Biological evaluation of synthetic α,β-unsaturated carbonyl based cyclohexanone derivatives as neuroprotective novel inhibitors of acetylcholinesterase, butyrylcholinesterase and amyloid-β aggregation
Graphical abstract
The pharmacological evaluation of compounds comprises BuChE and AChE inhibition, amyloid β-induced cytotoxicity in PC12 cells and effects on self-induced Aβ aggregation.
Introduction
Dementia is one of the main contributors to disability in older patients. Every health system in the world is being significantly affected by dementia, and resources and money are spent for the care of people suffering from this disease.1 The most common form of dementia is Alzheimer’s disease (AD), characterized by continuous loss of memory and other mental functions. AD usually takes a decade before it gets on course and causes the death of patients in a totally helpless state. The long period of AD causes huge financial and emotional burden on patients and their families.2
The damage to the cholinergic function is of main significance in AD as per ‘cholinergic hypothesis’, especially hippocampus and neocortex of the brain that deal with emotional responses, behaviour, memory and learning. The most evident clinical finding in AD is brain atrophy which is characterized by decreased levels of acetylcholine owing to its fast hydrolysis by an enzyme acetylcholinesterase (AChE).3 Acetylcholinesterase inhibitors are used for the treatment of AD and they work by increasing the acetylcholine level in brain.4 The cholinesterase inhibitors (ChE) usually maintain the functions of brain for 10–12 months in almost half of patients.5 The main enzyme of central nervous system (CNS) is AChE and was regarded as the ‘cholinergic target’ for AD treatment. Hence, it has gained the attention of researchers for AD treatment owing to its involvement in cholinergic neurotransmission. Earlier, BChE was presumed not having considerable role in cholinergic neurotransmission,6, 7, 8, 9 however, recent research has shown that in addition to AChE, BChE also plays pivotal role in cholinergic neurotransmission.10, 11 Neurons, glia cells and endothelial cells express BChE.10 During CNS development, AChE and BChE play role to regulate cellular propagation and neurite growth in several species including rodents.10 Moreover, BChE is also found to have major role in normal CNS.10, 11, 12 According to ‘Amyloid hypothesis’ AChE plays role in secondary non-cholinergic functions such as elevation in the deposition of beta-amyloid (Aβ) as neurofibrillary tangles/senile plaques in the brain of suffering patients.13, 14, 15, 16 Aβ deposition has been discovered to play key role in the commencement and development of AD.17
Numerous research groups have found that the synaptic and neuronal activities are regulated by Aβ and its accumulation in brain leads to the combination of synaptic depression and aberrant network activity.18 Abnormal stimulation of glutamate receptors and injury to inhibitory interneurons leads to excitotoxicity, which seems to play key role in this pathogenic cascade.18, 19, 20 Therefore, it is considered that a drug which can dissociate that aggregate can prove to be a vital AD treatment.21, 22
The efforts to integrate the effect of AChE inhibitors and other therapeutic agents acting at numerous phases of AD pathological scenario have yielded positive results.23, 24 Inspired by these findings, the approach of using compounds that can hit multiple pharmacological targets as a single moiety, can give successful outcomes. Natural compound curcumin and its synthetic derivatives have shown the ability to hit multiple pharmacological targets. Curcumin inhibited aggregation and fibril formation of Aβ by binding to small Aβ species and is also reported to reduce amyloid pathology in Alzheimer transgenic mice.25, 26 Recently we have reviewed all reported synthetic analogues of curcumin showing effects on β-amyloid and discussed on their potential as therapeutic and diagnostic agents for AD.27 We have also reported the synthesis of curcumin like α,β-unsaturated carbonyl-based compounds as potent ChE inhibitors for the treatment of AD.28 In this work, we have studied the pharmacological activity of a series of novel curcumin like compounds possessing cyclohexanone moiety. The pharmacological evaluation of compounds comprises BuChE and AChE inhibition, amyloid β-induced cytotoxicity in PC12 cells and effects on self-induced Aβ aggregation.
Section snippets
Cytotoxicity of synthetic compounds in PC12 cells
MTT assay was performed to investigate the effect of compounds on cell viability using PC12 cells. The cells were treated with different concentrations (0.01–100 μM) of α,β-unsaturated carbonyl based cyclohexanone compounds for 24 h and the compounds were found to be nontoxic to PC12 cells at any concentrations tested.
Effects against Aβ-induced cell cyto-toxicity
Effects of compounds on Aβ-induced PC12 cell toxicity were investigated by MTT assay. In comparison to control cells, the Aβ-treated cells exhibited significantly reduced cell
Conclusion
A series of α,β-unsaturated carbonyl-based cyclohexanone derivatives were synthesized and evaluated as multifunctional anti-Alzheimer agents. The pretreatment of PC12 cells with synthetic compounds protected them against Aβ-induced cell death by 92%. Most compounds displayed better inhibitory potencies against Aβ aggregation than reference compounds. Compounds containing N-methyl-4-piperidone linker, showed high acetylcholinesterase and self-induced Aβ aggregation inhibitory activity as
Materials
Sigma–Aldrich, Merck and Acros Organics supplied all chemicals (above 98% purity). The chemicals were used as supplied without any modicication. BChE (E.C. 3.1.1.8, from horse serum, 1000 units), AChE (E.C.3.1.1.7 from Electric Eel, 500 units), donepezil hydrochloride, and MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] were procured from Sigma-Aldrich (St. Louis, MO, USA). Bachem (Bubendorf, Switzerland) supplied Aβ1–42. 5,5’-dithiobis-(2-nitrobenzoic acid (DTNB), sodium
Notes
The authors declare no competing financial interest.
Acknowledgments
The authors gratefully acknowledge the generous support provided by the Research Incentive Fund of Universiti Kebangsaan Malaysia, Arus Perdana grant (AP-2014-023). H.Q. is grateful to Wuhan University of Technology for financial support.
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