Protein kinase A phosphorylation of the multifunctional protein CAD antagonizes activation by the MAP kinase cascade |
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Authors: | Damian H Kotsis Elizabeth M Masko Frederic D Sigoillot Roberto Di Gregorio Hedeel I Guy-Evans David R Evans |
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Institution: | (1) Bio-Organic and Neurochemistry Laboratory, Central Leather Research Institute, Adyar, Chennai, 600 020, Tamilnadu, India;(2) Department of Biochemistry, Sri Ramachandra Medical College and Research Institute (Deemed University), Chennai, 600 116, India;(3) National Institute of Ocean Technology, Chennai, 601 302, India;(4) Department of Biotechnology, Sri Ramachandra Medical College and Research Institute (Deemed University), Chennai, 600 116, India |
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Abstract: | Aβ vaccination as a therapeutic intervention of Alzheimer’s has many challenges, key among them is the regulation of inflammatory
processes concomitant with excessive generation of free radicals seen during such interventions. Here we report the beneficial
effects of melatonin on inflammation associated with Aβ vaccination in the central and peripheral nervous system of mice.
Mice were divided into three groups (n = 8 in each): control, inflammation (IA), and melatonin-treated (IAM). The brain, liver, and spleen samples were collected
after 5 days for quantitative assessment of plasma lipid peroxides (LPO), an oxidative stress marker, and antioxidant enzymes
such as superoxide dismutase (SOD), catalase (CAT), glutathione (GSH), and glutathione peroxidase (Gpx). IA group mice have
shown the elevated concentration of LPO significantly while there was a reduction at antioxidant enzyme levels. In addition,
a significant (P < 0.05) reduction in neurotransmitters like dopamine (DA), 5-hydroxytryptamine (5-HT), and norepinephrine (NE) was also observed
in the IA group mice. Nevertheless, their metabolites, such as homovanillic acid (HVA) and 5-hydroxyindole acetic acid (5-HIAA)
increased significantly (P < 0.05) as compared to control. Samples were further evaluated at microscopic level to examine the neuropathological changes
by immunohistochemical methods. Melatonin treatment effectively reversed these above changes and normalized the LPO and antioxidant
enzyme levels (P < 0.05). Furthermore, melatonin salvaged the brain cells from inflammation. Our Immunohistochemical findings in the samples
of melatonin-treated animals (IAM group) indicated diminished expression of glial fibrillary acidic protein (GFAP) and nuclear
factor kappa B (NfκB) than those observed in the IA group samples. Our results suggest that administration of melatonin protects
inflammation associated with Aβ vaccination, through its direct and indirect actions and it can be an effective adjuvant in
the development of vaccination in immunotherapy for Alzheimer’s disease (AD). |
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Keywords: | Aβ Amyloid Melatonin ROS Enzymatic and non-enzymatic antioxidants GFAP NFκ B Neurotransmitters |
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