Modulation of LOX and COX pathways via inhibition of amyloidogenesis contributes to mitoprotection against β-amyloid oligomer-induced toxicity in an animal model of Alzheimer's disease in rats.
Several lines of evidence indicate that beta amyloid (β-A) production, neurofibrillary tangles and neuroinflammation are interrelated in the pathogenesis of Alzheimer's disease (AD). AD is associated with enhanced β-A production and accumulation resulting in neuroinflammation probably via activation of lipoxygenase (LOX) and cyclooxygenase (COX) pathways. Therefore, the present study was designed to investigate the role of LOX and COX inhibitors (zafirlukast and valdecoxib) in amyloidogenesis in β-A1-42 oligomer induced experimental AD in rats. The behavioral activities were assessed using actophotometer, novel object recognition test (ORT), Morris water maze (MWM) followed by biochemical assessments, determination of proinflammatory cytokines and mediators (TNF-α, IL-1β and PGE2), β-A1-42 levels and histopathological analysis. ICV administration of β-A1-42 oligomer produced significant impairment in memory consolidation. In addition to this significant increase in mito-oxidative stress, neuroinflammatory markers, acetylcholinesterase (AChE) toxicity, β-A1-42 level, neuronal cell death and neuroinflammation are more profound in β-A1-42 oligomer treated AD rats. Administration of zafirlukast (15 and 30mg/kg), and valdecoxib (5 and 10mg/kg) significantly improved the behavioral performances and showed significant reversal of mito-oxidative damage declining the neuroinflammation in β-A1-42 oligomer treated rats. Furthermore, more profound effects were observed at the sub-therapeutic dose combination of zafirlukast (15mg/kg) and valdecoxib (5mg/kg). The results of the present study indicate that protective effects of zafirlukast and valdecoxib are achieved through the blockade of release of LOX and COX metabolites therefore, representing a new therapeutic target for treating AD and other neurodegenerative disorders.
Department of Pharmacology, ISF College of Pharmacy, Ghal kalan, Moga 142-001, Punjab, India.
Jaspreet
J
Kalra
Department of Pharmacology, ISF College of Pharmacy, Ghal kalan, Moga 142-001, Punjab, India.
Puneet
P
Kumar
Brain Degeneration and Therapeutics Group, Pharmaceutical & Life Sciences Community of Research, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia.
Abu Bakar Abdul
AB
Majeed
Department of Pharmacology, ISF College of Pharmacy, Ghal kalan, Moga 142-001, Punjab, India; Brain Degeneration and Therapeutics Group, Pharmaceutical & Life Sciences Community of Research, Universiti Teknologi MARA (UiTM), 40450 Shah Alam, Selangor Darul Ehsan, Malaysia. Electronic address: atishprakash@gmail.com.
Atish
A
Prakash
D000544:Alzheimer Disease / Q000139:chemically induced / Q000378:metabolism*; D000682:Amyloid / Q000096:biosynthesis*; D016229:Amyloid beta-Peptides / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D004195:Disease Models, Animal; D007211:Indoles; D007276:Injections, Intraventricular; D007555:Isoxazoles / Q000494:pharmacology; D008084:Lipoxygenase / Q000378:metabolism*; D008124:Locomotion / Q000187:drug effects; D008297:Male; D008568:Memory / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D018696:Neuroprotective Agents / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D010446:Peptide Fragments / Q000008:administration & dosage / Q000378:metabolism / Q000633:toxicity*; D048448:Phenylcarbamates; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D021641:Recognition, Psychology / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D014105:Tosyl Compounds / Q000494:pharmacology; D000096926:Benzenesulfonamides
D000682:Amyloid; D016229:Amyloid beta-Peptides; D007211:Indoles; D007555:Isoxazoles; D008084:Lipoxygenase; D018696:Neuroprotective Agents; D010446:Peptide Fragments; D048448:Phenylcarbamates; D011451:Prostaglandin-Endoperoxide Synthases; D013449:Sulfonamides; D014105:Tosyl Compounds; C075222:amyloid beta-protein (1-42); C406224:valdecoxib; D000096926:Benzenesulfonamides; C062735:zafirlukast
Amyloid; Mitochondria; Object recognition test; Valdecoxib; Zafirlukast