Chapter 8 - Alkaloids as Potential Multi-Target Drugs to Treat Alzheimer's Disease

Abstract

Abstract Neurodegenerative diseases are characterized by the progressive and irreversible loss of neurons from specific regions of the brain. The pattern of neuronal loss is selective, affecting mainly the subcortical areas (nuclei of the base) and cerebral cortex, resulting in abnormality in the control of voluntary movement, impairment of memory, and cognitive ability. The progression of these debilitating and incurable conditions gives rise to dementia. The most known dementias are amyotrophic lateral sclerosis, Alzheimer's disease (AD), Parkinson's disease, and Huntington's disease. AD is the most prominent of these dementias, accounting for 60%–80% of the total dementia cases worldwide. AD is a multifactorial, neurodegenerative, progressive, and fatal disorder characterized by loss of cholinergic neurons in the hippocampus and cerebral cortex mainly affecting cholinergic neurotransmission. The major pathological characteristics of AD include extracellular deposition of amyloid beta (Aβ) plaques, intracellular formation of neurofibrillary tangles (NFTs) comprising hyperphosphorylated and aggregated tau protein, neuroinflammation, and neurodegeneration. Based on the cholinergic hypothesis, that states that a low production of acetylcholine (ACh) initiates AD, the first drugs approved to treat AD were cholinesterase enzyme inhibitors (IChE), which are responsible for the hydrolysis of ACh. Despite being only palliative, so far the best treatment for AD is based on three FDA-approved cholinesterase inhibitors, namely, galanthamine rivastigmine, donepezil, and an N-methyl- d -aspartate receptor antagonist, memantine, indicated for joint therapy in the severe phase of AD. New approaches including the observation of Aβ and NFTs lead to the amyloid and tau hypotheses as causes for AD development. Multi-target molecules able to inhibit cholinesterases and interfere with Aβ aggregation and/or tau protein hyperphosphorylation or neuroinflammation may be useful tools in the treatment of AD. Natural products have been a constant source of new approaches for the treatment of AD, especially plant alkaloids. For example, physostigmine (Physostigma venenosum), the prototype of rivastigmine, is an IChE and allosteric modulator of the central nicotinic receptor. Galanthamine (Galanthus woronowii) is a selective inhibitor of acetylcholinesterase, allosteric modulator of the central nicotinic receptor, inhibits Aβ aggregation, and promotes hippocampal neurogenesis. Berberis (Berberis mahonia) is an IChE, inhibits the formation and aggregation of Aβ, and reduces hyperphosphorylation of tau protein in some in vitro systems. Benzophenanthridine alkaloid chelerythrine (Chelidonium majus) is an IChE, inhibits Aβ aggregation, and induces Aβ disaggregation. The aim of this chapter is to review classes of alkaloid inhibitors of cholinesterases that have the potential to become multi-target prototypes for AD treatment.