The cause of AD has not been fully elucidated yet, and the treatment is mainly through the action of drugs on different neurotransmitter systems to enhance the advanced activities of the central nervous system, alleviate the various symptoms that appear during the disease process, and delay the further development of dementia.
I. Cholinergic drugs
1.Donepezil
It is a selective, non-competitive and reversible second-generation AchE inhibitor, which belongs to benzyl piperidine class and is highly selective.
It is metabolized by the liver, and adverse reactions are more common at the time of administration and less common during the maintenance phase, mainly nausea, vomiting and diarrhea. The results of short-term clinical trials have shown that the drug can improve cognitive function and overall function without serious adverse effects.
2.Lisdexamfetamine
It is a non-competitive carbamate cholinesterase inhibitor and butyrylcholinesterase inhibitor. It can selectively inhibit AchE in cerebral cortex and hippocampus, and has less effect on corticocerebellar pathway and striatal pathway, which can avoid inhibiting respiratory center and producing extrapyramidal symptoms.
The drug does not depend on the hepatic cytochrome P450 enzyme system for metabolism, and drug interactions rarely occur, and no hepatotoxicity has been reported. Esnon not only improves the clinical performance of patients with mild to moderate AD, but also is more effective in advanced severe AD. Common adverse effects include gastrointestinal symptoms and drowsiness, fatigue, etc.
3.Galantamine
It is a second-generation reversible competitive AchE inhibitor and nicotinic receptor modulator, with dual effects. Its selectivity is high, and its AchE inhibitory activity in neurons is 50 times higher than that of butyrylcholinesterase activity in plasma. It can significantly improve cognitive function and maintain daily living ability and behavior in AD patients. The peak blood time after oral administration is 2 h, and the T1/2 is 5 h to 6 h. Oral doses of 30 mg to 60 mg・d-1・Tid are rapidly absorbed and well tolerated. The main adverse effects are nausea, tachycardia, insomnia, etc.
4.Huperzine A
Huperzine A is a highly effective and reversible competitive AchE inhibitor, which is isolated from the Chinese herbal medicine Huperzine A by our scientists. It can easily pass the blood-brain barrier, significantly increase the Ach content in frontal, temporal and hippocampal brain regions, has a long effective time, and its strength of action is second only to donepezil, and repeated use does not increase the tolerance of AchE.
Lithospermidine A has multi-target effects, which can reduce glutamate-induced neuronal cell death; has obvious protection of neuronal cells against oxidative stress produced by β?amyloid peptide; can counteract the apoptotic effects of neuronal cells induced by hydrogen peroxide and protein kinase C inhibitors, etc. It can significantly improve cognitive function, behavioral and mood disorders, daily living ability and overall function in AD patients. The common dose is 0.4 mg・d-1・Bid・Po. Common adverse effects include dry mouth, drowsiness, gastrointestinal reactions, blurred vision, etc., which can generally be relieved or disappeared after dose reduction or discontinuation. At present, this drug has become the most successfully developed and promising drug for the treatment of AD in China.
II. Memantine
It is a non-competitive antagonist with low toxic affinity for glutamate receptors. It was started to be used for the clinical treatment of AD in Europe in 2002 and approved for clinical use by FDA in November 2003. Memantine protects nerve cells from the toxic effects of excessive excitatory amino acids and is effective not only in mild AD, but also significantly improves the clinical symptoms of severe dementia, and significantly increases the efficacy when combined with AchE inhibitors. It is well tolerated.
III. Antioxidants
Oxidative free radicals are thought to be involved in the process of AD brain cell death. Free radicals cause Αβ deposition, which reacts with neural membranes and leads to intracellular oxidative processes resulting in free radical release. Damage to neural membranes may be an important cause of pathological changes in AD. Drugs that reduce the production of free radicals in the brain and drugs that protect neurons from free radicals have the potential to slow down the process of lesions; therefore, antioxidants may have a therapeutic role in AD.
1.Silegiline
It is a selective and irreversible monoamine oxidase B inhibitor, which can reduce catecholamine degradation in the brain, inhibit neuronal degeneration and reduce mitochondrial free radicals, and has neuroprotective effects. Long-term administration can prevent and delay neuronal degeneration. The main adverse effect is postural hypotension.
2.Vitamin E
It has antioxidant effect, can reduce lipid peroxidation and improve the tolerance of hippocampal cells to ischemia; high oral dose can inhibit and remove the deposition of Αβ in the CA1 area of hippocampus and produce the effect of delaying aging.
3.Melatonin
It is an endogenous antioxidant hormone, which can promote the activity of various antioxidant enzymes in the body, directly scavenging free radicals or synergistically inhibiting the generation of free radicals; it can also interfere with the processing of APP, reduce the formation of Αβ, inhibit the aggregation of Αβ, reduce the deposition of Αβ, and make it easy to be absorbed or degraded by the body, thus inhibiting the neurotoxic effects of Αβ.
4.Ginkgo biloba extract
The active ingredients in the extract are ginkgo flavonoid glycosides, terpene lactones, ginkgolic acid, etc. The most studied one is Egb761, which has antioxidant effect and can scavenge free radicals to protect vascular endothelial cells. It can dilate cerebral blood vessels, increase cerebral blood flow, reduce blood viscosity and prevent thrombosis, and is suitable for mixed dementia (AD and vascular dementia).
IV. Immunotherapy
Divided into active immunotherapy and passive immunotherapy, it improves the clinical symptoms of AD by delaying and clearing the clustering of Αβ in brain tissue.
V. Brain cell metabolism activator
The occurrence of AD is closely related to the physiological and biochemical changes caused by aging. Brain cell metabolism activators can promote oxygen, sugar, nucleic acid, lipid and protein metabolism in cerebral cortex cells, improve adenylate kinase activity and nitrogen ATP/ADP ratio, and dilate cerebral blood vessels, improve blood circulation in the brain, enhance the reactivity, excitability and memory of patients, and have It has different degrees of improvement on cognitive impairment and some psychiatric symptoms of AD. These drugs include piracetam, aniracetam, and nafetilacetam.