Protection of dopaminergic neurons by 5-lipoxygenase inhibitor
Journal
Neuropharmacology
Journal Volume
73
Pages
380-387
Date Issued
2013
Author(s)
Abstract
Neuroinflammation and oxidative stress are important factors that induce neurodegeneration in age-related neurological disorders. 5-Lipoxygenase (5-LOX) is the enzyme responsible for catalysing the synthesis of leukotriene or 5-HETE from arachidonic acid. 5-LOX is expressed in the central nervous system and may cause neurodegenerative disease. In this study, we investigated the effect of the pharmacological inhibition of 5-lipoxygenase on 1-methyl-4-phenyl-1,2,3, 6-tetrahydropyridine (MPTP)/MPP+-induced dopaminergic neuronal death in midbrain neuroneglia co-cultures and in mice. It was found that 5-LOX was over-expressed in astrocytes after the injection of MPTP into C57BL6 mice. MK-886, a specific inhibitor of 5-LOX activating protein (FLAP), significantly increased [3H]-dopamine uptake, a functional indicator of the integrity of dopaminergic neurons, in midbrain cultures or the SH-SY5Y human dopaminergic cell line following MPP+ treatment. In addition, LTB4, one of 5-LOX's downstream products, was increased in the striatum and substantia nigra following MPTP injection in mice. LTB4 but not LTD4 and 5-HETE enhanced MPP+-induced neurotoxicity in primary midbrain cultures. MK-886 administration increased the number of tyrosine hydroxylase-positive neurons in the substantia nigra and the dopamine content in the striatum in MPTP-induced parkinsonian mice. Furthermore, the MPTP-induced upregulation of LTB4 in the striatum and substantia nigra was antagonised by MK-886. These results suggest that 5-LOX inhibitors may be developed as novel neuroprotective agents and LTB4 may play an important pathological role in Parkinson's disease. ? 2013 Elsevier Ltd. All rights reserved.
SDGs
Other Subjects
lipoxygenase inhibitor; animal experiment; animal model; article; astrocyte; brain region; cell survival; controlled study; corpus striatum; dopaminergic nerve cell; drug efficacy; drug mechanism; drug response; glia; human; human cell; mesencephalon; mouse; nerve cell necrosis; neuroprotection; neurotoxicity; nonhuman; Parkinson disease; priority journal; protein expression; substantia nigra; upregulation; 5-Lipoxygenase; FLAP; MK-886; Parkinson's disease; 5-Lipoxygenase-Activating Protein Inhibitors; 5-Lipoxygenase-Activating Proteins; Animals; Arachidonate 5-Lipoxygenase; Astrocytes; Cell Death; Coculture Techniques; Corpus Striatum; Dopamine; Dopaminergic Neurons; Humans; Hydroxyeicosatetraenoic Acids; Indoles; Leukotriene B4; Leukotriene D4; Male; Mesencephalon; Mice; MPTP Poisoning; Neuroprotective Agents; Substantia Nigra
Type
journal article