneration of substantia nigra dopaminergic neurons in the ventral midbrain, which results in a decrease in dopamine levels in the striatum [14]. α-Synuclein oligomers and aggregates play an important role in the pathogenesis and development process of PD [1,15]. Protein accumulations in cytoplasmic inclusions are called Lewy bodies.…”

“…Protein accumulations in cytoplasmic inclusions are called Lewy bodies. Our previous studies have shown that MPTP-induced oxidative stress promoted the oligomerization of α-synuclein that leads to the pathological aggregation of α-synuclein [15]. …”

Recent advances in autophagy-based neuroprotection

“…Decressac et al [78] showed that the US FDA-approved derivate of rapamycin, temsirolimus alleviated dopaminergic degeneration following AAV a-synuclein injection by inhibiting mTOR receptors and triggering a proautophagy response in Sprague-Dawley rats. Liu et al [79] reported that rapamycin increased dopaminergic neurons survival, decreased a-synuclein immunoreactivity, increased LC3 expression and ameliorated loss of 3,4-dihydroxyphenylacetic acid in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated mice. Beside activation of autophagy by inhibiting mTOR receptors, the effect of rapamycin was shown to be associated with the nuclear translocation of the transcriptional factor, TFEB.…”

SLC35D3 increases autophagic activity in midbrain dopaminergic neurons by enhancing BECN1-ATG14-PIK3C3 complex formation

“…Treatment with rapamycin is able to prevent the loss of TH (tyrosine hydroxylase)-positive neurons in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mouse model of PD likely via activation of the autophagic pathway. 6 It is likely that genes specifically expressed in DA neurons to regulate autophagy could be involved in protecting DA neuron loss.…”