A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25–35-impaired mouse cognitive function

Zhang, Zhengping; Chen, Rong; An, Wenji; Wang, Chunmei; Liao, Gao-Yong; Dong, Xiaoliang; Bi, Aijing; Yin, Zhimin; Luo, Lan

doi:10.1007/s00213-015-4133-5

Cited by 20 publications

(12 citation statements)

References 70 publications

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“…Interestingly, Morris water maze test, plus maze test and different biochemical analysis, demonstrated the restoration of normal learning and memory functions. Moreover, SCR-1693 (a nonselective calcium channel blocker) has been described to attenuate A β 25–35 -induced death in SH-SY5Y cells and to regulate A β -induced signal cascade in neurons [ 58 – 60 ]. However, the use of calcium channel blockers to mitigate AD outcomes is still much debated.…”

Section: Calcium and Admentioning

confidence: 99%

Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Magi

Castaldo

Macrì

et al. 2016

BioMed Research International

119

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Alzheimer's Disease (AD) is a neurodegenerative disorder characterized by progressive neuronal loss. AD is associated with aberrant processing of the amyloid precursor protein, which leads to the deposition of amyloid-β plaques within the brain. Together with plaques deposition, the hyperphosphorylation of the microtubules associated protein tau and the formation of intraneuronal neurofibrillary tangles are a typical neuropathological feature in AD brains. Cellular dysfunctions involving specific subcellular compartments, such as mitochondria and endoplasmic reticulum (ER), are emerging as crucial players in the pathogenesis of AD, as well as increased oxidative stress and dysregulation of calcium homeostasis. Specifically, dysregulation of intracellular calcium homeostasis has been suggested as a common proximal cause of neural dysfunction in AD. Aberrant calcium signaling has been considered a phenomenon mainly related to the dysfunction of intracellular calcium stores, which can occur in both neuronal and nonneuronal cells. This review reports the most recent findings on cellular mechanisms involved in the pathogenesis of AD, with main focus on the control of calcium homeostasis at both cytosolic and mitochondrial level.

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Section: Calcium and Admentioning

confidence: 99%

Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Magi

Castaldo

Macrì

et al. 2016

BioMed Research International

119

View full text Add to dashboard Cite

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“…It also inhibited the generation and release of Aβ in cells. Zhang et al, reported its concentration dependent selective, reversible and noncompetitive inhibitor of AChE, (IC 50 = 680 nM) but not BChE in vitro and in vivo [86]. It inhibited all four types of calcium channels at 10 μM concentration non-selectively and reduced Aβ 25-35 -induced SH-SY5Y cell death with higher efficacy than donepezil.…”

Section: Tacrine Analogsmentioning

confidence: 99%

“…It was also better than donepezil and memantine in improving the Aβ 25-35 -induced long-term and short-term learning memory impairment in animal model. It provided protection against glutamate excite toxicity, neuronal damage and Aβ neurotoxicity which indicated that it is a potential lead molecule for AD treatment [86]. The analog 44 incorporating N,N-dimethylene side chain and fluorination at cyclohexane ring of tacrine moiety in analog 43 also showed still higher AChE inhibitory activity (IC 50 = 45nM) than 43 with moderate calcium ions channel blocking property (57.2% at 50,000 nM) [84].…”

Section: Tacrine Analogsmentioning

confidence: 99%

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

Saxena¹

2019

AND

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Alzheimer's Disease (AD) is characterized by the loss of memory and learning ability in elderly patients affecting large population worldwide. The enzyme Acetylcholinesterase (AChE), (E.C.3.1.1.7) plays a major role in the hydrolysis of the released neurotransmitter acetylcholine. Most of the clinically used drugs to treat AD are Acetylcholinesterase Inhibitors (AChEIs). These drugs can provide symptomatic benefits only and suffer with loss of therapeutic potential with time. Therefore, there is an urgent need of novel cholinesterase inhibitors with wider therapeutic window for the treatment of AD. The strategies targeting the AChE enzyme along with other target(s) like Butyrylcholinesterase (BChE), amyloid-β (Aβ), β-secretase-1 (BACE), metals (Cu 2+ , Zn 2+ , or Fe 2+), antioxidant properties and free radical scavenging capacity have been mainly focused in the last five years. A number of hybrid molecules incorporating sub-structures with the desired well-established pharmacological profile into a single scaffold have been investigated. The main sub structures used in developing these molecules are derived from diverse chemical classes such as acridine, quinoline, carbamates, huperzine and other heterocyclic analogs. It has been followed by optimization of activity through structural modifications of the prototype molecules for developing the Structure Activity Relationship (SAR). This has led to the development of novel molecules with desired AChE inhibitory activity along with other desirable pharmacological properties. This review summarizes the current therapeutic strategies for the development of these AChEI in the last seven years.

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“…Commercial products of donepezil are primarily available as conventional oral dosage forms such as tablets and capsules [8,9]. AD patients need to take the tablet or capsule once a day [10].…”

Section: Introductionmentioning

confidence: 99%

PLGA Microspheres with Alginate-Coated Large Pores for the Formulation of an Injectable Depot of Donepezil Hydrochloride

et al. 2020

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As the main symptom of Alzheimer’s disease-related dementia is memory loss, patient compliance for donepezil hydrochloride (donepezil), administered as once-daily oral formulations, is poor. Thus, we aimed to design poly(lactic-co-glycolic acid) (PLGA) microspheres (MS) with alginate-coated large pores as an injectable depot of donepezil exhibiting sustained release over 2–3 weeks. The PLGA MS with large pores could provide large space for loading drugs with high loading capacity, and thereby sufficient amounts of drugs were considered to be delivered with minimal use of PLGA MS being injected. However, initial burst release of donepezil from the porous PLGA MS was observed. To reduce this initial burst release, the surface pores were closed with calcium alginate coating using a spray-ionotropic gelation method. The final pore-closed PLGA MS showed in vitro sustained release for approximately 3 weeks, and the initial burst release was remarkably decreased by the calcium alginate coating. In the prediction of plasma drug concentration profiles using convolution method, the mean residence time of the pore-closed PLGA MS was 2.7-fold longer than that of the porous PLGA MS. Therefore, our results reveal that our pore-closed PLGA MS formulation is a promising candidate for the treatment of dementia with high patient compliance.

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A novel acetylcholinesterase inhibitor and calcium channel blocker SCR-1693 improves Aβ25–35-impaired mouse cognitive function

Abstract: All these findings indicated that SCR-1693, as a double-target-direction agent, is a considerable candidate for AD therapy.

Cited by 20 publications

References 70 publications

Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

Intracellular Calcium Dysregulation: Implications for Alzheimer’s Disease

The Structural Hybrids of Acetylcholinesterase Inhibitors in the Treatment of Alzheimer’s Disease: A Review

PLGA Microspheres with Alginate-Coated Large Pores for the Formulation of an Injectable Depot of Donepezil Hydrochloride

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