Natural Alkaloids as Multi-Target Compounds towards Factors Implicated in Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) is the most common cause of dementia in elderly people; currently, there is no efficient treatment. Considering the increase in life expectancy worldwide AD rates are predicted to increase enormously, and thus the search for new AD drugs is urgently needed. A great amount of experimental and clinical evidence indicated that AD is a complex disorder characterized by widespread neurodegeneration of the CNS, with major involvement of the cholinergic system, causing progressive cognitive decline and dementia. The current treatment, based on the cholinergic hypothesis, is only symptomatic and mainly involves the restoration of acetylcholine (ACh) levels through the inhibition of acetylcholinesterase (AChE). Since the introduction of the Amaryllidaceae alkaloid galanthamine as an antidementia drug in 2001, alkaloids have been one of the most attractive groups for searching for new AD drugs. The present review aims to comprehensively summarize alkaloids of various origins as multi-target compounds for AD. From this point of view, the most promising compounds seem to be the β-carboline alkaloid harmine and several isoquinoline alkaloids since they can simultaneously inhibit several key enzymes of AD’s pathophysiology. However, this topic remains open for further research on detailed mechanisms of action and the synthesis of potentially better semi-synthetic analogues.

Petrosamine isolated from marine sponge Petrosia sp. demonstrates protection against neurotoxicity in vitro and in vivo

“…Promptly focusing on AChE IC50, in 2000 the FDA has approved rivastigmine, a synthetic alkaloid and irreversible inhibitor of AChE, for the treatment of mild-to moderate AD, still used to date. Rivastigmine has an AChE IC50 5.5 µM [ 5 , 45 ], while petrosamine has an AChE IC50 0.091 µM, being 60 × more effective in the inhibition of this enzyme, proving how petrosamine can be more efficient in AD treatment when compared with the two of the three anticholinesterase agents approved by the FDA (rivastigmine and galanthamine, as mentioned before). Stevensine has also been an alkaloid isolated from the sponge Axinella verrucose , collected from the Golf of Naples with an AChE IC50 12.2 µM [ 45 , 46 ].…”

Bioactive Components of Areca Nut: An Overview of Their Positive Impacts Targeting Different Organs

“…Besides this, MAO-induced changes in brain monoamine neurotransmitter levels are also associated with AD. Thus, acting as an MAO inhibitor, areca nut extract may also potentially decrease the expression of MAO-B in platelets and the brain in AD patients [ 133 ].…”

Alkaloids as New Leads for Neurodegenerative Diseases

“…It has had a significant influence on affected individuals, carers, and society in both developed and developing countries [2]. The abundance of experimental and clinical evidence suggests that Alzheimer's disease is a complicated disorder characterized by extensive neurodegeneration of the central nervous system with significant involvement of the cholinergic system, resulting in gradual cognitive decline and dementia [3]. New approaches, such as the detection of amyloid-beta (Aβ) and tumor necrosis factors (NFTs), lead to the amyloid and tau theories as potential causes of Alzheimer's development.…”

“…Galanthamine (Galanthus woronowii) is a selective acetylcholinesterase inhibitor, an allosteric modulator of the central nicotinic receptor, an inhibitor of Aβ aggregation, and an inducer of hippocampus neurogenesis [4]. Alkaloids have been one of the most appealing classes for searching for novel medications since the release of the Amaryllidaceae alkaloid as a drug in 2001 [3].…”