Review of screening methods for acetylcholinesterase inhibitors from natural sources
Alzheimer’s disease (AD) is a chronic neurodegenerative disease that is more common in individuals aged 65 and above. Clinically, it is characterized by memory impairment, aphasia, loss of function, dementia, impairment of visual spatial skills, and executive dysfunction. Currently, AD has become a pressing social and medical issue that needs to be addressed globally. According to the 2020 World Alzheimer’s Disease Fact and Data Report, there were over 52 million global patients with the disease that year. On average, one person develops AD every 3 seconds, and it is expected that this number will increase to 152 million by 2050. In China, over 14.5 million people are suffering from AD, accounting for about a quarter of the world’s total cases and ranking first in the world. However, there has been no significant progress in drug development for this disease at present. Between 1998 and 2017, over 146 AD drugs worldwide declared clinical failure, with a clinical failure rate as high as 97.3%. In 2019, China’s independently developed drug “GV-971” was announced to be launched, which will provide patients with new medication options. But the drug is only effective for patients with mild to moderate AD and can only improve their cognitive function to a certain extent. Therefore, the situation of AD new drug development remains severe.

At present, research on the characteristic pathological changes of AD has found that there is abnormal deposition of amyloid beta protein (A β) on the surface of the patient’s brain, forming senile plaques; And the excessive phosphorylation of Tau protein in the patient’s brain leads to the formation of neurofibrillary tangles in nerve cells, accompanied by the proliferation of glial cells. At present, the pathogenesis of AD mainly includes the “β – amyloid protein (A β) hypothesis”, “Tau protein hypothesis”, “oxidative stress theory”, “metal ion metabolism disorder theory”, “neuroinflammation hypothesis”, “cholinergic injury theory”, etc. The cholinergic injury theory is the earliest proposed theory about the pathogenesis of AD, and it is also the theoretical basis for the development of most AD drugs at present. This hypothesis suggests that the loss of cholinergic activity is related to the severity of symptoms in AD patients. Autopsy of AD patients revealed loss of neurons in the basal forebrain region, decreased activity of acetylcholinesterase and choline acetyltransferase, resulting in reduced ability to uptake and synthesize choline, decreased learning and memory function, and cognitive impairment. Therefore, developing drugs that can improve the function of the cholinergic system in the body has always been an important direction for treating Alzheimer’s disease.

Acetylcholinesterase (AChE) belongs to the serine hydrolase class and is mainly present in the nervous system. Its active center is mainly composed of three parts: the hydrolysis site, anions, and hydrophobic regions. AChE is a key enzyme in biological nerve conduction, which can catalyze the hydrolysis of the neurotransmitter acetylcholine (ACh) in the cholinergic synaptic cleft into choline and acetic acid, terminate signal stimulation, and block the normal transmission of nerve signals in the body. Existing research has shown that ACh is the most important neurotransmitter involved in learning and memory, therefore increasing the level of ACh in the brain can effectively improve the cognitive and learning memory abilities of AD patients. Acetylcholinesterase inhibitor (AChEI) is a substance that can reversibly inhibit AChE. It can accumulate ACh at synapses, increase its content, ensure the normal transmission of neural signals in the body, and improve learning and memory functions. It is currently the most widely used AD treatment drug in clinical practice.

Natural products are currently the largest and best source of drugs due to their advantages such as structural diversity. With the rapid development of extraction, separation, and structural identification technologies, the speed and competitiveness of developing drugs from natural products have significantly increased, providing new ideas for finding novel AChEIs with a wide range of effects, minimal toxic side effects, and suitable for long-term use. At the same time, with the continuous innovation of scientific technology for screening AChEIs, the continuous advancement of scientific instruments, and the gradual deepening of research on the exact etiology of AD, we firmly believe that more compounds with novel chemical structures and significant effects will be discovered from natural products, ultimately defeating AD.