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significant complication, this treatment has not yet been able to become part of standard
clinical management strategies (Petros, Lamb et al. 1994; Grover, Zaccardelli et al. 1999).
2.3.4 (ii) Nervous system - central and peripheral
NO has become accepted as a non-endogenous messenger, signal mediator and non classical
neurotransmitter with NO synthases (see Chapter 3.4 'Nitric oxide synthase isoenzymes')
detected in varying amounts in all areas of both animal and human brain @redt and Snyder
1990). NO synthases are highly similar to NADPH diaphosphorase which is found in about
2Vo of the neurons in the cerebral cortex @astian and Hibbs 1994), and the two enzymes are
closely colocalised in both the brain and the peripheral nervous system. Glutamate is the
main excitory neurotransmitter and an interaction between this and NO was demonstrated
early (Garthwaite, Charles et al. 1988). After specific receptor stimulation, NO is released
from a postsynaptic source to act at a presynaptic region on one or more neurons in any
direction. This results in an increase in glutamate and a stable increase in synaptic
transmission, a phenomenon known as long-term potentiation @liss and Collingndge 1993),
which is linked to memory formation (ODell, Hawkins et al. 1991). Experiments in animals
have shown that inhibiting NO synthesis by analogue competitive inhibitors impairs learning
behaviour (Son, Hawkins et al. 1996). NO has also been shown to have a role in feeding
behaviour, nocioception and olfaction (Bagetta, Iannone et al. 1993). An increasing body of
work has continued to demonstrate the importance of NO in both short and long term memory
(Susswein, Katzoff et al. 2004). In addition, the NO produced by the perivascular nerves of
the cerebral arteries directly modulates vascular control (Gonzalez, Barroso et al. 1997). NO
may also have a role in modulating pain (Moore, Babbedge et al. 1993).
At low concentrations, NO plays a role in vasodilatation and neurotransmission, however at
higher concentrations it can be neurotoxic. It also may be that NO can possess either
neurodestructive or neuroprotective properties depending on its oxidation reduction status
(see Chapter 3 'Reactions with nitric oxide'). Microglial cells, which are of monocyte-
macrophage derivation, can express the form of NOS which gives very high levels of NO (see
Chapter 3: inducible NOS) within the central nervous system. These cells are implicated in
the pathogenesis of neurodegenerative disease with excess generation of NO and high
glutamate levels acting via receptors shown to mediate cell death in focal ischemia, Krabbe's
disease, Huntington's disease and Alzheimer's disease (Choi 1988; Meldrum and Garthwaite
1990; Snyder L993; Vodovotz, Lucia et al. 1996; Dawson and Dawson 1998; Akiyama,
Barger et al. 2000). For example, NOS inhibitors blocked ischemic damage following middle
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