Brain cholinesterase action

SPMD sample extracts, e.g., certain organochlorine pesticides (OCPs), are known to inhibit cholinesterase activity. Therefore, these results were not unexpected. However, it was surprising that a similar response was not observed with brain cholinesterase activity. It is possible that brain cells can more readily metabolize the chemicals, that the chemicals did not pass the brain blood barrier or that the effects occurred earlier in the exposure period, effectively allowing the activity to recover. Considering the numerous neurotoxic chemicals potentially entering aquatic ecosystems or present as airborne vapor phase chemicals, the neurotoxic mode of action related to exposure to contaminants is of increasing interest. Evidence presented in this work demonstrate that SPMDs concentrate members of this class of toxicants. 

These include the effects of nerve agents on y-amino-butyric acid neurons and cyclic nucleotides. In addition, changes in brain neurotransmitters, such as dopamine, serotonin, noradrenaline, as well as acetylcholine, following inhibition of brain cholinesterase activity, have been reported. These changes may be due in part to a compensatory mechanism in response to overstimulation of the cholinergic system or could result from direct action of nerve agent on the enzymes responsible for noncholinergic neurotransmission. 

Released ACh is broken down by membrane-bound acetylcholinesterase, often called the true or specific cholinesterase to distinguish it from butyrylcholinesterase, a pseudo-or non-specific plasma cholinesterase. It is an extremely efficient enzyme with one molecule capable of dealing with something like 10000 molecules of ACh each second, which means a short life and rapid turnover (100 ps) for each molecule of ACh. It seems that about 50% of the choline freed by the hydrolysis of ACh is taken back into the nerve. There is a wide range of anticholinesterases which can be used to prolong and potentiate the action of ACh. Some of these, such as physostigmine, which can cross the blood-brain barrier to produce central effects and neostigmine, which does not readily... 

The discovery of the loss of the cholinergic neurons and acetylcholine in the brain of Alzheimer s disease patients led to the use of drugs that would enhance the actions of acetylcholine in the brain. Therapeutic agents approved for the treatment of Alzheimer s disease are the cholinesterase inhibitors, drugs that block the breakdown of acetylcholine and increase the availability of the neurotransmitter in synapses (see Chapter 12). These drugs are palliative only and do not cure or prevent neurodegeneration. 

The medicinal chemistry of Alzheimers is complicated by the fact that the etiology of this disease is still far from clear. Evidence points to an association with decreased levels of acetyl choline in the brain. Many of the drugs that have been introduced to date for treating this disease thus comprise agents intended to raise the deficient levels of that neurotransmitter by inhibiting the loss of existing acetylcholine due to the action of cholinesterase. A compound based on an indene that, perhaps surprisingly, inhibits that enzyme has been proposed for the treatment of Alzheimer s. Aldol condensation of piperidine aldehyde (4-2) with the indanone (4-1) from cyclization of 3,4-dimethoxycinnamic acid leads to the olefin (4-3). Catalytic reduction removes the double bond to afford donepezil (4-4) [3]. 

CHOLINE AND CHOLINESTERASE. An enzyme iucetylchnlinesie rase I is specific for the hy droly sis of acetylcholine to acetic ueid and choline in the animal body. It is found in the brain, nerve cells and red blood cells and is important in the mechanism of nerve action. Acetylcholine w as first synthesized in 1867. It consists of a combination of chnlinc and acetic acid in an ester linkage. The component parts til the acetylcholine molecule are both normal constituents nf the animal body. Acetylcholine has the structure ... 

Therapeutic application of AChE inhibitors requires the need to monitor the activity of this enzyme on the periphery. Since the brain is the target organ for all potential cholinergic drugs, any peripheral measures can provide important information about a compound efficacy and mechanism of action. Such studies are relatively non-invasive and simple. The reliable correlation between peripheral and central cholinesterase inhibition in humans depend on many factors, clearly vary from drug to drug, and require detailed pharmacokinetic studies. 

Pyridostigmine bromide competitively binds to nerve tissue AchE. The binding is reversible and has been shown to protect AchE against irreversible inhibition by organophosphorus nerve agents. Pyridostigmine is a quarternary compound and does not readily cross the blood-brain barrier. Thus, it is not expected to affect or protect brain AchE. Cholinesterase inhibition, which is a mechanism of action, is also responsible for toxicity. 

There are no effective therapies for Alzheimer s disease and no cure. Treatment aims to enhance cholinergic transmission. The most useful drugs are central acetylcholinesterase inhibitors, for example donepezil. Acetylcholinesterase is the enzyme that normally breaks down acetylcholine after it has interacted with its receptors at the synapse. Inhibition of this enzyme in the brain increases the amount of acetylcholine available and prolongs its action. These drugs produce a modest improvement in memory or slow progression of symptoms in some patients. The response to anti-cholinesterase drugs may take several weeks. Their use is limited by side effects, which can be severe. 

---