Morphing cholinesterase inhibitor amiridine into multipotent drugs for the treatment of Alzheimer's disease

Biomedicine & Pharmacotherapy, Journal Year: 2024, Volume and Issue: 173, P. 116399 - 116399

Published: March 15, 2024

The search for novel drugs to address the medical needs of Alzheimer's disease (AD) is an ongoing process relying on discovery disease-modifying agents. Given complexity disease, such aim can be pursued by developing so-called multi-target directed ligands (MTDLs) that will impact pathophysiology more comprehensively. Herewith, we contemplated therapeutic efficacy amiridine drug acting as a cholinesterase inhibitor converting it into class MTDLs. Applying linking approach, have paired core building block with memantine/adamantylamine, trolox, and substituted benzothiazole moieties generate MTDLs endowed additional properties like N-methyl-d-aspartate (NMDA) receptor affinity, antioxidant capacity, anti-amyloid properties, respectively. top-ranked amiridine-based compound 5d was also inspected in silico reveal butyrylcholinesterase binding differences its close structural analogue 5b. Our study provides insight broadening their target-engaged profile from inhibitors towards potential implications AD therapy.

Language: Английский

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Glutamate: Molecular Mechanisms and Signaling Pathway in Alzheimer’s Disease, a Potential Therapeutic Target

Molecules, Journal Year: 2024, Volume and Issue: 29(23), P. 5744 - 5744

Published: Dec. 5, 2024

Gamma-glutamate is an important excitatory neurotransmitter in the central nervous system (CNS), which plays role transmitting synapses, plasticity, and other brain activities. Nevertheless, alterations glutamatergic signaling pathway are now accepted as a element Alzheimer's disease (AD) pathophysiology. One of most prevalent types dementia older adults AD, progressive neurodegenerative illness brought on by persistent decline cognitive function. Since AD has been shown to be multifactorial, variety pharmaceutical targets may used treat condition. N-methyl-D-aspartic acid receptor (NMDAR) antagonists acetylcholinesterase inhibitors (AChEIs) two drug classes that Food Drug Administration authorized for treatment AD. The AChEIs approved galantamine, donepezil, rivastigmine. However, memantine only non-competitive NMDAR antagonist This review aims outline involvement glutamate (GLU) at molecular level pathways associated with demonstrate target therapeutic potential its receptor. We will also consider opinion leading authorities working this area, drawback existing strategies, direction further investigation.

Language: Английский

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Conventional Versus New Treatment: Comparing the Effects of Acetylcholinesterase Inhibitors and N-Methyl-D-Aspartate Receptor Antagonist With Aducanumab

Cureus, Journal Year: 2022, Volume and Issue: unknown

Published: Nov. 3, 2022

Alzheimer’s dementia (AD) is the most common major neurocognitive impairment and fifth leading cause of death in older adults United States. The diagnosis clinical; however, laboratory tests imaging frequently rule out secondary causes dementia. Unfortunately, treatment available for AD does not reverse dementia, but it may help improve symptoms slow progression disease. conventional - acetylcholinesterase inhibitor (AChEI) therapy N-methyl-D-aspartate (NMDA) receptor antagonist considered to enhance executive function, overall cognition, activities daily living. AChEIs such as donepezil, rivastigmine, galantamine are approved mild-to-moderate Furthermore, memantine, an NMDA antagonist, authorized moderate-to-severe Aducanumab, newest drug available, amyloid-beta (Aβ) monoclonal antibody only mild AD. Treatment with either or memantine more cost-effective than aducanumab best supportive care. Aducanumab has particular recommendations strict monitoring several adverse effects, including amyloid-related abnormalities. effects include gastrointestinal symptoms, dizziness, confusion, headaches. Therefore, should be performed periodically at clinician’s discretion clinical response tolerability medication. Conventional therapies symptom management still beneficial patients caregivers. this time, aducanumab’s risks outweigh benefits a questionable approval process by Food Drug Administration (FDA). However, given potential disease-modifying capabilities aducanumab, other options become possibly reducing inflammation, preventing Aβ plaques from clumping, keeping tau proteins tangling.

Language: Английский

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Targeting terminal pathway reduces brain complement activation, amyloid load and synapse loss, and improves cognition in a mouse model of dementia

Brain Behavior and Immunity, Journal Year: 2024, Volume and Issue: 118, P. 355 - 363

Published: March 12, 2024

Complement is dysregulated in the brain Alzheimer's Disease and mouse models of disease. Each complement derived effectors, opsonins, anaphylatoxins membrane attack complex (MAC), have been implicated as drivers disease but their relative contributions remain unclarified. Here we focussed on MAC, a lytic pro-inflammatory effector, AppNL−G−F amyloidopathy model. To test role back-crossed to generate mice deficient C7, an essential MAC component. C7 deficiency ablated formation, reduced synapse loss amyloid load improved cognition compared complement-sufficient at 8–10 months age. Adding back caused increased formation acute synapses C7-deficient mice. explore whether was viable therapeutic target, C7-blocking monoclonal antibody administered systemically for one month aged 8–9 months. Treatment deposition, density cognitive performance isotype control-treated The findings implicate driver pathology highlight potential inhibition level therapy

Language: Английский

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Brain-penetrant complement inhibition mitigates neurodegeneration in an Alzheimer's disease mouse model

Brain, Journal Year: 2024, Volume and Issue: unknown

Published: Aug. 29, 2024

Abstract Complement activation is implicated in driving brain inflammation, self-cell damage and progression of injury Alzheimer's disease other neurodegenerative diseases. Here, we investigate the impact delivery a complement-blocking antibody on neurodegeneration an mouse model. We engineered brain-penetrant recombinant targeting pro-inflammatory membrane attack complex. Systemic administration this APPNL-G-F mice reduced levels complement products, demonstrating successful entry target engagement. Prolonged treatment decreased synapse loss, amyloid burden inflammatory cytokine levels, concomitant with cognitive improvement compared to controls. These results underscore potential complement-inhibiting drugs as promising therapeutics, downstream plaques disease.

Language: Английский

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