Nobiletin prevents amyloid β1-40-induced cognitive impairment via inhibition of neuroinflammation and oxidative/nitrosative stress

Reihaneh Ghasemi-Tarie; Zahra Kiasalari; Marzieh Fakour; Maryam Khorasani; Sedigheh Keshtkar; Tourandokht Baluchnejadmojarad; Mehrdad Roghani

doi:10.1007/s11011-022-00949-y

Nobiletin prevents amyloid β_1-40-induced cognitive impairment via inhibition of neuroinflammation and oxidative/nitrosative stress

Metab Brain Dis. 2022 Jun;37(5):1337-1349. doi: 10.1007/s11011-022-00949-y. Epub 2022 Mar 16.

Authors

Reihaneh Ghasemi-Tarie¹, Zahra Kiasalari², Marzieh Fakour³, Maryam Khorasani¹, Sedigheh Keshtkar¹, Tourandokht Baluchnejadmojarad⁴, Mehrdad Roghani⁵

Affiliations

¹ Department of Physiology, School of Medicine, Shahed University, Tehran, Iran.
² Neurophysiology Research Center, Department of Physiology, Shahed University, Tehran, Iran.
³ Department of Physiology, School of Medicine, Shahed University, Tehran, Iran. ma.fakour@gmail.com.
⁴ Department of Physiology, School of Medicine, Iran University of Medical Sciences, Tehran, Iran.
⁵ Neurophysiology Research Center, Department of Physiology, Shahed University, Tehran, Iran. mroghani@shahed.ac.ir.

PMID: 35294678
DOI: 10.1007/s11011-022-00949-y

Abstract

Alzheimer's disease (AD) is presented as an age-related neurodegenerative disease with multiple cognitive deficits and amyloid β (Aβ) accumulation is the most important involved factor in its development. Nobiletin is a bioflavonoid isolated from citrus fruits peels with anti-inflammatory and anti-oxidative activity as well as anti-dementia property that has shown potency to ameliorate intracellular and extracellular Ab. The aim of the present study was to assess protective effect of nobiletin against Aβ_1-40-induced cognitive impairment as a consistent model of AD. After bilateral intrahippocampal (CA1 subfield) injection of Aβ_1-40, rats were treated with nobiletin (10 mg/kg/day; p.o.) from stereotaxic surgery day (day 0) till day + 7. Cognition function was evaluated in a battery of behavioral tasks at week 3 with final assessment of hippocampal oxidative stress and inflammation besides Nissl staining and 3-nitrotyrosine (3-NT) immunohistochemistry. Analysis of behavioral data showed notable and significant improvement of alternation in Y maze test, discrimination ratio in novel object recognition task, and step through latency in passive avoidance test in nobiletin-treated Aβ group. Additionally, nobiletin treatment was associated with lower hippocampal levels of MDA and ROS and partial reversal of SOD activity and also improvement of Nrf2 with no significant effect on GSH and catalase. Furthermore, nobiletin attenuated hippocampal neuroinflammation in Aβ group as shown by lower tissue levels of TLR4, NF-kB, and TNFa. Histochemical findings showed that nobiletin prevents CA1 neuronal loss in Nissl staining in addition to its alleviation of 3-nitrotyrosine (3-NT) immunoreactivity as a marker of nitrosative stress. Collectively, these findings indicated neuroprotective and anti-dementia potential of nobiletin that is partly attributed to its anti-oxidative, anti-nitrosative, and anti-inflammatory property associated with proper modulation of TLR4/NF-kB/Nrf2 pathways.

Keywords: Alzheimer’s disease; Amyloid beta; Cognition; Neuroinflammation; Nobiletin; Oxidative-nitrosative stress.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Alzheimer Disease* / metabolism
Amyloid beta-Peptides / metabolism
Amyloid beta-Peptides / toxicity
Animals
Cognitive Dysfunction* / chemically induced
Cognitive Dysfunction* / drug therapy
Cognitive Dysfunction* / metabolism
Flavones
Hippocampus / metabolism
Maze Learning
NF-E2-Related Factor 2 / metabolism
NF-kappa B / metabolism
Neurodegenerative Diseases* / metabolism
Neuroinflammatory Diseases
Nitrosative Stress
Oxidative Stress
Peptide Fragments / pharmacology
Rats
Toll-Like Receptor 4 / metabolism

Substances

Amyloid beta-Peptides
Flavones
NF-E2-Related Factor 2
NF-kappa B
Peptide Fragments
Toll-Like Receptor 4
nobiletin