Yaacob, Wan Muhammad Hilmi Wan
(2020)
Elucidating the mechanisms of lipopolysaccharide-induced cognitive impairment in rats treated with tualang honey and its methanolic extraction.
Masters thesis, Universiti Sains Malaysia.
Abstract
Alzheimer’s disease (AD) is a neurodegenerative disease characterized by
progressive loss of cognitive functions. The search for cognitive enhancers from
natural products derivative has gained much attention. As a natural antioxidant
source, Tualang honey (TH) produced by wild bees (Apis dorsata) is expected to
have a positive influence on human health, including cognitive function. Four types
of honey such as raw TH, irradiated TH, TH methanolic (MTH) and ethyl acetate
extract were tested in the preliminary study and it was found that MTH exhibited the
highest antioxidant potentials. Therefore, this study aimed to elucidate the
mechanism of TH and MTH on lipopolysaccharide (LPS)-induced cognitive
impairment in rats, and compare with memantine, one of the standard drugs used in
the management of AD. A total of 100 male Sprague Dawley rats were randomly
divided into 5 groups: (i) control, (ii) untreated LPS, (iii) LPS treated with 200
mg/kg TH, (iv) LPS treated with 150 mg/kg MTH and (v) LPS treated with 10 mg/kg
memantine. All treatments were administered intraperitoneally once daily for 14
days. LPS was injected into the rats at Day 4 of the treatments to create
neuroinflammatory responses that cause cognitive dysfunctions. Spatial and
recognition memory functions were assessed using Morris water maze (MWM) and
novel object recognition (NOR) tests. Twenty four hours after completing
behavioural tests, all rats were sacrificed and hippocampal tissues were removed.
Localization and expression of inflammatory markers in the hippocampal tissue were
determined by immunohistochemistry analysis and Western blot. The levels of
antioxidant enzymes, oxidative damage and amyloid deposition in rats’ hippocampal
homogenates were determined by commercially available ELISA kits. Nissl staining
of hippocampal slices was employed to determine neuronal count. The
administration of LPS to rats resulted in spatial and recognition memory impairment.
LPS also caused a significant increase in neuroinflammation as evidenced by the
increase in COX-2, iNOS and TNF-α expression in hippocampal tissues. There was a
marked reduction in the levels of antioxidant enzymes such as CAT, GPx, GR and
SOD with the concomitant increase in MDA level and amyloid deposition following
LPS administration. LPS also caused reduction in the number of Nissl positive
neurons in all hippocampal regions. TH and MTH treatments for 14 days
significantly improved spatial and recognition memory. Besides, TH and MTH were
able to reduce neuroinflammation, oxidative stress, amyloid deposition as well as
improve Nissl positive neuronal count in the hippocampus. The neuroprotective
effects of TH and MTH were found to be comparable with memantine. In
conclusion, this study showed that both TH and MTH could prevent LPS-induced
spatial and recognition memory impairment via its anti-inflammatory, antioxidant
and anti-amyloidogenic properties. Both TH and MTH have the potential to be used
as alternative therapy to protect against memory decline in AD patients.
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