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Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.

ABSTRACT: We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca(2+) levels in MC65 cells upon removal of tetracycline (TC). In this report, we examined the effects by a bivalent compound with a longer spacer (21MO) in MC65 cells. Our results demonstrated that 21MO suppressed the change of MMP, possibly via interaction with the mitochondrial complex I in MC65 cells. Interestingly, 21MO did not show any effects on the Ca(2+) level upon TC removal in MC65 cells. Our previous studies suggested that the mobilization of Ca(2+) in MC65 cells, upon withdraw of TC, originated from ER, so the results implicated that 21MO may preferentially interact with mitochondria in MC65 cells under the current experimental conditions. Collectively, the results suggest that bivalent compounds with varied spacer length and cell membrane anchor moiety may exhibit neuroprotective activities via different mechanisms of action.

SUBMITTER: Saathoff JM

PROVIDER: S-EPMC4831581 | biostudies-other | 2016 Mar

REPOSITORIES: biostudies-other

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Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.

Saathoff John M JM Liu Kai K Chojnacki Jeremy E JE He Liu L Chen Qun Q Lesnefsky Edward J EJ Zhang Shijun S

Molecules (Basel, Switzerland) 20160325 4

We have recently developed a bivalent strategy to provide novel compounds that potentially target multiple risk factors involved in the development of Alzheimer's disease (AD). Our previous studies employing a bivalent compound with a shorter spacer (17MN) implicated that this compound can localize into mitochondria and endoplasmic reticulum (ER), thus interfering with the change of mitochondria membrane potential (MMP) and Ca(2+) levels in MC65 cells upon removal of tetracycline (TC). In this r ...[more]

PMID: 27023508

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Project description:BackgroundAlzheimer's disease (AD) as a neurodegenerative disease occupies 3/5-4/5 cases among patients with dementia, yet its pathogenetic mechanism remains unclear. Geraniol, on the other hand, is a well-known extract from essential oils of aromatic plants and has been proven that it has outstanding neuroprotective effects as well as ameliorating influence in memory impairment. Therefore, the present study aims to elucidate the potential of geraniol against AD by network pharmacology-based approach combined with molecular modeling study.Materials and methodsFirstly, we evaluated the druggability of geraniol by ADME method. Then, we obtained the geraniol targets and AD-related targets from multiple open data sources. Afterward, we calculated the intersection through a Venn diagram to find common targets, and via Panther classification system to categorize them. In order to gain a macroscopic understanding of these common targets, we carried out GO terms and KEGG pathways enrichment analyses, according to which we constructed a compound-target-pathway-disease network. In addition, we built a preliminary PPI network which was further analyzed both functionally and topologically. Consequently, five hub targets were sorted out. Finally, we conducted molecular docking and molecular dynamic simulation to validate our findings.ResultsIn the present study, the pharmacological properties of geraniol were assessed according to ADME and Lipinski's rule, which demonstrate promising druggability. Then, from 10,972 AD-related targets and 33 geraniol targets, 29 common targets were identified, among which 38.1% of them are metabolite interconversion enzymes, 23.8% are protein modifying enzymes, 33.3% are transmembrane receptors, and the rest are transporters. Enrichment analyses hint that geraniol is involved in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction. We also built a preliminary PPI network to investigate the interplay between these targets and their extensive interactions. Then, by functionally clustering the preliminary PPI network, we gained a cluster of proteins which formed a subnetwork with score of 8.476, and 22 nodes. Its results of GO terms and KEGG pathways enrichment analyses once again suggests that geraniol actively participates in cholinergic synapse, serotonergic synapse, and neuroactive ligand-receptor interaction, which are believed to be strongly associated with AD pathogenesis. Besides, topological analyses of the preliminary PPI network helped find 5 hub targets (i.e., CHRM3, PRKCA, PRKCD, JAK1, JAK2). To verify their interaction with geraniol molecule, we conducted molecular docking, and found that CHRM3 possesses the highest affinity in binding, indicating that geraniol molecules are closely bound to each hub target, and CHRM3 may serve as a key target of geraniol against AD. It was then further confirmed by molecular dynamic simulation, the result of which supports our hypothesis.ConclusionThe present study shares a mechanistic insight of the potential of geraniol against AD, giving a reference to future experimental studies.

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Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.

Publications

Mechanistic Insight of Bivalent Compound 21MO as Potential Neuroprotectant for Alzheimer's Disease.

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