Neuroprotective effects of multifaceted hybrid agents targeting MAO, cholinesterase, iron and β‐amyloid in ageing and Alzheimer's disease

Abstract

Alzheimer's disease (AD) is accepted nowadays as a complex neurodegenerative disorder with multifaceted cerebral pathologies, including extracellular deposition of amyloid β peptide-containing plaques, intracellular neurofibrillary tangles, progressive loss of cholinergic neurons, metal dyshomeostasis, mitochondrial dysfunction, neuroinflammation, glutamate excitoxicity, oxidative stress and increased MAO enzyme activity. This may explain why it is currently widely accepted that a more effective therapy for AD would result from the use of multifunctional drugs, which may affect more than one brain target involved in the disease pathology. The current review will discuss the potential benefits of novel multimodal neuroprotective, brain permeable drugs, recently developed by Youdim and collaborators, as a valuable therapeutic approach for AD treatment. The pharmacological and neuroprotective properties of these multitarget-directed ligands, which target MAO enzymes, the cholinergic system, iron accumulation and amyloid β peptide generation/aggregation are described, with a special emphasis on their potential therapeutic value for ageing and AD-associated cognitive functions. This review is conceived as a tribute to the broad neuropharmacology work of Professor Moussa Youdim, Professor Emeritus in the

Glucagon-like peptide-1 mediates effects of oral galactose in streptozotocin-induced rat model of sporadic Alzheimer’s disease

“…This study combines two current trends, a nutrient as a possible therapeutic agent and brain glucose hypometabolism as the therapeutic target, both explored here following the administration of a single agent which might have direct (glucose/energy replenishing) and indirect (neuroprotective factor stimulating) effects in the STZ-icv rat model of sAD. The hypothesis proposed here complies with the current theories that multimodal compounds/drugs which combine more than one mechanism of action and/or 13 have more than one target might be more efficient than single-target drugs in AD treatment [34,61]. It is important to mention that oral galactose might have additional effects, like stimulation of the secretion of another incretin, glucose-dependent insulinotropic polypeptide (GIP), in the gut [62].…”

Iron Metabolism, Ferroptosis, and the Links With Alzheimer’s Disease

“…Indeed, iron deposition has been involved in the two misfolding process. SP and NFT complexes cover redox-active transition metals (Sayre et al, 2000;Weinreb et al, 2016).…”

Neurobiology and neuropharmacology of monoaminergic systems

“…The article by Butini et al is an illustration of the pharmacological profile and chemical requirements of new antipsychotic or anti-Parkinsonian drugs to achieve good efficacy with low or no side-effects (Butini et al, 2016). Several receptors or enzymes are usually targeted leading to the new popularity of multitarget drug design (Millan, 2009;Ramsay et al, 2016;Weinreb et al, 2016).…”