Biomedical Engineering Reference
In-Depth Information
Presynaptic terminal
Presynaptic terminal
NH
2
Glial cell
HOOC
COOH
H
2
N
GABA (
15.1
)
COOH
Gln/αKG
SSA
Glu (
15.2
)
b, c
e
Glu
GABA
Gln/αKG
Gln
SSA
Gln
a
d
b, c
e
Glial uptake
Glu
GABA
Release
Release
Neuronal uptake
Neuronal uptake
Receptors
Receptors
Postsynaptic terminals
FIGURE 15.1
Schematic illustration of the biochemical pathways, transport mechanisms, and receptors at Glu
and GABA operated neurons. Enzymes are indicated by the following:
a
, glutaminase;
b
, glutamine synthase;
c
, aspartate synthase;
d
, l-glutamic acid decarboxylase (GAD);
e
, GABA aminotransferase (GABA-AT).
are under excitatory and inhibitory controls by Glu and GABA, the balance between the activities
of the two is of utmost importance for CNS functions. Both neurotransmitter systems are involved
in the regulation of a variety of physiological mechanisms and dysfunctions of either of the two can
be related to various neurological disorders in the CNS.
The transmission processes mediated by Glu and GABA are very complex and highly regulated.
A general and simple model for the Glu and GABA neurotransmissions is shown in Figure 15.1.
Glu and GABA are formed in their respective presynaptic nerve terminals and upon depolarization
released into the synaptic cleft in a high concentration to activate postsynaptic ionotropic recep-
tors that directly modify the membrane potential of the receptive neuron, generating an excitatory
or inhibitory postsynaptic potential. This basic system is further modulated through G-protein-
coupled receptors for a variety of neuroactive substances including Glu and GABA themselves.
Subsequently Glu and GABA are removed from the synaptic cleft into surrounding neurons and
glia cells via specialized transporters to restore the neurotransmitter balance. The reuptaken Glu
and GABA are enzymatically metabolized to form glutamine (Gln) or
α
-ketoglutarate (
α
KG) and
succinic acid semialdehyde (SSA), respectively.
15.2 THERAPEUTIC PROSPECTS FOR GABA AND GLUTAMIC
ACID NEUROTRANSMITTER SYSTEMS
The therapeutic potentials of manipulating these neurotransmitter systems seem to be unlimited.
Therefore, virtually all of the known molecular components of the GABA and Glu neurotrans-
mitter systems have been considered as potential therapeutic targets. The therapeutic indications
are numerous and include neurodegenerative disorders, e.g., Alzheimer's disease, Parkinson's dis-
ease, Huntington's chorea, epilepsy and stroke, and other neurologic disorders, e.g., schizophrenia,
depression, anxiety, and pain. Furthermore narcolepsy, spasticity, muscle relaxation, and insomnia
are among the vast number of therapeutic possibilities and i nally cognitive enhancers can be men-
tioned as a much pursued therapeutic application.
GABA-based therapeutics have been in clinical use for some time, where the most successful
therapeutic application to date involve the upregulation of GABA activity by the modulation of the
ionotropic GABA
A
receptor, notably by benzodiazepines (BZD) and barbiturates. Vigabatrin (
15.3
)
