Abstract
Context: Alzheimer’s disease (AD) is the most common form of dementia affecting the aged population and neuroinflammation is one of the most observed AD pathologies. NF-κB is the central regulator of inflammation and inhibitor κB kinase (IKK) is the converging point in NF-κB activation. Celastrol is a natural triterpene used as a treatment for inflammatory conditions. Objective: This study determines the neuroprotective and inhibitory effect of celastrol on amyloid beta1-42 (Aβ1-42) induced cytotoxicity and IKKβ activity, respectively. Materials and methods: Retinoic acid differentiated IMR-32 cells were treated with celastrol (1 μM) before treatment with Aβ1-42 (IC30 10 μM) for 24 h. The cytotoxicity and IKK phosphorylation were measured by MTT and western blotting analysis, respectively. We screened 36 celastrol analogues for the IKKβ inhibition by molecular docking and evaluated their drug like properties to delineate the neuroprotective effects. Results: Celastrol (1 μM) inhibited Aβ1-42 (10 μM) induced IκBα phosphorylation and protected IMR-32 cells from cell death. Celastrol and 25 analogues showed strong binding affinity with IKKβ as evidenced by strong hydrogen-bonding interactions with critical active site residues. All the 25 analogues displayed strong anti-inflammatory properties but only 11 analogues showed drug-likeness. Collectively, molecule 15 has highest binding affinity, CNS activity and more drug likeness than parent compound celastrol. Discussion and conclusion: The decreased expression of pIκBα in celastrol pretreated cells affirms the functional representation of inhibited IKKβ activity in these cells. The neuroprotective potentials of celastrol and its analogues may be related to IKK inhibition.
Highlights
Alzheimer’s disease (AD) is the most common form of dementia affecting the elderly population
It has been agreed well that the inflammatory response in AD is complex with the role of microglia in the pathogenesis of AD
The burgeoning number of research on inflammation and AD has shown that the pro-inflammatory environment negatively affects the ability of microglial cells to involve in phagocytosis and subsequent retention of amyloid beta (Ab) oligomers within the cells (Fiala et al 2005; Zelcer et al 2007; Hickman et al 2008; Yamamoto et al 2008)
Summary
Alzheimer’s disease (AD) is the most common form of dementia affecting the elderly population. There is an urgent demand for the prevention or disease modifying therapies for AD Chronic neuroinflammation is another characteristic pathology of AD as evident by the presence of activated microglia and astrocytes around the neuritic plaques in addition to increased pro-inflammatory signalling (Vehmas et al 2003; Glass et al 2010; Zotova et al 2010). IjB is site phosphorylated by the IKK and targeted for proteasome degradation, NF-jB translocates into the nucleus and activates target genes Both IKKa and IKKb are able to phosphorylate IjB, IKKb has been shown to be predominant in canonical pathway activating NF-jb in response to Ab (Barger et al 1995; Barger & Mattson 1996). IKKb represents as an attractive target in the NF-jB pathway for the development of anti-inflammatory-based
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