Drugs used in Alzheimer disease
The causes and symptoms of Alzheimer’s disease (AD)
According to the definition of the International Classification of Diseases (ICD-10), dementia - a complex of symptoms of pluricausal etiology. It is caused by brain disease and is usually chronic and progressive. In AD such higher cortical functions as memory, thinking, understanding, ability to learn and speak, perception of time and space as well as the ability to care for oneself are impaired.
1 Drugs used in Alzheimer disease
The damage of cognitive functions is accompanied by diminished emotional control, dysfunctional social behaviour and decreased motivation. Consciousness is not affected in dementia states.
An increased number of dementia states and depression syndromes are observed in people above the age of 65. The number of dementia cases increases in geometric progression and doubles every 5 years. About 350 000 people suffer from Alzheimer’s disease in Poland and about 25 mln worldwide.
2 Drugs used in Alzheimer disease A person’s age and a history of dementia in his or her family are considered to be hazard factors related to Alzheimer’s disease.
Women are observed to be affected by Alzheimer’s disease more often than men. However this is not a result of sex differences but a reflection of the fact that women live longer.
Less educated people seem to be affected more often and more severely.
Between 10% and 15% of cases of AD are of genetic origin. 3 Drugs used in Alzheimer disease
At present the following classification of AD cases is used: early-onset Alzheimer’s disease (affecting individuals aged below 60-65) late-onset Alzheimer’s disease.
Early-onset AD has a familial nature and many mutations that cause this kind of disorder are known. They are observed in: the gene encoding amyloid precursor protein, located on chromosome 21 the gene of presenilin 1, located on chromosome 14 the gene of presenilin 2, located on chromosome 1.
In the case of late-onset AD, the presence of the gene encoding apolipoprotein E4 is considered the main genetic factor.
4 Drugs used in Alzheimer disease
The many somatic causes of AD include among others:
metabolic diseases – hypothyreosis, diabetes, arterial hypertension toxic causes – alcohol, metal intoxication, chemical compounds and drugs.
5 Drugs used in Alzheimer disease The amyloid precursor protein (APP) is situated in the cell membrane. The sequence of beta-amyloid (the word beta means, that the protein is concertina- shaped, also called a pleated sheet) consists of 40 to 43 rests of amino acid. The point mutations of the APP gene are responsible for some forms of familial AD.
6 Drugs used in Alzheimer disease Different secretases participate in the transformation of APP.
-Secretase cleaves -amyloid between the 16th and 17th amino acid, thus preventing the creation of -amyloid 40/42 and its deposition in the brain. The extracellular domain APPs that is cut off has very important neurotrophic and neuroprotective properties.
APPS especially stabilizes the homeostasis of calcium ions in neurons and protects neurons from being over-stimulated by the stimulating transmitter, glutamic acid.
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An alternative transformation caused by -secretase leads to the formation of -amyloid.
-Secretase, which cuts the extracellular part of APP, leaves the whole sequence of -amyloid near the C-end fragment of protein.
Next, -secretase releases - amyloid.
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Under normal conditions the main created peptide is soluble -amyloid (A1-40); only approx. 10% of A are peptides A1-42 and A1-43.
-Amyloid acts neurotoxically only in fibrous form. The longer the chain of A, the greater its ability to aggregate.
One of the known mutations causes an equal increase in the biosynthesis of both forms of amyloid, A40 and A42, another leads to the appearance of the easily precipitated A 42. This fibrogenous -amyloid plays an important role in creating senile plaques, but it isn’t the only factor responsible for their creation.
9 Drugs used in Alzheimer disease
-Amyloid acts neurotoxically, because it induces the creation of free radicals and impairs the transport of glucose in neurons, which leads to the damage and death of cells.
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Presenilins are built from amino acids and permeate the cell membrane many Lumen of a tubule times, creating loops that Membrane of Golgi protrude outside and inside apparatus the membrane. If presenilins are to be active they have to be cut inside one of these loops by an enzyme, presenilinase. Presenilins modulate the metabolism of -APP in such a way that they behave like gamma- Cytoplasm secretase, thus controlling the length of A.
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Presenilins play an important role in regulating the level of calcium, in moving proteins in cells and in the neuron membrane as well as in differentiation of nerve cells and in apoptosis. Mutations of the genes of presenilins 1 and 2 lead to the onset of AD very early on, even before age 30. Mutations within the code gene of APP and the code genes of presenilins also increase the production of -amyloid A42. The genes of presenilins 1 and 2, similarly to the gene of APP, are causative genes because any changes in them cause AD.
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Apolipoprotein E appears in large amounts in nervous tissues and plays a vital role in the functioning of the peripheral and central nervous systems. It is produced predominantly in astrocytes and carried by low-density lipoprotein into neurons.
Apolipoprotein E is a serum protein which takes part in the transport of cholesterol. The gene of ApoE occurs in chromosome 21 in three variants – E2, E3 and E4. The isoform ApoE2 demonstrates protective action but ApoE4 increases the risk of developing AD. In people with AD ApoE4 is most often observed.
Individuals who have inherited the gene of apoE4 in both chromosomes are 8 times more likely to suffer from AD and the disease can appear at a younger age. In 50 per cent of patients with late-onset FAD (familial-Alzheimer’s disease) alleles ApoE-4 are observed on the long arm of chromosome 21 (16% in the control group). In 40 per cent of persons with sporadic Alzheimer’s disease (SAD) such location of these alleles is observed.
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Apolipoprotein E: increases accumulation of -amyloid in neurofibrillary structures is an important AD risk factor is not solely responsible for the onset of AD is not a specific AD factor
The gene of apolipoprotein E is recognized as a risk gene, because the presence of this gene increases the AD risk factor but it does not mean the certainty that AD will appear.
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Hyperphosphorylated tau proteins are the next factor causing the atrophy of neurons. These proteins are coded on chromosome 17. In physiological state, tau protein is one of the proteins which stabilize microtubules. In Alzheimer’s disease tau proteins form paired helical filaments and neurofibrillary tangles which surround the cores of senile plaques. Senile plaques consist of -amyloid, apolipoprotein E and other proteins. Senile plaques accumulate in intracellular spaces and are accompanied by the cells of inflammatory reaction, called microglia. Microglial cells are cerebral analoqus of macrophages. They try to decompose and Damaged microtubules remove damaged neurons and, possibly, senile plaques.
15 Drugs used in Alzheimer disease In Alzheimer patients the following is observed:
decreasing number of neurons (by up to about 80%), especially those whose neurotransmitters are acetylocholine and glutamic acid; in these regions of the brain the plicate are becomes smooth diminishing mass of the whole brain by about 10-15% compared with a healthy person at the same age diminishing area of the hippocampus, which is responsible for memory processes diminishing cerebral cortex, especially its front part by about 30%; the cerebral cortex participates in reasoning and other important processes.
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Morphologic changes are accompanied by biochemical changes:
increased concentration of apolipoprotein E in plasma and cerebrospinal fluid decreased choline acetyltransferaze in the cerebral cortex and the hippocampus, by about 70%, which results in a decreased concentration of ACh decreased glucose metabolism in the cells of the temporal lobes of the cerebral cortex, by above 40%.
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The beginning of Alzheimer’s disease is difficult to discern. A person’s memory is slightly worsening and his or her work is becoming less efficient in spite of a significant effort. Such symptoms can accompany different diseases and result from exhaustion or stress. In the further stages of the disease memory defects are compounded by difficulty in remembering new facts and an inability to concentrate. Changes like those are also typical of the normal process of ageing. Although they are troublesome they don’t eliminate an Alzheimer person from social life.
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The next stage of the disease is called dementia. More and more serious memory lapses occur. A sick person loses his or her sense of time and space and is often lost in what used to be familiar surroundings and unable to find the way home. Next, close relatives are no longer recognised, conversation becomes impossible and difficulty in getting dressed is observed. All those problems are accompanied by psychical changes such as frequent mood swings from aggression to apathy. In the final stage of AD, the patient’s consciousness is affected and the ability to move disappears. The person cannot stay upright or control his or her bodily functions.
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Those changes, over a period of 5 years, make the sick person totally dependent on the care of other people. In most cases that period ends with the person’s death. The longest time of survival does not exceed 12 years. Alzheimer’s disease develops the earliest in people with Down’s syndrome.
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Although the pathophysiology of AD is relatively well- understood, no drug that can stop the progress of AD is available.
Recent advances in the understanding of neurodegeneration in AD have not resulted in therapies able to slow it down.
At present, the goal of treatment of Alzheimer patients is to improve memory and cognition or at least reduce their loss in order to maintain the patient’s functional independence. 21 Drugs used in Alzheimer disease
In the treatment of AD the following efforts are undertaken:
the treatment of impaired cognitive functions by using nootropic drugs and drugs that improve blood flow in the brain symptomatic treatment (cholinesterase inhibitors and antagonist of NMDA receptors) therapy aimed at causal treatment treatment delaying disease progression pharmacological treatment of psychopathological symptoms non-pharmacological aid.
22 Symptomatic treatment
Symptomatic treatment is aimed at increasing cholinergic and glutaminergic transmission. ACh and glutamate are vital for the processes of learning and memorising. Degeneration in the basal forebrain profoundly reduces the content of acetylcholine and the activities of choline acetyltransferase. Although other neurotransmitters can be involved, the loss of acetylcholine occurs early and correlates with the impairment of memory.
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NEURON CHOLINERGICZNY Seryna Fragments of -amyloid can block: GLUKOZA GLUKOZA CO2 Etanoloamina Pirogronian S-adenozylo- • pyruvic dehydrogenaze metionina Pirogronian Cholina Acetylo-CoA • synthesis and fixation of ACh in cerebral Cholina vescicles Acetylo-CoA Acetylo- transferaza CoA cholinowa • uptake of choline ACh
ACh ACh ACh • effectiveness of creating secondary signals by muscarinic receptors. ACh błona presynaptyczna AChE ACh CHOLINA szczelina synaptyczna Kwas octowy błona postsynaptyczna AChE C G R EFEKTOR Kompleks receptora błonowego
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The inhibition of acetylcholine esterase in the area of the brain responsible for complex thinking processes partly explains why disorders of behavior and cognition are observed. At present the only effective form of treatment is the inhibition of the activity of cholinesterases.
25 Cholinesterase inhibitors
Drugs in this class vary in the way they inhibit the activity of acetylcholinesterase. Reversible inhibitors, such as tacrine and donepezil, bind to acetylcholinesterase and inhibit formation of the enzyme-acetylcholine complex.
Pseudoirreversible inhibitors, such as rivastigmine, do not directly inhibit the formation of the enzyme-acetylcholine complex but decrease enzyme activity directly.
The duration of action of these drugs depends not only on the type of inhibition produced, but also on the rate of enzyme resynthesis.
Cholinesterase inhibitors cause increased synaptic transmission by inhibiting the activity of AChE in the area of the synaptic cleft. 26 Cholinesterase inhibitors
There are two types of cholinesterase in the central nervous system: acetylcholinesterase (AChE) butyrylcholinesterase (BuChE).
Until recently the significance of BuChE was not fully appreciated in spite of the fact that both enzymes control the level of acetylcholine and that they can play an important role in the development and progression of AD. Although their molecular structures are similar, their distribution, substrate specificity and functions are different.
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These significant differences between the two types of cholinesterase are responsible for the fact that they are different biochemically.
That explains why AChE and BChE perform different functions in a healthy and affected brains. In the brain of a healthy person AChE is responsible for 80% of the activity of cholinoesterases. AChE occurs mainly in neurons.
BChE is bound mainly with glial cells. AChE is more efficient at low concentrations of substrate and is inhibited by the excess of acetylcholine. BChE is more efficient at high concentrations of ACh, when AChE is inhibited.
28 Cholinesterase inhibitors
In advanced AD the activity of AChE can be significantly decreased in some regions of the brain, when the activity of BChE is increased. The ratio of BChE to AChE changes rapidly in the regions of the cerebral cortex affected by the disease. There is evidence that BChE can play an important role in the aggregation of -amyloid, which appears in the early stage of AD when senile plaques are formed.
After adding -amyloid to a tissue culture an increase in its neurotoxicity was observed. It demonstrates that inhibiting BChE can have a potential therapeutic effect in AD. A potential relationship between one of the forms of BChE and the probability of developing AD has been demonstrated in genetic studies in the case of people who have a gene for apolipoprotein Apo4.
29 Chemical structure and characteristic of action of I-AChE
Action Drug Tacrine inhibitor: non-competitive reversible NH2 selectivity: BuChE > AChE
frequency of administration : 4 x daily; t0,5 of elimination = 3 h N metabolism: hepatic – CYT P450 1A2 unwanted effect: cholinergic, hepatotoxic Donepezil, ARICEPT inhibitor: mix reversible N 1 selectivity: AChE > BuChE O H CO 4 frequency of administration: 1 x daily; t0,5of elimination = 70 h 3 1 6 2 5 metabolism: hepatic – CYT P450 3A4 i 2D6 H3CO Unwanted effect: cholinergic
Rivastigmine,EXELON CH3 CH3 inhibitor: non-competitive reversible H N N selectivity: AChE = BuChE O H C frequency of administration: 2 x daily; t0,5of elimination = 1,5 h 3 N O H CH3 metabolism: hepatic – esterases unwanted effect: cholinergic OH Galantamine, NIVANIL, REMINYL H inhibitor: competitive reversible O selectivity: AChE > BuChE H3CO frequency of administration: 2 x daily; t0,5 of elimination = 5,5 h N metabolism: hepatic – CYT P450 3A4 i 2D6 CH 3 unwanted effect: cholinergic
30 Cholinesterase inhibitors
Treatment with cholinesterase inhibitors should not be interrupted. When drug administration is discontinued cognitive ability rapidly declines and it is impossilbe to restore it by resuming treatment. Treatment with cholinesterase inhibitors can begin at any time after diagnosis. Because large doses have the greatest benefits and the most adverse effects, it is recommended that dosage is gradually increased to the maximal tolerated dose.
Cholinesterase inhibitors elevate the natural level of ACh but do not stimulate the cholinergic receptors tonically or generally. Cholinesterase inhibitors specific to the brain delay the inactivation of ACh after its release to the synaptic cleft and in this way they prolong the activity of this neurotransmitter in the central nervous system (CNS).
31 Antagonists of NMDA receptors (N-methyl-D-aspartate)
In hypoxia an increased release of glutamate is observed, which increases the stimulation of receptors. The glutamate neurotransmitter plays an important role in the process of neurodegeneration. The pathomechanism of epilepsy and degenerative diseases such as Parkinson’s disease, Alzheimer’s disease or Huntington’s disease is related to an excessive release of glutamic acid and aspartic acid.
In Alzheimer’s disease a pathological, constant elevation of the concentration of glutamate in the synaptic cleft is observed. Memantine acts as a modulator of glutaminergic neurotransmission.
32 Antagonists of NMDA receptors (N-methyl-D-aspartate)
It blocks NMDA receptors when the release of glutamate is pathologically increased. NMDA receptors are activated by glutamate and in the nervous cells of the brain they are responsible for the direct inflow of calcium ions. Thus they are vital for the transfer of learning and memory signals. Chronic overstimulation of NMDA receptors by an excess of glutamate damages cells because of overloading them with calcium ions.
Memantine can protect nervous cells from damage and improve the functions of previously damaged nervous cells. Its action depends on its concentration, so it does not completely inhibit glutaminergic transmission but only modulates it. In this way it decreases noise levels and allows the reception of memory signals.
NH2 Memantine, AXURA CH3 3,5-Dimethyl-1-adamantanamine H3C 33 Measures aimed at causal treatment
When the neurotoxicity of -amyloid and the transformations of APP are understood, it may be possible to use causal treatment. Efforts are being made to influence the stages of the pathologic mechanism which results in the formation of senile plaques and neurofibrillary degeneration by strengthening neurons and stopping neurodegeneration.
34 Measures aimed at causal treatment
Clinical tests are done to:
diminish the concentration of apolipoprotein E or reduce inflammatory reaction
inhibit the creation of -amyloid (activation of -secretase or inhibition of -secretase)
break amyloid deposits (so called breakers – short peptides of a similar structure as -amyloid but with sequences that are not included in the -sheet).
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What may be especially beneficial is the transformation of APP caused by -secretase, which results in neuropretective action. It is possible due to the stimulation of M1-muscarinic receptors by the selective agonists of M1-receptors. The density of M1-receptors in the brain is relatively high. Stimulation of these receptors on the surfaces of neurons and glia cells increases the creation of APPs and reduces the parallel decomposition of APP by -secretase. Research on cell cultures has shown that talsaclidine, an M1- selective muscarinic agonist increases the rate of secreting APPs over 25 times.
36 Measures aimed at causal treatment
Double inhibitors of - and -secretases, which directly inhibit neurotoxic -amyloid, are recognized as interesting drugs for the causal treatment of AD to be used in the future. Protease inhibitors of that type are in the first phase of preclinical tests.
The fact that -amyloid is first released in a non-toxic form and next, after aggregation, acts neurotoxically is the basis for research aimed at finding drugs that inhibit aggregation of -amyloid. Such action is demonstrated by Congo red.
37 Measures aimed at causal treatment
Fibrous amyloids are very resistant to proteases. There is strong evidence that the fibrous amyloid causes amyloidosis. One of the symptoms of amyloidosis is storage of normal plasmic proteins in fibrous amyloid. These proteins are called SAP (Serum Amyloid P-Component). SAP is a natural protein that appears in the human body and is sometimes stored in amyloids, which has a harmful effect. As a result, amyloid plaques do not decompose and amyloidosis aggravates. The compound CPHPC, which is a competitive inhibitor of places where SAP is bound, is undergoing clinical trials. CPHPC causes two molecules of SAP to bind and the dimmer that is created is rapidly removed from the liver. Decreased number of protein circulating in plasma leads to the removed of SAP from plaques and destabilizes the amyloid.
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There are many indicators that AD has chronic- inflammatory progression. Microglia cells parcipitate in inflammatory brain reactions. They are activated by various stimulants, including fibrous -amyloid.
Activated microglia cells release many cytotoxic substances such as proteases, anionoradical superoxide, hydrogen peroxide, nitrogen oxide, prostaglandins, leukotriens, cytokines (IL-1, IL-6, TNF) and a complementary factor. It is believed that a new generation of anti-inflammatory drugs can be effective in the treatment of AD. Drugs used to treat other diseases, such as dapsone (used in leprosy) or naproxen (NSAID), are also being tested now. 39 Treatment slowing the progression of AD
In this case the mechanisms that protect biological membranes from the harmful action of lipid peroxidation are employed .
To slow the progression of AD the following are also used:
Propentophylline, a xanthine derivative, which stimulates the synthesis and release of the neuron growth factor in the basal forebrain Acetyl-L-carnitine, an intracellular carrier of acetyl groups through mitochondrial membranes that promotes acetylcholine release, which increases choline acetyltransferase activity, and has antioxidant action 40 The pharmacologic treatment of psychopathologic symptoms
The patient’s deteriorating memory and impaired interaction with the surrounding world compounded by anxiety, depression, sleep difficulties, aggression, hallucinations and delusions put a great strain on the Alzheimer person and his or her carers.
To treat those symptoms neuroleptic, antidepressive and sedative drugs are used. Administering such drugs requires special caution because of the possible adverse effects, for example serotoninergic, extrapyramidal and central anticholinergic symptoms, and excessive sedation.
41 Non-pharmagologic assistance
In the first stage of the disease memory exercises are effective. Sometimes therapy with music is applied too. In the final stage, occupational therapy and physical exercises that strengthen the muscles of the pelvis minor to maintain the function of the sphincters are helpful.
The carers also need assistance. The Alzheimer’s Association, a national organization with local chapters, has been formed to provide support for Alzheimer’s caregivers. It is a valuable source of information and advice.
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