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Protection of dopaminergic neurons by 5-lipoxygenase inhibitor
- Source :
- Neuropharmacology. 73:380-387
- Publication Year :
- 2013
- Publisher :
- Elsevier BV, 2013.
-
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 neuron-glia 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 [(3)H]-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.
- Subjects :
- Male
Indoles
Dopamine
5-Lipoxygenase-Activating Proteins
Substantia nigra
Striatum
Pharmacology
Leukotriene B4
Neuroprotection
Leukotriene D4
Mice
Cellular and Molecular Neuroscience
chemistry.chemical_compound
Mesencephalon
Dopaminergic Cell
Hydroxyeicosatetraenoic Acids
medicine
Animals
Humans
Arachidonate 5-Lipoxygenase
Cell Death
Dopaminergic Neurons
MPTP
Dopaminergic
Neurotoxicity
MPTP Poisoning
medicine.disease
Coculture Techniques
Corpus Striatum
Substantia Nigra
Neuroprotective Agents
nervous system
chemistry
5-Lipoxygenase-Activating Protein Inhibitors
Astrocytes
Neuroscience
medicine.drug
Subjects
Details
- ISSN :
- 00283908
- Volume :
- 73
- Database :
- OpenAIRE
- Journal :
- Neuropharmacology
- Accession number :
- edsair.doi.dedup.....2c24316b62649abbeaa2c7610f589ff1