Pathological changes in AD involve cholinergic neuronal pathways that project from the basal forebrain to the cerebral cortex and hippocampus. These pathways are thought to be intricately involved in memory, attention, learning, and other cognitive processes. In fact an early pathophysiological feature of Alzheimer’s disease that is associated with memory loss and cognitive deficits is a deficiency of acetylcholine as a result of selective loss of cholinergic neurons in the cerebral cortex, nucleus basalis, and hippocampus. These deficits are brought about by decreased concentrations of acetylcholine, which are modulated by the enzyme cholinesterase. This enzyme is of neuronal origin and functions to metabolize acetylcholine at synapses throughout the nervous system. In other words, cholinesterase breaks down acetylcholine, a neurotransmitter which assists in human memory and cognition processes. So, while the precise mechanism of rivastigmine’s action is unknown, it is postulated to exert its therapeutic effect by enhancing cholinergic function. It binds reversibly with and inactivates chlolinesterase (acetylcholinesterase and butyrylcholinesterase), and prevents the hydrolysis of acetycholine. Thus it leads to an increased concentration of acetylcholine at cholinergic synapses for memory and cognitive functioning. The anticholinesterase activity of rivastigmine is relatively specific for brain acetylcholinesterase and butyrylcholinesterase compared with those in peripheral tissues.
Therefore, by inhibiting cholinesterase, more acetylcholine is available to the patient. This is effective in treatment of AD, since acetylcholine is at significantly lower levels in AD patients than in normally functioning people. However, it should be noted that CholinEsterase Inhibition (ChEI) is a symptomatic, not causal, treatment of AD, because ChEI simply increases the concentration of acetylcholine in the brain.
A feature of AD is that as it progresses and cortical neurons are lost, levels of acetylcholinesterase progressively decline, while levels of butyrylcholinesterase increase. Butyrylcholinesterase can and does take over the function of metabolizing acetylcholine at the synapse, when acetylcholinesterase is lost. This is a phenomenon that has been demonstrated in an acetylcholinesterase knockout mouse model and which probably occurs in AD. Rivastigmine, but not its competitors, inhibits both acetylcholinesterase and butyrylcholinesterase by covalently binding to active sites on these enzymes, blocking their function.
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