Tackling neuroinflammation and cholinergic deficit in Alzheimer's disease: Multi-target inhibitors of cholinesterases, cyclooxygenase-2 and 15-lipoxygenase.
The great interest of the researchers in this field is due to the importance of selective COX-2 inhibitors as a relatively safe and effective set of compounds which could present different properties such as antirheumatic, anti-inflammatory, antiplatelet, anti-Alzheimer's disease, anti-Parkinson's disease, and anticancer.
The in silico study displayed that puerarin had the potential to penetrate across the blood-brain barrier and had high stability in molecular docking and dynamics simulation with acetylcholinesterase (AChE), cyclooxygenase-2 (COX-2) and caspase-3 (C3), which play a central role in the development of AD.
The current review substantiates our understanding of the mechanisms of COX-2-induced AD and establishes foundations for the design of feasible therapeutic strategies to treat AD.-Guan, P.-P., Wang, P. Integrated communications between cyclooxygenase-2 and Alzheimer's disease.
Histopathologically, the alkaloidal fraction-treated 3xTg-AD mice exhibited a significant reduction in tauopathy and astrogliosis, as well as a significant decrease in the proinflammatory marker COX-2 and an increase in pAkt.
Subsequently, rescue experiments revealed that miR-125b induced neuron apoptosis, inhibited neurite outgrowth and promoted inflammation, also increased PTGS2 and CDK5 expressions but decreased FOXQ1 expression in lnc-MALAT1 overexpression treated AD models.
After transfection by PTGS2 and miR-103 mimic plasmid in PC12 cellular AD model, the total neurite growth was shortened compared with miR-103 mimic group, and cells apoptosis was enhanced which indicated PTGS2 mimic attenuated the influence of miR-103 mimic on progression of AD.
On the other hand, neuroinflammation and cyclooxygenase-2 (COX-2) enzyme have gained increased interest as key factors involved early in AD, although the signaling pathways and pathophysiologic mechanisms underlying a link between sAβ-induced neurotoxicity and inflammation are still unclear.
This cell-based litmus gene assay identified six genes (CCL20, CEMIP, IL1B, IL8, PRG2, PTGS2) as potential biomarkers of plasma quality control and the SPC25 gene as a diagnostic biomarker of Alzheimer's disease (AD).
It has been reported that inhibition of COX-2 beside traditional effects of NSAIDs, reduces the risk of colorectal, breast and lung cancers and also slow the progress of Alzheimer's disease.Zarghi et al. reported 8-benzoyl-2-(4-(methylsulfonyl)phenyl)quinoline-4-carboxylic acid (AZGH 102) as a novel compound with similar IC50 to celecoxib besides improved selectivity index (COX-1/COX-2 inhibitory potency) in comparison with celecoxib.
Importantly, mice already presented an overexpression of COX-2 at postnatal day 30, before neurodegeneration begins; which suggests that neuroinflammation may underlie the posterior neurodegeneration observed in individuals with Down syndrome and in Ts65Dn mice and could be a factor for the premature appearance of Alzheimer's disease.</i>.
As our sample size was limited, large-scale, well-designed studies are necessary to validate the association between the COX-2 765G>C polymorphism and AD.
In summary, our meta-analysis results showed that ABCA1 rs2422493 polymorphism was a risk factor for AD while PTGS2rs20417 variant showed a protective effect on AD risk.
A total of 7 case-control studies about COX-2rs20417 polymorphisms and AD risk, and 3 studies about COX-2rs689466 and AD risk were included in this meta-analysis.
Although the levels of COX-2 and its metabolic product prostaglandin (PG)E2 are elevated in the brain of AD patients, the mechanisms for the development of AD remain unknown.
This study shows that 24-hydroxycholesterol, 27-hydroxycholesterol, and 7β-hydroxycholesterol, the three oxysterols potentially implicated in AD pathogenesis, induce some pro-inflammatory mediator expression in human neuroblastoma SH-SY5Y cells, via Toll-like receptor-4/cyclooxygenase-2/membrane bound prostaglandin E synthase (TLR4/COX-2/mPGES-1); this clearly indicates that oxysterols may promote neuroinflammatory changes in AD.
Beta-adrenergic receptor blockade is also implicated in AD due to its effects on matrix metalloproteinases, mitogen-activated protein kinase pathways, prostaglandins, cyclooxygenase-2, and nitric oxide synthase.
This study suggested that -1195G/A polymorphism of the COX-2 gene is associated with the risk of AD, and the A allele represents a protective factor in patients with AD.
Polymorphism -765 G/C in COX-2-encoding gene promoter is associated with development of Alzheimer's disease, depression, carcinoma of the pancreas in smokers, breast cancer and rheumatoid arthritis.
As NSAIDs inhibit the enzymatic activity of the inflammatory cyclooxygenases COX-1 and COX-2, these findings suggest that downstream prostaglandin signaling pathways function in the preclinical development of AD.