Toxicology of Industrial Compounds

Kainic acid
K.J.VAN DEN BERG ET AL. 243
Kainic acid (KA), a glutamate agonist, is a potent model neurotoxin that
causes neurodegeneration in a number of limbic structures including
hippocampus, amygdala, piriform cortex (Sperk et al. 1983; Ben-Ari,
1985). It is generally assumed that the mechanism of action involves
interaction of KA with a special class of glutamate receptors and release of
endogenous excitatory amino acids in levels that are detrimental to
neurons (Meldrum and Garthwaite, 1990).
Kainic acid did induce, in a single systemic dose (12 mg kg −1 ), highly
increased concentrations of GFAP in a number of target structures. For
instance in hippocampus and amygdala GFAP levels did rise to 650 and
960 per cent of control levels (Figure 18.1, upper right panel). Recent
results from this laboratory have revealed that in a time-course study (Van
den Berg and Gramsbergen, 1993) maximum levels are obtained after 4
weeks that remained highly elevated in most target brain regions for at
least a period of 6 months (Figure 18.2). The quantitative data on GFAP
concentrations were supported by increased GFAP immunoreactivity in
hippocampal sections visualized by immunohistochemical procedures. In
addition to the damage in the hippocampus, permanently enhanced GFAP
levels were found in other brain regions, e.g. piriform cortex, septum
(Gramsbergen and Van den Berg, 1994) known to be targets of KA
neurotoxicity.
Synaptophysin levels were significantly reduced by KA in hippocampus
and amygdala to a comparable degree (Figure 18.1, lower right panel).
These data indicate a decrease in synaptophysin content encountered in
brain regions where neuronal elements are known to be lost by these
model neurotoxins. The magnitude of the changes in synaptophysin
concentrations were much smaller than those of GFAP in the same brain
structures. This may be explained by the fairly selective neuronal loss in
specific layers of, for instance, the hippocampus, by TMT and KA. The
effect is thus rather diluted in a biochemical procedure. Once an effect is
scored, more detailed biochemical analysis is possible by using a punch
technique after microdissection of brain nuclei (Palkovits and Brownstein,
1988). Alternatively, a follow-up by histopathological procedures, for
example by the cupric silver degeneration stain, would provide further
details of neuronal damage (O’Callaghan and Jensen, 1992). In the
experiments described above there was no clear correlation between the
graded regional GFAP response and decrease of synaptophysin
concentration. This may suggest a differential region-specific response of
astrocytes towards neuronal injury.
In our laboratory cerebral calcium accumulation was determined
recently after a single systemic dose of KA (12 mg kg −1 , i.p.), given to adult
rats. A rapid uptake of 45 Ca was observed in various regions of the brain. A