Monoamine oxidase inhibitors Parkinson disease

Monoamine oxidases Inhibitors Depressive illness Parkinson s disease Neuroprotection neurorescue... 

Bromocriptine is a dopamine agonist acting by direct stimulation of the dopamine receptors. In Parkinson s disease, it is reserved for use in patients who are intolerant to levodopa or in whom levodopa alone is not sufficient. Orphenadrine is an antimuscarinic indicated in Parkinson s disease. Antimuscarinics tend to be more effective than levodopa in targeting tremor rather than rigidity and bradykinesia. Moclobemide is an antidepressant referred to as a reversible monoamine oxidase inhibitor (RIAAA) type A. 

Arguably the first modern class of antidepressants, monoamine oxidase inhibitors (MAOIs) were introduced in the 1950s but are now rarely used in clinical practice because of toxicity and potentially lethal food and drug interactions. Their primary use now is in the treatment of depression unresponsive to other antidepressants. However, MAOIs have also been used historically to treat anxiety states, including social anxiety and panic disorder. In addition, selegiline is used for the treatment of Parkinson s disease (see Chapter 28). 

Banisterine from Banisteria caapi and Nicotiana tabacum is a monoamine oxidase inhibitor that is similar pharmacologically to selegiline (deprenyl), which is used in the treatment of Parkinson s disease. 

Weinstock M, et al. A novel cholinesterase and brain-selective monoamine oxidase inhibitor for the treatment of dementia comorbid with depression and Parkinson s disease. Prog. Neuropsy-chopharmacol. Biol. Psychiatry, 2003, 27(4), 555-561. 

Because of undesirable side effects associated with monoamine oxidase inhibitor therapy (see section 2.3.2), pharmaceutical companies nearly abandoned research on new analogs in the 1960s. The early MAO inhibitors were nonselective and irreversible. Today, efforts toward the development of monoamine oxidase inhibitors are focused on selective MAQA or MAOB inhibitors. Selective MAOB inhibitors are being examined in the treatment of, for example, schizophrenia, Alzheimer s disease, and Parkinson s disease. MAO-B inhibitors might be effective in the treatment of depression, but relatively little woik has been done in this area. Selegiline... 

Youdim MB (1980) Monoamine oxidase inhibitors as anti-depressant drugs and as adjunct to L-dopa therapy of Parkinson s disease. J Neural Transm Suppl 16 157-161... 

Reserpine depletes the brain of dopamine and it is interesting that it produces only a slight increase in extrapyramidal symptoms in cases of severe Parkinsonism although it retains its tranquillizing activity . There is evidence also that, as in reserpinized animals, monoamine oxidase inhibitors do not increase the amount of dopamine in the brain of Parkinsonian patients, though accumulation of noradrenaline does occur. This has led some to suggest that in Parkinson s disease there is a reserpine-like principle in brain which interferes with the storage of dopamine. 

Meperidine has a strong adverse reaction when given to patients receiving a monoamine oxidase inhibitor. This drug interaction has been seen recently in patients with Parkinson s disease taking the monoamine oxidase-selective inhibitor selegiline (Eldepryl). 

Many other infrequent symptoms and abnormal laboratory findings have been associated with levodopa treatment. Metabolites cause the urine to turn reddish and then black. Many drug interactions are possible few are confirmed, but this possibility should be watched. Some monoamine oxidase inhibitors reported effective in Parkinson s disease caused hypertensive reactions in combination with levodopa, but tricyclic antidepressants... 

Chen, J.J., Swope, D.M., and Dashtipour, K. 2007. Comprehensive review of rasagiline, a second-generation monoamine oxidase inhibitor, for the treatanent of Parkinson s disease. Clin Ther, 2S (9) 1825-49. 

Ubiquitous mitochondrial monoamine oxidase [monoamine oxygen oxidoreductase (deaminating) (flavin-containing) EC 1.4.3.4 MAO] exists in two forms, namely type A and type B [ monoamine oxidase (MAO) A and B]. They are responsible for oxidative deamination of primary, secondary, and tertiary amines, including neurotransmitters, adrenaline, noradrenaline, dopamine (DA), and serotonin and vasoactive amines, such as tyramine and phenylethylamine. Their nonselec-tive and selective inhibitors ( selective MAO-A and -B inhibitors) are employed for the treatment of depressive illness and Parkinson s disease (PD). 

Monoamine oxidase exists in two forms, MAOa and MAOb. The former is more active against NA and 5-HT than it is against DA, which is a substrate for both, even though, like S-phenylethylamine, it is more affected by MAOb. H seems likely that MAOb is the dominant enzyme in human brain and inhibitors of it, such as selegiline, have some value in the treatment of Parkinson s disease by prolonging the action of the remaining endogenous DA as well as that formed from administered levodopa. 

Inside the cytoplasm of the presynaptic neuron the monoamines are exposed to the mitochondrial outer membrane-bound enzyme monoamine oxidase (MAO). MAO breaks the monoamines down into inactive metabolites before they are taken up into the vesicles. However, if MAO is inhibited, then the monoamines enter the vesicles and are available for release. MAO inhibitors, such as moclobemide, have been used in the treatment of depression, since they increase the availability of noradrenaline and serotonin. Selegiline is used for Parkinson s disease, since it raises dopamine levels. 

Levodopa, the metabolic precursor of dopamine, is the most effective agent in the treatment of Parkinson s disease but not for drug-induced Parkinsonism. Oral levodopa is absorbed by an active transport system for aromatic amino acids. Levodopa has a short elimination half-life of 1-3 hours. Transport over the blood-brain barrier is also mediated by an active process. In the brain levodopa is converted to dopamine by decarboxylation and both its therapeutic and adverse effects are mediated by dopamine. Either re-uptake of dopamine takes place or it is metabolized, mainly by monoamine oxidases. The isoenzyme monoamine oxidase B (MAO-B) is responsible for the majority of oxidative metabolism of dopamine in the striatum. As considerable peripheral conversion of levodopa to dopamine takes place large doses of the drug are needed if given alone. Such doses are associated with a high rate of side effects, especially nausea and vomiting but also cardiovascular adverse reactions. Peripheral dopa decarboxylase inhibitors like carbidopa or benserazide do not cross the blood-brain barrier and therefore only interfere with levodopa decarboxylation in the periphery. The combined treatment with levodopa with a peripheral decarboxylase inhibitor considerably decreases oral levodopa doses. However it should be realized that neuropsychiatric complications are not prevented by decarboxylase inhibitors as even with lower doses relatively more levodopa becomes available in the brain. 

B.M.H. Youdim, Y.S. Bakhle, Monoamine oxidase isoforms and inhibitors in Parkinson s disease and depressive illness, Br. J. Pharmacol. 147 (2006) 5287-5296. 

Deprenyl. Deprenyl, a selective monoamine oxidase B inhibitor that enhances dopaminergic function, is used in the treatment of Parkinson s disease. An open-label study (Jankovic et al., 1994) suggested that deprenyl could be effective for the treatment of ADHD in children with TS. A placebo-controlled crossover study (Feigin et al., 1996) of 24 subjects with ADHD and a tic disorder found that deprenyl was safe and effective at doses ranging from 5 to 10 mg/day. Only one subject showed an increase in tics. Interpretation of these results, however, is hampered by the clear evidence of an order effect. Subjects who received active drug first showed a 37% improvement in ADHD... 

Another approach to the therapy of Parkinson s disease involves the use of enzyme inhibitors. For example, inhibition of the enzyme monoamine oxidase B (MAO-B) by selegiline (4.105) improves the duration of L-DOPA therapy because it inhibits the breakdown of dopamine but not of NE. Likewise, inhibitors of catechol-O-methyl-transferase (COMT) can also be exploited as agents for the treatment of Parkinson s disease. L-DOPA and dopamine become inactivated by methylation the COMT enzyme responsible for this metabolic transformation can be clocked by agents such as entacapone (4.106) or tolcapone (4.107), allowing higher levels of L-DOPA and dopamine to be achieved in the corpus striamm of the brain. 

These reactions, which have provided a means of inhibiting the flavin-linked monoamine oxidases, enable us to end on a clinical note. The monoamine oxidases are responsible for the deamination of monoamines such as adrenaline, noradrenaline, dopamine, and serotonin, which act as neurotransmitters. Imbalances in the levels of monoamines cause various psychiatric and neurological disorders Parkinson s disease is associated with lowered levels of dopamine, and low levels of other monoamines are associated with depression. Inhibitors of monoamine oxidases may consequently be used to treat Parkinson s disease and depression. The flavin moiety is covalently bound to the enzyme by the thiol group of a cysteine residue (equation 9.17). The acetylenic suicide inhibitor N,N-dimethyl-propargylamine inactivates monoamine oxidases by alkylating the flavin on N-5.25 A likely mechanism for the reaction is the Michael addition of the N-5 of the reduced flavin to the acetylenic carbon 2... 

Tabakman R, Lecht S, Lazarovici P. Neuroprotection by monoamine oxidase B inhibitors a therapeutic strategy for Parkinson s disease Bioessays. 2004 26 80-90. 

The free phenols that are produced in the brain (when they break off during the reaction with AChE), are related to the drug selegiline (Fig. 12.8), which is a monoamine oxidase B (MAO-B) inhibitor, so that they also exhibit such inhibitory activity. MAO-B inhibitors are helpful in Parkinson s disease, mainly because they cause an increase in the level of dopamine, and are also antidepressants. These compounds are currently under investigation as treatment for Alzheimer s disease complicated by other cognitive deficits. 

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