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. 2018 Aug 2:9:730.
doi: 10.3389/fphar.2018.00730. eCollection 2018.

In-Silico Characterization and in-Vivo Validation of Albiziasaponin-A, Iso-Orientin, and Salvadorin Using a Rat Model of Alzheimer's Disease

Mahmood Rasool  1 , Arif Malik  2 , Sulayman Waquar  2 , Qura Tul-Ain  2 , Tassadaq H Jafar  2 , Rabia Rasool  2 , Aasia Kalsoom  2 , Muhammad A Ghafoor  2 , Sheikh A Sehgal  3 , Kalamegam Gauthaman  1 , Muhammad I Naseer  1 , Mohammed H Al-Qahtani  1 , Peter N Pushparaj  1
Affiliations

In-Silico Characterization and in-Vivo Validation of Albiziasaponin-A, Iso-Orientin, and Salvadorin Using a Rat Model of Alzheimer's Disease

Mahmood Rasool et al. Front Pharmacol. .

Abstract

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia, excessive acetylcholinesterase (AChE) activity, formation of neurotoxic amyloid plaque, and tau protein aggregation. Based on literature survey, we have shortlisted three important target proteins (AChE, COX2, and MMP8) implicated in the pathogenesis of AD and 20 different phytocompounds for molecular docking experiments with these three target proteins. The 3D-structures of AChE, COX2, and MMP8 were predicted by homology modeling by MODELLER and the threading approach by using ITASSER. Structure evaluations were performed using ERRAT, Verify3D, and Rampage softwares. The results based on molecular docking studies confirmed that there were strong interactions of these phytocompounds with AChE, COX2, and MMP8. The top three compounds namely Albiziasaponin-A, Iso-Orientin, and Salvadorin showed least binding energy and highest binding affinity among all the scrutinized compounds. Post-docking analyses showed the following free energy change for Albiziasaponin-A, Salvadorin, and Iso-Orientin (-9.8 to -15.0 kcal/mol) as compared to FDA approved drugs (donepezil, galantamine, and rivastigmine) for AD (-6.6 to -8.2 Kcal/mol) and interact with similar amino acid residues (Pro-266, Asp-344, Trp-563, Pro-568, Tyr-103, Tyr-155, Trp-317, and Tyr-372) with the target proteins. Furthermore, we have investigated the antioxidant and anticholinesterase activity of these top three phytochemicals namely, Albiziasaponin-A, Iso-Orientin, and Salvadorin in colchicine induced rat model of AD. Sprague Dawley (SD) rat model of AD were developed using bilateral intracerebroventricular (ICV) injection of colchicine (15 μg/rat). After the induction of AD, the rats were subjected to treatment with phytochemicals individually or in combination for 3 weeks. The serum samples were further analyzed for biomarkers such as 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxynonenal (4-HNE), tumor necrosis factor-alpha (TNF-α), cyclooxygenase-2 (COX-2), matrix metalloproteinase-8 (MMP-8), isoprostanes-2 alpha (isoP-2α), and acetylcholine esterase (AChE) using conventional Enzyme Linked Immunosorbent Assay (ELISA) method. Additionally, the status of lipid peroxidation was estimated calorimetrically by measuring thiobarbituric acid reactive substances (TBARS). Here, we observed a statistically significant reduction (P < 0.05) in the oxidative stress and inflammatory markers in the treatment groups receiving mono and combinational therapies using Albiziasaponin-A, Iso-Orientin, and Salvadorin as compared to colchicine alone group. Besides, the ADMET profiles of these phytocompounds were very promising and, hence, these potential neuroprotective agents may further be taken for preclinical studies either as mono or combinational therapy for AD.

Keywords: Albiziasaponin A; Alzheimer's disease; acetylcholinesterase (AChE); in silico modeling; in vivo rat model; iso-orientin; molecular docking; salvadorin.

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Figures

Figure 1
Figure 1
2D chemical structures of selected three top-ranked phytocompounds (A), Albiziasaponin-A (B), Iso-Orientin and (C), Salavadorin.
Figure 2
Figure 2
The docked complexes of COX2 (light blue) and MMP2 (light green). Top-ranked 3 phytocompounds (A,B) Albiziasaponin-A (green), (C,D) Iso-orientin (magenta), and (E,F) Salvadorin (dark green).
Figure 3
Figure 3
The comparative docked complexes of AChE (khaki). Top-ranked 3 phytocompounds (A) Albiziasaponin-A (green), (C) Iso-orientin (magenta), (E) Salvadorin (dark green) and FDA approved drugs (B) donepezil (purple), (D) galantamine (blue) and (F) rivastigmine (dark red).
Figure 4
Figure 4
The mechanism of Alzheimer's disease (AD). It shows the role of Acetylcholine Esterase (AchE) and oxidative stress in the neurodegeneration. Oxidative stress and AchE up-regulates the activity of Amyloid precursor proteins (APPs). Moreover, oxidative stress is involved in the activation of several MMPs and enzymes cyclooxygenase-2 (COX-2). MMPs are directly responsible for the degradation of extracellular membrane (ECM) that leads to neurodegeneration. Under the action of enzyme β-secretase APPs gets converted into serum APPβ that later with the action of γ-secretase is converted into amyloid-β sheets. These amyloid-β sheets ultimately form amyloid β plaques. Alzheimer disease is often characterized with the presence of amyloid β plaques, neurofibrillary tangles, and hyperphosphorylated tau proteins. Tau proteins are hyperphosphorylated under the action of GSK3β which is activated by the activity of sAPPβ. Cumulatively, all of the discussed factors are involved in the neurodegeneration, which leads to the Alzheimer disease. Most of the drugs used in the following case are AchE inhibitors. They halt the AchE so, there will be enough neurotransmission present for the proper neuronal functioning. Likewise, in the current study, salvadorin, albiziasaponin and iso-orientin, significantly blocked the activity of AchE to cause neuroprotection.
Figure 5
Figure 5
Interactions of top ranked compounds against 3 targeted proteins (A,B) Albiziasaponin-A, (C,D) Iso-orientin, and (E,F) Salvadorin. Ligplot showed that Atoms of compounds and the interacting residues in the standard element colors respectively Iso-orientin and Salvadorin against AChE, Cox-2 and MMP8. The Ligplot did not show any Pi-Pi interactions of the selected compounds with the respective target proteins.
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