Biomedical Engineering Reference
In-Depth Information
called ampokines such as aniracetam (
16.4
) has also been pursued as a way to treat AD. Finally, the
effects of steroids and nonsteroidal anti-inl ammatory drugs (NSAIDs) on the inl ammation and of
antioxidants on the oxidative damages observed in AD are also being investigated.
16.2 CHOLINERGIC SYNAPTIC MECHANISMS AS THERAPEUTIC TARGETS
The neurotransmitter acetylcholine (ACh,
16.5
) is found throughout the body, where it regulates a
wide range of important functions. In the periphery, cholinergic signaling is, for example, of key
importance for cardiac function, gastric acid secretion, gastrointestinal motility, and smooth muscle
contractions. In the CNS, cholinergic neurotransmission is involved in numerous processes underly-
ing cognitive functions, learning and memory, arousal, reward, motor control, and analgesia.
The cholinergic synapse and the complex events underlying cholinergic neurotransmission are
depicted in Figure 16.4. ACh exerts its physiological effects via signaling through two distinct recep-
tor classes: muscarinic ACh receptors (mAChRs) and nicotinic ACh receptors (nAChRs), which
mediate the metabolic (slow) and the fast response to ACh, respectively. Once ACh is released into
the synaptic cleft, two cholinesterases, acetylcholinesterase (AChE, EC 3.1.1.7) and butyrylcholin-
esterase (BuChE, EC 3.1.1.8), are responsible for its conversion into choline (
16.6
), which subse-
quently is taken up into the presynaptic terminal.
16.3 CHOLINESTERASES
The events underlying cholinergic neurotransmission depicted in Figure 16.4 are not that different
from those in other neurotransmitter systems, as these also involve the biosynthesis and storage
of the neurotransmitter in synaptic vesicles, synaptic release, and activation of different recep-
tor classes and reuptake by transporter systems. The only extraordinary feature of the cholin-
ergic synapse is the presence of two synaptic enzymes converting the neurotransmitter into its
precursor in order for it to be taken back up by the presynaptic terminal. The AChE and BuChE
belong to the “a/b hydrolase fold protein” superfamily comprising serine hydrolases such as
cholinesterases, carboxylesterases, and lipases. Both cholinesterases are present in cholinergic
synapses in the CNS, in the parasympathic synapses in the periphery, and in the neuromuscular
junction. Whereas AChE is selective for ACh hydrolysis, BuChE accommodates and degrades
several other substrates, including numerous neuroactive peptides. Of the two enzymes most
attention has been paid to AChE, since it is responsible for ~80% of the total cholinesterase
activity in the brain and has a remarkable high turnover (in the 10
4
s
−1
range) compared to
BuChE.
16.3.1 C
HOLINESTERASE
I
NHIBITORS
The physiological signii cance of AChE activity is rel ected by the observation that it is targeted by
numerous “natural” and synthetic toxins, ranging from snake and insect venoms to pesticides and
nerve gasses used in chemical warfare. The efforts in the design of AChEIs in medicinal chemistry
have been greatly facilitated by the availability of crystal structures of AChE complexed with ligands.
Based on the nature of their activity, AChEIs can be divided into two main classes: (1) irreversible
organophosphorus inhibitors and (2) reversible inhibitors. Compounds such as dyl os (
16.7
) and sarin
(
16.8
) belong to the former class, which due to the irreversible nature of their action are characterized
by having a long duration of action in the body, since AChE activity only is restored after resynthesis
of the enzyme.
The reversible AChEIs were the i rst drugs developed for the symptomatic treatment of AD, and
the drug class is still dominating the i eld. Inhibition of synaptic cholinesterase activity has proven
to be efi cacious in the treatment of AD, as the effect of this amplii cation of the natural spatial and
temporal tone of ACh-mediated signaling seems to be preferable to the constant stimulus resulting
from direct activation of mAChRs or nAChRs by agonists.
