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J. A. RIBEIRO AN. R. ACAD. NAC. FARM.

potential neurotoxin within the mammalian brain. Experimental
evidence suggests that hyperactivity of the glutamate NMDA-receptor
mediated current system contributes to neuronal death. Also, this
neural injury is followed by gliosis which has been linked to the
severity of brain lesions. In this context, investigation of substances
that can selectively inhibit the glutamate NMDA receptor subtype in
humans, while also therapeutically controlling glial cell responses and/
or triggering the release of neuroprotective factors from these cells
following brain insults, would be of great help in neuroprotection.
This has led to the application of pharmacological strategies to limit
the lesions and subsequent neurological deficits. The research on
pharmacological agents will help to promote functional rewiring of
brain after injury in order to obtain neural repair and neurological
rehabilitation.

So, the immediate question is: what occurs at a glutamatergic
synapse during insults? The actual consensus is that too much
glutamate is being released and the NMDA-R «till then silent» is
opened and becomes too much permeable to Ca2+ ions. Because the
cell suffers from energy supply i.e. there is no ATP available for the
Ca2+ pumps to expel the excess of Ca2+, the neurons die. According
to this theory if one inhibits glutamate release during insults and/or
inhibits NMDA-R activation one could save neurons from the
deleterious effects of glutamate.

How one could inhibit glutamate release during insults?

It is well known that if one measures synaptic transmission
activity (e.g EPSPs) from rat hippocampal slices, and hypoxia is
applied for 90 minutes, this insult inhibits and eventually completely
blocks synaptic transmission, an effect that is completely recovered
when hypoxia is terminated. It is well established that the inhibitory
neurotransmitter, gamma-amino-butyric acid (GABA), inhibits
glutamatergic transmission in normoxic conditions but it does not
work during hypoxia (see 19).

If GABA, the main inhibitory transmitter in the brain, is not
apparently effective during hypoxia to control glutamate involvement
in the hypoxia insult, the question one could ask is: which other

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