Multitarget therapeutic strategies for Alzheimer’s disease

Ibrahim, Mostafa M.H.; Gabr, Moustafa T.

doi:10.4103/1673-5374.245463

Cited by 127 publications

(34 citation statements)

References 25 publications

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“…manifests anti-inflammatory (Ding et al, 2017), anti-oxidative Sutalangka et al, 2013), anti-apoptotic (Guo et al, 2015) and anti-Aβ effects Liu et al, 2017;Zhang M. et al, 2017) in AD. These effects meet the need for a multimodal AD therapy (Ubhi and Masliah, 2013;Ibrahim and Gabr, 2019). Considering of the advantages of MA, such as safety and convenience, additional studies of MA effects on AD should be performed.…”

Section: Discussionmentioning

confidence: 99%

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

et al. 2020

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Background: The astrocytic phospholipase A 2 (PLA 2 )-arachidonic acid (AA) pathway is crucial in understanding the reduction of cerebral blood flow (CBF) prior to cognitive deterioration. In complementary and alternative medicine, manual acupuncture (MA) is used as one of the most important therapies for Alzheimer's disease (AD). The beneficial effects of MA on CBF were reported in our previous study. However, the underlying molecular mechanism remains largely elusive.Objective: To investigate the effect of MA on the astrocytic PLA 2 -AA pathway in SAMP8 mice hippocampi.Methods: SAMP8 mice were divided into the SAMP8 control (Pc) group, the SAMP8 MA (Pm) group and the SAMP8 donepezil (Pd) group. SAMR1 mice were used as the SAMRl control (Rc) group. Mice in the Pd group were treated with donepezil hydrochloride at 0.65 µg/g. In the Pm group, MA was applied at Baihui (GV20) and Yintang (GV29) for 20 min. The above treatments were administered once a day for 26 consecutive days. The Morris water maze was applied to assess spatial learning and memory. Immunofluorescence staining, western blot and liquid chromatographytandem mass spectrometry were used to investigate the expression of related proteins and measure the contents of the metabolic intermediates of the PLA 2 -AA pathway.Results: Compared with that in the Rc group, the escape latency in the Pc group significantly increased (p < 0.01); whereas, the platform crossover number and percentage of time and swimming distance in the platform quadrant decreased (p < 0.01). The hippocampal expression of PLA 2 , cyclooxygenase-1, cytochrome P450 proteins 2C23 and the levels of AA, prostaglandin E 2 and epoxyeicosatrienoic acids of the Pc group was drastically higher than that in the Rc group (p < 0.01). These changes were reversed by MA and donepezil (p < 0.01 or p < 0.05). Frontiers in Neuroscience | www.frontiersin.org February 2020 | Volume 13 | Article 1354 Ding et al. Acupuncture Regulates PLA 2 -AA PathwayConclusion: MA can effectively improve the learning and memory abilities of SAMP8 mice and has a negative regulatory effect on the PLA 2 -AA pathway. We propose that the increase of the arterial tone, which is induced by the inhibition of vasodilatory pathway, may be a reason for the beneficial effect of MA on CBF.Keywords: manual acupuncture, Alzheimer's disease, astrocyte, hippocampus, phospholipase A 2 , arachidonic acid, cerebral blood flow absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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Section: Discussionmentioning

confidence: 99%

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

et al. 2020

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“…According to the World Alzheimer’s Report 2016, 46.8 million people worldwide were predicted by dementia in 2015 and the number of patients was predicted to triple by 2050. AD clinically includes the progressive degeneration of brain tissue that is influenced by the absence in acetylcholine (ACh) and has multifactorial pathology [ 1 , 2 , 3 , 4 , 5 ]. Accumulation of extracellular amyloid-beta (Aβ) in senile plaques, loss of cholinergic activity in certain parts of brain and intracellular neurofibrillary tangles including the hyperphosphorylated tau protein as well as neuroinflammation, responsible for neurodegenerative processes observed in AD [ 6 , 7 , 8 ].…”

Section: Introductionmentioning

confidence: 99%

Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives

et al. 2019

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Alzheimer’s disease (AD), one of the main causes of aged dementia, is a progressive and degenerative neurological disorder characterized by loss of cognition and memory. Although the symptomatic treatment of AD, particularly acetylcholinesterase inhibitors (AChEIs) based on the ‘cholinergic hypothesis’, has been successful in clinic, at present there is no cure for this disease. In this study, we designed compounds carrying benzimidazole and triazole rings on the same chemical skeleton so as to investigate their potential acetylcholinesterase and butyrylcholinesterase activity. Furthermore, molecular modeling study was performed to determine the binding mode of the best inhibitor to the AChE. Among them, compounds 3d and 3h, which featured 3,4-dihydroxy substitution at the phenyl ring and 5(6)-chloro substitution at the benzimidazole ring were found to be potent inhibitors of AChE. The inhibition kinetics of the two most active derivatives 3d and 3h were further studied. The kinetic displayed increasing slope and increasing intercept, which is consistent with a mixed inhibition. The IC50 and Ki values of 3d are 31.9 ± 0.1 nM and 26.2 nM, respectively. Compound 3h exhibited IC50 of 29.5 ± 1.2 nM and Ki of 24.8 nM. The above data compared favorably with data for donepezil (21.8 ± 0.9 nM) the reference compound in our study.

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“…Current drug design strategies are based on “ one drug-one target” paradigm (Schneider et al, 2014), that until now failed to provide effective treatments against AD, due to the multifactorial nature of the disease (Kumar et al, 2018; Ibrahim and Gabr, 2019). Multi-target approaches for the rational design of novel drug candidates, also called multitarget-directed ligands (MTDL) strategies, have been used to develop a variety of hybrid compounds capable to act simultaneously in diverse biological targets (Viegas-Junior et al, 2007; Hughes et al, 2016; Agatonovic-Kustrin et al, 2018; Batool et al, 2018; de Freitas Silva et al, 2018; González et al, 2019).…”

Section: Multi-target Approaches For Admentioning

confidence: 99%

Dreaming of a New World Where Alzheimer’s Is a Treatable Disorder

Catania

Giaccone

Salmona

et al. 2019

Front. Aging Neurosci.

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Alzheimer’s disease (AD) is the most common form of dementia. It’s a chronic and untreatable neurodegenerative disease with irreversible progression and has important social and economic implications in terms of direct medical and social care costs. Despite prolonged and expensive efforts employed by the scientific community over the last few decades, no effective treatments are still available for patients, and the development of disease-modifying drugs is now a really urgent need. The recent failure of clinical trials based on the immunotherapeutic approach against amyloid-β(Aβ) protein questioned the validity of the “amyloid cascade hypothesis” as the molecular machinery causing the disease. Indeed, most attempts to design effective treatments for AD have been based until now on molecular targets suggested to be implicated in AD pathogenesis by the amyloid cascade hypothesis. However, mounting evidence from scientific literature supports the view of AD as a multifactorial disease that results from the concomitant action of multiple molecular players. This view, together with the lack of success of the disease-modifying single-target approaches, strongly suggests that AD drug design needs to be shifted towards multi-targeted compounds or drug combinations acting synergistically on the main core features of disease pathogenesis. The discovery of drug candidates targeting multiple factors involved in AD would greatly improve drug development. So, it is reasonable that upcoming strategies for the design of preventive and/or therapeutic agents for AD point to a multi-pronged approach including more than one druggable target to definitely defeat the disease.

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Multitarget therapeutic strategies for Alzheimer’s disease

Cited by 127 publications

References 25 publications

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

Benign Regulation of the Astrocytic Phospholipase A2-Arachidonic Acid Pathway: The Underlying Mechanism of the Beneficial Effects of Manual Acupuncture on CBF

Synthesis and AChE-Inhibitory Activity of New Benzimidazole Derivatives

Dreaming of a New World Where Alzheimer’s Is a Treatable Disorder

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