Alzheimer's disease (AD) is a devastating
neurodegenerative disorder without a cure. Hence, developing an effective treatment or
protective agent is crucial for public health. The present study aims to characterize orange peel extract (OPE) through in vitro and in silico studies. Furthermore, it examines the protective effect of OPE against experimentally-induced
Alzheimer's disease in rats. The total phenolic and
flavonoid content of OPE was 255.86 ± 1.77 and 52.06 ± 1.74 (mg/100 g), respectively.
Gallic acid, the common
polyphenol in OPE detected by HPLC was 3388.60 μg/100 g. OPE
antioxidant IC50 was 67.90 ± 1.05, 60.48 ± 0.91, and 63.70 ± 0.30 by DPPH,
ABTS and
Hydroxyl radical scavenging activity methods, respectively. In vitro anti-
acetylcholinesterase (AChE) IC50 was 0.87 ± 0.025 mg/mL for OPE and 2.45 ± 0.001 mg/mL for
gallic acid. Molecular docking analysis for human AChE (4EY7) with
donepezil,
gallic acid, and
acetylcholine showed binding energy ΔG values of -9.47, -3.72, and -5.69 Kcal/mol, respectively.
Aluminum chloride injection (70 mg/Kg/day for 6 weeks) induced Alzheimer's-like disease in male rats. OPE (100 and 200 mg/kg/d) and
gallic acid (50 mg/kg/d) were administered orally to experimental animals for 6 weeks in addition to
aluminum chloride injection (as protective). OPE was found to protect against
aluminum chloride-induced neuronal damage by decreasing both gene expression and activity of
acetylcholinesterase (AChE) and a decrease in
amyloid beta (Aβ42)
protein level,
thiobarbituric acid-reactive substances (
TBARS), and
nitric oxide (NO), and increased
reduced glutathione (GSH) level and activity of the
antioxidant enzymes in the brain tissues. Additionally, gene expressions for
amyloid precursor
protein (APP) and
beta secretase enzyme (BACE1) were downregulated, whereas those for presinilin-2 (PSEN2) and beta cell lymphoma-2 (BCL2) were upregulated. Furthermore, the reverse of mitochondrial alternation and restored brain ultrastructure might underlie neuronal dysfunction in AD. In conclusion, our exploration of the
neuroprotective effect of OPE in vivo reveals that OPE may be helpful in ameliorating brain oxidative stress, hence protecting from
Alzheimer's disease progression.