Novel fatty acid-binding protein 3 ligand inhibits dopaminergic neuronal death and improves motor and cognitive impairments in Parkinson's disease model mice.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
/ adverse effects
Animals
Antiparkinson Agents
/ administration & dosage
Blood-Brain Barrier
/ drug effects
Cell Death
/ drug effects
Cognitive Dysfunction
/ drug therapy
Disease Models, Animal
Dopaminergic Neurons
/ drug effects
Fatty Acid Binding Protein 3
/ metabolism
Levodopa
/ administration & dosage
Ligands
Male
Mice
Mice, Inbred C57BL
Motor Activity
/ drug effects
Neuroprotective Agents
/ administration & dosage
Parkinson Disease
/ drug therapy
Protein Aggregation, Pathological
/ drug therapy
alpha-Synuclein
/ metabolism
Cognitive function
FABP3
MPTP
Parkinson's disease
α-Synuclein
Journal
Pharmacology, biochemistry, and behavior
ISSN: 1873-5177
Titre abrégé: Pharmacol Biochem Behav
Pays: United States
ID NLM: 0367050
Informations de publication
Date de publication:
04 2020
04 2020
Historique:
received:
30
09
2019
revised:
22
02
2020
accepted:
28
02
2020
pubmed:
4
3
2020
medline:
8
1
2021
entrez:
4
3
2020
Statut:
ppublish
Résumé
The main symptom of Parkinson's disease (PD) is motor dysfunction and remarkably approximately 30-40% of PD patients exhibit cognitive impairments. Recently, we have developed MF8, a heart-type fatty acid-binding protein (FABP3)-specific ligand, which can inhibit α-synuclein (α-syn) oligomerization induced by arachidonic acid in FABP3 overexpressing neuro2A cells. The present study aimed to determine whether MF8 attenuates dopaminergic neuronal death and motor and cognitive impairments in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mice model. MF8 can penetrate the blood-brain barrier and its peak brain concentration (21.5 ± 2.1 nM) was achieved 6 h after the oral administration (1.0 mg/kg). We also compared its effects and pharmacological action with those of L-DOPA (3,4-dihydroxy-l-phenylalanine). PD model mice were developed by administering MPTP (25 mg/kg, i.p.) once a day for five consecutive days. Twenty-four hours after the final MPTP injection, mice were administered MF8 (0.3, 1.0 mg/kg, p.o.) or L-DOPA (25 mg/kg, i.p.) once a day for 28 consecutive days and subjected to behavioral and histochemical studies. MF8 (1.0 mg/kg, p.o.), but not L-DOPA, inhibited the dopaminergic neuronal death in the ventral tegmental area and the substantia nigra pars compacta region of the MPTP-treated mice. MF8 also improved both, motor and cognitive functions, while L-DOPA ameliorated only motor dysfunction. Taken together, our results showed that MF8 attenuated the MPTP-induced dopaminergic neuronal death associated with PD pathology. We present MF8 as a novel disease-modifying therapeutic molecule for PD, which acts via a mechanism different from that of L-DOPA.
Identifiants
pubmed: 32126223
pii: S0091-3057(19)30489-7
doi: 10.1016/j.pbb.2020.172891
pii:
doi:
Substances chimiques
Antiparkinson Agents
0
FABP3 protein, rat
0
Fatty Acid Binding Protein 3
0
Ligands
0
Neuroprotective Agents
0
alpha-Synuclein
0
Levodopa
46627O600J
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
9P21XSP91P
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
172891Informations de copyright
Copyright © 2020 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors have no conflicts of interest to declare.