Alzheimer’s disease (AD) is a progressive, fatal neurodegenerative disease that is characterized by deteriorating cognitive and memory functions, gradual loss of daily living skills, and various mental and behavioral disorders. It has become an increasingly popular topic of concern and research, as it poses a great disability safety problem and economic burden to society and families. With the in-depth research on its etiology, pathogenesis and molecular biology, several hypotheses have been developed to describe the etiology and pathogenesis of Alzheimer’s disease from different aspects. In recent years, various therapeutic pathways have been proposed based on these hypotheses, and the main drugs for these therapeutic pathways are reviewed as follows.
1. Acetylcholinesterase inhibitors (AchEI)
1.1 Tcrine (Tcrine) is known by the trade name cognex (Pecosol) [1]. It is a non-selective reversible AchEI with high lipid solubility, which can cross the blood-brain barrier after oral administration and remain in the center for a long time, inhibiting AchEI activity and increasing the binding of Ach to nicotinic receptors. 80 mg/d for 3 mo can improve the cognitive ability and orientation of AD patients, and has good efficacy in mild and moderate patients. Patients with good efficacy, its adverse effects are hepatotoxicity and gastrointestinal reactions, which affect its clinical application.
1.2 Donepezil (Donepezil), also known as Aricept (E2020), was developed by Eisai/Pfzer and launched in the US and UK in January and April 1997, respectively [2], and is a second-generation, highly specific, reversible AchEI with better selectivity and specificity than tacrine, strong central AchE inhibition, long half-life, and tolerability. It has a long half-life, is well tolerated, has less hepatotoxicity, and improves cognition and daily living ability in patients with mild AD. The initial dose is 5mg/d and gradually increased to 10mg/d after 4-6w. It can reduce gastrointestinal discomfort when taken at bedtime and should be taken during the daytime for insomnia.
1.3 Exelon, also known as Rivastigmine, is a selective AChEI and butyrylcholinesterase inhibitor (BuChEI), which was tested in phase III clinical trials in 1996, marketed in Switzerland in 1997, and approved by the US FDA for the treatment of AD in 1999 [3]. It is a new type of pseudo-irreversible central AChEI. it is well tolerated, less toxic to the liver than the previous two, and has no peripheral activity, and is effective in patients with all types of dementia. The initial dose of Bid, 1.5mg/dose, is adjusted within 4w, and the maximum amount is Bid, 6mg/dose.
1.4 Shiksin A (Shuangyiping), an alkaloid extracted from the Chinese herb Shiksin, Shanghai Institute of Drug Research, Chinese Academy of Sciences, is the first and most promising drug for the treatment of AD in China. It is a reversible and potent AChEI, with high oral bioavailability, long duration of action and low side effects. With central selectivity, the inhibitory effect of AChE is 180 times higher than that of tacrine. Studies in more than 10 clinical centers in China have shown that it is effective in the treatment of memory impairment, with a higher therapeutic index than tacrine and galantamine, and no significant toxic effects have been observed [4].
1.5 Galantamine (Galantamine) is a selective and reversible AChEI that can modulate nicotinic receptors while inhibiting AChE for additional release of ACh. It can cross the blood-brain barrier, increase central ACh levels, improve memory capacity in animals and humans, and has a therapeutic effect on dementia caused by AD and cerebrovascular disease [5]. It was administered once daily at morning and evening meal. It is started at 8 mg/d, changed to a maintenance dose of 16/mg after 4 weeks, after which it can be increased to 24 mg/d depending on the therapeutic effect and tolerability.
2. Cholinergic receptor agonists
Mainly M and N receptors, especially selective M1 receptor agonists, not only improve the function of the cholinergic nervous system in the brain, but also may slowly downregulate the degenerative process of neurons in the brain of AD patients by regulating the formation process of normal amyloid precursor proteins [6]. Such drugs are still in clinical trials, among which SR-46659A, Xanomeline, and AF102B have been shown to improve dementia symptoms in clinical trials, respectively.
2.1 SR-46659A
This product is selective for M1 receptors with high affinity and has less effect on M2 receptors in the heart. It has been marketed in France for the treatment of AD and can significantly improve its cognitive ability.
2.2 Xanomeline
It is one of the most effective M1 receptor agonists found so far. It can increase the blood concentration of Ach and accelerate the ACh cycle by reducing the ACh receptors in the postsynaptic terminal. A double-blind method and placebo-controlled trial showed that the cognitive ability and motor behavior of AD patients improved significantly after taking high doses of Xanomeline. However, it has greater gastrointestinal and cardiovascular system adverse effects, and attempts are being made to overcome this drawback with non-oral methods.
3. Drugs to promote neuronal metabolism
3.1 CereBroLysin is a brain protein hydrolase, which can directly cross the blood-brain barrier into brain nerve cells, promote nerve cell protein synthesis, restore the function of damaged but not yet degenerated nerve cells, accelerate the movement of glucose through the blood-brain barrier, improve the energy supply of brain tissue, increase the activity of adenylate activating enzyme, and promote ATP synthesis, which can significantly improve AD patients’ memory function, mood, fatigue and other symptoms of AD patients.
3.2 Actovegin is a protein-free peptide neurotrophin extracted from calf serum, which can easily cross the blood-brain barrier and act in various ways on the central nervous system, regulating and improving the metabolism of neurons, promoting synapse formation, inducing neuronal differentiation and protecting neuronal cells from various ischemic and neurotoxic damages. The neurotrophic activity can significantly slow down the process of AD.
3.3 Estrogen Estrogen has cholinergic neurotrophic and protective effects, promotes the production of cortical neuronal cells, restores neuronal function, and enhances the therapeutic effect of AchEI on AD. At present, there are therapies such as estrogen alone, cycle plus progestin or compound hormone and progestin continuous administration, which can significantly improve patients’ depression and anxiety, improve cognitive ability and have better comprehensive efficacy.
4. Anti-inflammatory drugs
In view of the microglia proliferation around the age spots in the brain of AD patients as an alteration of inflammatory immune response, anti-inflammatory therapy is considered as a possible way to treat AD. The main drugs in this category are aspirin, indomethacin, and chloroquine. Studies have proven that this class of anti-inflammatory drugs reduces the risk of developing AD and delays and prevents the onset of AD due to their ability to inhibit microglia proliferation, anti-platelet aggregation, and interfere with the formation of age spots [7].
5. Free radical scavengers
The oxidation of unsaturated fatty acids on neuronal cell membranes generates a large number of free radicals, leading to neuronal peroxidative damage and causing neuronal degeneration, so scavengers are considered to be an effective way to treat AD. The level of this hormone in AD patients is significantly lower than that of normal elderly people, so the application of melatonin will be beneficial to the treatment of AD. . Vitamin E, vitamin C, beta-carotene and trace elements such as selenium and other antioxidants also help free radical scavenging, such drugs can effectively protect the brain, prevention and treatment of AD.
6. Neurogenesis drugs
The development of AD will be alleviated if the damaged or necrotic nerve cells of AD patients can be regenerated, so the direction of research in this area is fundamental and has great potential for development. Nerve growth factor is one of the most intensively studied drugs to date. Nerve growth factor in the central nervous system is produced by brain tissue in the target areas of cholinergic nerves, such as the hippocampus and frontal cortex, and is taken up after binding to nerve growth factor receptors in the axon terminals of cholinergic nerves and transported via the axoplasm to the basal ganglia where its cytosol is located. In addition to its trophic effect on cholinergic neurons, it is also effective in preventing degeneration and death of cholinergic neurons due to brain injury in mammals and in improving recognition dysfunction in aged animals [8]. Another drug developed by NeoTherapeutics, Inc.
Neotrofin (potassium salt of LetePrinim), developed by NeoTherapeutics, has been entered into phase III clinical trials. Studies have shown that Netrofin has short-term efficacy as well as long-term utility, as demonstrated by its ability to significantly increase the growth of stem cells in the hippocampal tissue of the brain and to differentiate into new neural cells that can repair neurodegenerative damage in AD patients.
7 Chinese medicine treatment
There are many discussions on this disease in Chinese medicine, such as “if phlegm is confused in the mind, one will forget a lot of things”. Most of the treatments are based on tonifying the kidney and benefiting the brain, activating blood circulation and resolving stagnation. The active ingredients of some natural drugs and Chinese patent medicines that are being researched and applied in China, such as serpentine, inhibit central AChE activity, delay cell aging and improve cognitive ability; Ginkgo biloba extract can reduce the generation of free radicals and directly scavenge free radicals, reduce lipid cell peroxidation and inhibit neural cell death caused by amyloid precursor proteins. It has a significant improvement effect on mild to moderate AD; Huangpi amide is a pro-intellectual compound isolated from the Chinese medicine Huangpi leaf, which can promote ACh synthesis and increase the nutrition of cholinergic nerves, and its pro-intellectual effect is 100 times that of brain rehabilitation; Schisandrol has a significant protective effect on the mitochondrial damage of brain synapses caused by free radicals, which can delay aging and prevent AD; Ginsenoside has memory promotion and anti-apoptosis It is used to treat memory loss and prevent the development of AD, and has been clinically shown to promote the recovery of brain function in AD patients.
8. Conclusion
In recent years, the research on AD has been extended to neuropathology, genetics, immunology, etc., and the understanding of AD has been deepened to the molecular and genetic levels, but there is still a lack of sufficient understanding of the real causes and pathogenesis of the disease, so there are no efficient and ideal drugs for prevention and treatment at home and abroad. Therefore, the treatment of AD should be comprehensive, including social, psychological, rehabilitation and pharmaceutical aspects, with emphasis on early diagnosis and early treatment. We can believe that with the development of medical science and the deepening research on the pathogenesis of AD, the prevention and cure of AD will eventually become a reality.