Pharmacokinetics, biodistribution and neuroprotective effects of thymoquinone-loaded nanostructured lipid carrier on high fat cholesterol diet induced Alzheimer's disease rat model
Alzheimer's disease (AD) is one of the ultimate forms of dementia in people 65 years of age and older, slowly growing out of slight forgetfulness to the requirement for comprehensive care. Globally, close to 36 million people suffer from Alzheimer's disease or related dementia. In Malay...
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| Format: | Thesis |
| Language: | English English |
| Published: |
2022
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| Subjects: | |
| Online Access: | http://psasir.upm.edu.my/id/eprint/113057/1/113057.pdf |
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| Summary: | Alzheimer's disease (AD) is one of the ultimate forms of dementia in people 65
years of age and older, slowly growing out of slight forgetfulness to the
requirement for comprehensive care. Globally, close to 36 million people suffer
from Alzheimer's disease or related dementia. In Malaysia, there are
approximately 50,000 people with AD. One of the traditional AD risks is
hypercholesterolemia. Hypercholesterolemia is commonly linked to oxidative
stress and lipid oxidation which play an important role in the development of AD.
Currently, there is still no viable cure for AD. Thus, the need for therapies that
offer neuroprotective properties is in demand. One of the promising approaches
is the use of the natural product. Thymoquinone (TQ), a bioactive compound
from Nigella sativa that exhibit antioxidant property, can protect the neuron cells
from degrading. Nevertheless, TQ has low solubility in blood and poor oral
bioavailability. Consequently, a nanostructured lipid carrier (NLC) has been
developed as a drug delivery vehicle to overcome the limitations of TQ (herein
referred to as TQ-NLC). This study aimed to determine the role of oral and
intravenous administration in pharmacokinetics and bioavailability of TQ-NLC as
well as the neuroprotective effects of TQ-NLC as a potential drug candidate for
the management of AD. The pharmacokinetics and biodistribution study of TQNLC
was carried out in healthy male Sprague Dawley rats via oral and
intravenous administration (100 and 25 mg/kg, respectively) using gamma ray
counter and gamma camera. In vivo study of neuroprotective effect of TQ-NLC
via oral administration (12.5, 25 and 50 mg/kg) includes Morris water maze test,
lipid profile level, neurodegenerative features, oxidative stress level and protein
expression analysis. Oral administration of TQ-NLC demonstrated improved
relative bioavailability compared with intravenous administration. The movement
of TQ-NLC through the intestinal lymphatic system is postulated to bypass the
first metabolism, thus, increasing the relative bioavailability. However, oral
administration is more slowly absorbed as the AUC0-∞ was 4.539 times lower
than intravenous administration. During the Morris water maze test, the animals
treated with 25 mg/kg of TQ-NLC showed an increase in the time spent at the
targeted quadrant and reduced total cholesterol compared to the negative
control (untreated) (p<0.05). In addition, the animals treated with 25 mg/kg of
TQ-NLC showed shorter escape latency in comparison to the negative control
(untreated), but it was not statistically significant. In addition, the animals treated
with 50 mg/kg of TQ-NLC showed a reduction in MDA level and protein carbonyl
compared to negative control (untreated). Protein analyses in the brain
hippocampus revealed reduction in levels of the Aβ, BACE1 and ApoE while
enhanced the Aβ clearance and degradation by increasing the level of IDE and
LRP1 in the brain. In conclusion, in vivo data demonstrated the beneficial effects
of TQ-NLC in ameliorating neurodegenerative changes particularly in AD
biomarkers through the effects on oxidative stress, Aβ production and
improvement in cognitive function. The finding therefore implicates the potential
application of TQ-NLC for management of neurodegenerative diseases
particularly AD. |
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