Nervous system diseases cholinergic

The discovery that ACh was a transmitter in the peripheral nervous system formed the basis for the theory of neurotransmission. ACh is also a neurotransmitter in the mammalian brain however, only a few cholinergic tracts have been clearly delineated. ACh is an excitatory neurotransmitter in the mammalian CNS. There is good evidence that ACh (among other neurotransmitters) is decreased in certain cognitive disorders, such as Alzheimer s disease. 

Caldwell (4) prepared aryl substituted olefins, (IV), which were effective in activating nicotinic cholinergic receptors and used in the treatment of central nervous system disorders including Alzheimer s disease. 

The toxins that inhibit the AChE are called anticholinesterase (anti-ChE) agents. They cause acetylcholine to accumulate in the vicinity of cholinergic nerve terminals, and thus are potentially capable of producing effects equivalent to excessive stimulation of cholinergic receptors throughout the central and peripheral nervous systems (Long, 1963). Nevertheless, several members of this class of compounds are widely used as therapeutics agents others that cross the blood-brain barrier have been approved or are in clinical trial for the treatment of Alzheimer s disease. 

One of the major concerns aroused by exposures to chemicals that affect the nervous system is their potential to adversely impact cognitive functions such as learning and memory. Such a concern certainly has precedent. Lead exposure at high levels can leave children with permanent mental retardation. Recently, it has been demonstrated that even very low levels of lead exposure (i.e., environmental exposures) can produce subtle changes in cognitive processes. Pesticides are known to exert pronounced effects on cholinergic neurotransmitter systems, the very system that has been repeatedly implicated as a causative factor in Alzheimer s disease. 

Alzheimer s disease is associated with a progressive loss of cholinergic neurons in the brain that results in memory disturbances and cognitive dysfunction. One strategy for the treatment of Alzheimer s patients has been the use of acetylcholinesterase (AChE) inhibitors such as rivastigmine to enhance choUnergic activity in the central nervous system,... 

Tacrine (initially 10 mg p.o. q.i.d.) is indicated in the treatment of mild to moderate dementia of the Alzheimer s type. Although many neuronal systems are affected in Alzheimer s disease, the decline in central cholinergic activity is one of the most pronounced neurotransmitter deficits. Tacrine s primary effect is the reversible inhibition of cholinesterase—butyrylcholinesterase more than acetylcholinesterase. This inhibition increases the level of acetylcholine in the central nervous system. In fact, increased levels of acetylcholine have been detected in the cerebrospinal fluid of patients receiving tacrine (see also Figure 12). 

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