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Figure 2: Colour-coded Images from Autoradiographs their ubiquitous distribution and multiple functions. In fully PTZ-
Showing the Overall Changes for Kainate-binding
kindled rats and in the PTZ model of a repeated series of seizures,
Sites of Control and Pentylenetetrazole-treated Rats
kainate-binding sites are significantly reduced (see Figure 2).
fmol/mg protein 279 253 777 1026 1275
Therefore, the overall differences reported for the glutamate
receptors among mice and rats could be related to the post-seizure
times at which the measurements were performed. Despite these
model-specific differences, it should be emphasised that a
combined inhibition of AMPA and NMDA receptors prevents PTZ-
induced tonic–clonic seizures.
In contrast to the more ubiquitous
downregulation of kainate receptors, dopamine receptors (D1 and
D2) become reduced in a more region-specific manner, mostly
affecting the amygdala.
Effects have also been described or
postulated for the other monoaminergic receptors, mainly as
compensatory responses to PTZ kindling.
Despite the fact that PTZ has been shown to be an antagonist at
control PTZ GABA
receptors by means of a rat model of repeated series of
seizures, no changes in GABA
binding occurred. However, a
Scale bars code receptor densities in fmol/mg protein. The same scaling was used for
significant increase in benzodiazepine (BZ)-binding sites was
pentylenetetrazole (PTZ)-treated and control brains. For further details refer to Cremer
observed. Since GABA and BZ-binding sites are localised atet al., 2009.
different positions within the functional GABA
a persistent decrease occurred in the striatum.
Within the the subunit composition of the GABA
receptors may change in
so-called epileptic circuitry,
hippocampal, cerebellar and striatal such a way that BZ can potentiate GABAergic inhibition, as
alterations of A1 binding occurred immediately and persisted, discussed in further detail by Cremer et al.
whereas increases in cortical regions developed during kindling. In
an elegant comparison, the authors also showed that in a colony of Taken together, there are multiple PTZ-induced changes in
‘tottering mice’ (a model closely resembling absence epilepsy), A1 neurotransmission at the receptor level, indicating that these
binding is unaltered compared with PTZ models, indicating that alterations occur in order to compensate for seizure-induced
different semiology may affect A1 binding.
adverse neurological effects. As the major changes remain
restricted to cerebral regions belonging to the so-called epileptic
Furthermore, a clear model-dependent difference was also revealed circuitry,
the observed alterations are most likely seizure-
for the A1 receptor, as mice used in the kainate model exhibited a associated and not attributable to more general pharmacological
reduction in hippocampal A1-binding sites due to the early occurring effects of PTZ. Therefore, the changes reported in terms of receptors
neurodegeneration. This indicates that a significant amount of A1- and/or transmitter synthesis, release and recycling are indicative of
binding sites are post-synaptically localised,
and particularly the induction of multiple neurotransmission-related CGECs.
highlights specific differences between models with initial
neurodegeneration and the PTZ model with no or comparatively Oxidative and Nitrosative Stress
late neurodegeneration. As neurodegeneration is associated with For various PTZ models, oxygen- and pH-related changes were
glial changes (mainly with astrocyte proliferation) leading to gliosis, reported early in the history of seizure semiology.
As in most other
a hallmark of epilepsy, the above-discussed data indicate that a models of experimental epilepsy, clear signs of oxidative stress
possible glial A1 expression does not compensate for neuronal A1 occur shortly after PTZ application, such as alterations of the thiol
reduction in the kainate model. In contrast to the data obtained in redox state and lipid and protein oxidation.
mice, repeated series of PTZ-induced seizures in the Wistar rat led
to a reduction in G-protein-coupled high-affinity A1-binding sites.
The reason for these contradicting results could be related to either
As in most other models of
species-specific differences or to the use of different ligands in the
experimental epilepsy, clear signs of
presence or absence of guanosine 5’[β,y-imido]triphosphate.
oxidative stress occur shortly after
pentylenetetrazole application, such as
(AMPA)-receptor binding increases in a transient time-dependent
following PTZ-induced seizure episodes, whereas no
alterations of the thiol redox state and
significant changes were reported for the rat 24 hours after the last
lipid and protein oxidation.
However, focusing on the N-methyl-D-
aspartic acid (NMDA) receptor in mice, a long-lasting upregulation
of NMDA-binding sites occurs in mice, which has also been seizures and kindling, the formation of the reactive hydroxyl radical
seen in rats.
and an increase in NO metabolites has been reported,
consequently results in seizure-induced, region-specific protein
Kainate receptors have long been associated with epilepsy, but nitration.
Seizure- and NO-related protein nitration are part of an
despite the obvious use of the so-called kainate model, their direct initially protective response cascade. This hypothesis is supported
relation to epileptic seizures is still a matter for discussion due to by the fact that convulsive doses of PTZ are lethal to mice lacking
78 EUROPEAN NEUROLOGICAL REVIEW