Bidmon_subbed_Layout 1 28/10/2009 11:36 Page 77
Seizure Semiology, Neurotransmitter Receptors and Cellular-s tress Responses in Epilepsy Models
In this article, we will focus on certain aspects of the widely used Figure 1: Bioelectric Neocortical Activity During
pentylenetetrazole (PTZ) model. Today, PTZ is no longer of
Repetitive Tonic–Clonic Seizures Elicited by Systemic
Administration of Pentylenetetrazole in Rat (A–C) and
therapeutic use except in rare cases of barbiturate intoxication.
Cat (D) Models
Referring to PubMed, more than 5,200 publications are listed using
the chemical convulsant PTZ when addressing pharmacological and
A B
epileptological questions. PTZ exerts its action by binding to the
picrotoxin-recognition site and benzodiazepine-binding site of
the post-synaptic gamma-aminobutyric acid A (GABA
A
) receptor.
13,14
Thus, PTZ reduces the effects of endogenous GABA and other
inhibitory transmitters, which renders the system in a
hyperexcitable state. In the case of a convulsive dose, PTZ induces
generalised tonic–clonic seizure activity within seconds. C
The So-called Pentylenetetrazole Model
There is no single PTZ model; rather, several varieties exist. This
seems to be a major reason for controversy concerning
data achieved using one of the different PTZ models. First of all,
species-specific differences certainly exist when applying PTZ to
mice, rats, dogs and other animals. Furthermore, basic research on D
epilepsy has shown well-established strain-specific differences, as
well as differences between individuals of a single strain or
breeding group. In addition to the use of PTZ in various species, PTZ
is typically used in three major experimental set-ups: injection of a
single convulsive dose, as a kindling model by repeatedly injecting
a subconvulsive dose and by repeatedly injecting a low but
A: A schematic representation of the recording positions in the rat. Three epicortical
electrodes were bilaterally positioned over the forelimb and hindlimb motor areas and one
convulsive dose with longer seizure-free periods in between
right-sided over visual areas were switched against a reference electrode in the frontal nasal
(usually described as repeated series of seizures).
bone. B: Simultaneous recordings of the cortical direct current (DC) potential (slow potential
fluctuations superimposed by the fast waves of the conventional electroencephalogram
[EEG]) from the sites indicated in A. The time-scale has been compressed; the duration of the
Confusion often arises when a comparison is made between the
recording in B circa was 30 minutes. C: Recording of the episode marked in B with example
C as conventional EEG and DC potential. The time-scale was extended; duration of the
results of a single species with a specific type of the aforementioned
recording in C was circa 30 seconds. D: Simultaneous recordings of the cortical DC potential
models, because much of the data are incomparable. This is so
and of the membrane potential (MP) of a layer V pyramidal cell (motor cortex) during four
successive tonic–clonic seizures. Graphical superimposition; interruptions 20 –60 seconds.
because most authors apply different doses of PTZ (range 18
Source: Speckmann E-J, 1986.
10–110mg/kg), or in the case of kindling they use different time
intervals, such as every 24 or 48 hours. Finally, the total period of observed in ischaemic cerebral insults and second cellular-
treatment varies from two to eight weeks. response mechanisms induced by seizure activity, which at least at
the beginning occur independently of neuronal death or cell death
These circumstances often cause confusion when referring to in general.
observations made by simply referring to the term PTZ model.
15
This
article focuses on the common phenomena using the PTZ model. Most authors argue that models in which neurodegeneration occurs
First, in each form of PTZ treatment seizure activity occurs with a are justified as they resemble the situation observed in patients
with epilepsy.
18–20
However, successful therapeutic intervention in
epilepsy may depend on the understanding and rapid treatment of
early symptoms, which may precede the situation observed in
The pentylenetetrazole model has the cerebral tissue dissected from patients with a long history of seizure
advantage that one chemical is used to
semiology. Therefore, the PTZ models may offer the opportunity to
address this latter aspect, as the PTZ model of ‘repeated series
study two different mechanisms of seizures’ using PTZ 40mg/kg bodyweight produces a pattern of
associated with epilepsy.
seizures that matches that observed in patients (see Figure 1). As it
is beyond the scope of this article to address all aspects of PTZ-
induced seizures as previously described and discussed,
4
we would
like to focus on effects reported for neurotransmitter receptors and
short latency, and second, neurodegeneration is absent or induced associated stress responses.
very late. These are two advantages of this model compared with
other models such as the kainate or pilocarpin models, in which Pentylenetetrazole-induced
neurodegeneration is always associated with the initial seizure Seizures and Neurotransmission
response.
16,17
Additionally, the PTZ model has the advantage that For PTZ-kindled mice and during acutely PTZ-induced tonic–clonic
one chemical is used to study two different mechanisms associated seizures in mice, clear time-dependent changes in the amount of
with epilepsy, i.e. processes primarily related to neurodegeneration adenosine (A1) receptors are known, which also depend on the
that have been observed in tissue resected from patients with duration of the kindling process.
22–26
In general, A1-binding sites were
epilepsy, and in many aspects are also similar to situations increased in cortical, hippocampal and cerebellar regions, whereas
EUROPEAN NEUROLOGICAL REVIEW 77