Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease. / Pupyshev, Alexander B.; Tikhonova, Maria A.; Akopyan, Anna A. et al.
In: Pharmacology Biochemistry and Behavior, Vol. 177, 01.02.2019, p. 1-11.Research output: Contribution to journal › Article › peer-review
}
TY - JOUR
T1 - Therapeutic activation of autophagy by combined treatment with rapamycin and trehalose in a mouse MPTP-induced model of Parkinson's disease
AU - Pupyshev, Alexander B.
AU - Tikhonova, Maria A.
AU - Akopyan, Anna A.
AU - Tenditnik, Michael V.
AU - Dubrovina, Nina I.
AU - Korolenko, Tatyana A.
N1 - Copyright © 2018 Elsevier Inc. All rights reserved.
PY - 2019/2/1
Y1 - 2019/2/1
N2 - The neuroprotective effect of autophagy activation by rapamycin and trehalose was studied in a mouse model of Parkinson's disease (PD) induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both rapamycin (10 mg/kg/day, 7 days) and trehalose (2% in drinking water, 7 days) increased the expression of LC3-II (a marker of autophagy activation) in the frontal cortex and striatum of normal C57Bl/6J mice, with signs of an additive effect. Autophagy stimulation in the striatum was confirmed by a lysosomal osmotic test. In the model of MPTP-induced PD, the two drugs were applied starting from the 2nd day after subchronic daily MPTP administration (20 mg/kg/day, 4 days). A marked increase in LC3-II expression in the striatum was detected under the action of trehalose and in the S. nigra after combined treatment with rapamycin and trehalose. The drugs had a positive effect for recovery of dopaminergic neurons and neuroprotection after MPTP-induced PD-like injury. The therapeutic effect was proven by active restoration of tyrosine hydroxylase (TH) content in the striatum and S. nigra and by improved cognition measured by the passive avoidance learning task. The results revealed the additive effect of the combined treatment with rapamycin and trehalose on dopaminergic deficits (according to the levels of TH expression in the nigrostriatal system) but not on the behavioral performance in the mouse PD model. Thus, the autophagy activation through different pathways by the combination of rapamycin and trehalose reverses both neuronal dopaminergic and behavioral deficits in vivo and seems to be a promising therapy for PD-like pathology.
AB - The neuroprotective effect of autophagy activation by rapamycin and trehalose was studied in a mouse model of Parkinson's disease (PD) induced by neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Both rapamycin (10 mg/kg/day, 7 days) and trehalose (2% in drinking water, 7 days) increased the expression of LC3-II (a marker of autophagy activation) in the frontal cortex and striatum of normal C57Bl/6J mice, with signs of an additive effect. Autophagy stimulation in the striatum was confirmed by a lysosomal osmotic test. In the model of MPTP-induced PD, the two drugs were applied starting from the 2nd day after subchronic daily MPTP administration (20 mg/kg/day, 4 days). A marked increase in LC3-II expression in the striatum was detected under the action of trehalose and in the S. nigra after combined treatment with rapamycin and trehalose. The drugs had a positive effect for recovery of dopaminergic neurons and neuroprotection after MPTP-induced PD-like injury. The therapeutic effect was proven by active restoration of tyrosine hydroxylase (TH) content in the striatum and S. nigra and by improved cognition measured by the passive avoidance learning task. The results revealed the additive effect of the combined treatment with rapamycin and trehalose on dopaminergic deficits (according to the levels of TH expression in the nigrostriatal system) but not on the behavioral performance in the mouse PD model. Thus, the autophagy activation through different pathways by the combination of rapamycin and trehalose reverses both neuronal dopaminergic and behavioral deficits in vivo and seems to be a promising therapy for PD-like pathology.
KW - Autophagy
KW - Dopaminergic neurons
KW - LC3-II
KW - Mouse
KW - MPTP
KW - Neuroprotection
KW - Parkinson's disease
KW - Rapamycin
KW - S. nigra
KW - Striatum
KW - Trehalose
KW - Doparuinergic neurons
KW - ENHANCER
KW - NEURODEGENERATION
KW - FLUX
KW - ALPHA-SYNUCLEIN
KW - RAT MODEL
KW - MONITORING AUTOPHAGY
KW - AMYLOID-BETA
KW - DEFICITS
KW - ALZHEIMERS
KW - IN-VIVO MODELS
UR - http://www.scopus.com/inward/record.url?scp=85059352304&partnerID=8YFLogxK
U2 - 10.1016/j.pbb.2018.12.005
DO - 10.1016/j.pbb.2018.12.005
M3 - Article
C2 - 30582934
AN - SCOPUS:85059352304
VL - 177
SP - 1
EP - 11
JO - Pharmacology Biochemistry and Behavior
JF - Pharmacology Biochemistry and Behavior
SN - 0091-3057
ER -
ID: 18069276