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Seizure Semiology, Neurotransmitter Receptors and Cellular-s tress Responses in Epilepsy Models
neuronal nitric oxide synthase (nNOS) expression, and Figure 3: Changes in COX-2- and NOS-I-positive Neurons
subconvulsive doses of PTZ affect nNOS knockout mice more
in Control and Pentylenetetrazole-treated Rats
severely than wild-type mice. It is further supported by the fact that
NO-modulated seizure augmentation versus seizure suppression in
wild-type mice seems to be dependent on the concentration of NO.
41
Pl
Am
Pl
Am
Pl
The Topography of Stress Responses
As explained above, it is now well-established that seizure-related
Am
hyperactivity is associated with oxidative stress. From a
neurophysiological point of view, certainly one of the most
convincing aspects for an association of neuronal excitation and
oxidative responses is related to the arachidonic acid pathway
and prostaglandin synthesis via cyclo-oxygenases (COX-1, COX-2); in
ABC
particular, the inducible form COX-2 is constitutively expressed in a
region-specific manner in many cerebral neurons in which COX-2
expression and activity is regulated by synaptic activity. In addition,
Although not as strong as in rat models
for cerebral ischaemia, COX-2 expression
is induced in human patients with
epilepsy and in the model of repeated
pentylenetetrazole-induced seizures.
it should be noted that under normal physiological conditions
cerebral regions well-known for their high constitutive COX-2
DE
expression are those that belong to the epileptic circuitry.
12
Furthermore, NMDA-receptor-induced c-fos expression is Images from frontal sections through brains of adult Wistar rats showing the constitutive
prostaglandin-dependent and the calcium-dependent activation of
presence of cyclo-oxygenase-2 (COX-2) (brown or green) in control (A, D, saline-treated) and
after repeated pentylenetetrazole (PTZ) injections for two weeks, as described in reference 40,
cyclooxygenases results in superoxide production (for a review see 24 hours after the last seizure episode in an individual with low seizure score (B) and in one with
Yermakova and O’Banion
42
).
highest seizure score (C, E). Neurons expressing COX-2 (green, D, E) and neurons expressing
neuronal nitric-oxide-synthase (NOS-I) (red, D, E) are tightly connected via the numerous long
NOS-I-containing neuronal processes. In control animals, only a few single strongly COX-2-
For PTZ models, it is known that COX inhibitors (anti-inflammatory
positive neurons were present, whereas after seizure episodes most neurons showed strong
COX-2 expression. In rats with high seizure scores, neuronal processes containing NOS-I also
drugs and non-steroidal anti-inflammatory drugs [NSAIDs])
46
appeared to be affected (E). As NO and oxygen radicals are highly reactive diffusible gases, this
attenuate seizure activity.
43,44
Although not as strong as in rat
tight association is most important for their interaction when produced in an excessive,
uncontrolled manner. Am = amygdala; PI = piriform cortex. Bars: 0.2mm A–C; 10µm D–E.
models for cerebral ischaemia,
45,46
COX-2 expression is induced in
human patients with epilepsy
47
and in the model of repeated PTZ- Figure 4: Association of HSP-27-positive Astrocytes
induced seizures (see
and COX-2-positive Neurons in Piriform Cortex in a
Figure 3). COX-2-expressing neurons are
Pentylenetetrazole-treated Rat
shown to be closely associated with the processes of neurons
expressing nNOS, thus revealing a direct topographical link
between COX-2-related superoxide and NOS-I-related NO
production. As the normal constitutive neuronal expression of COX-
2 and the seizure-induced induction of COX-2 take place in a
region-specific manner, COX-2-related production of oxygen
radicals may represent the basis for region-specific pathological
changes attributed to seizure-induced oxidative stress.
Some of the most affected cortical regions are the piriform and
entorhinal cortices, which exhibit not only high COX-2 expression
(see Figure 3), but also one of the highest packing densities of NOS-
I- expressing cortical neurons.
48,49
This association of neurons
responding with the production of radicals such as superoxide and
nitric oxide, which results in the formation of peroxynitrite,
46
may
be one reason for the fact that seizure-induced protein nitration
and glutamine synthetase inhibition are much more easily 40 Bar: 30µm. Image showing the co-distribution of seizure-induced heat-shock protein
detectable in piriform and entorhinal cortices than in other regions.
40 (HSP)-27 expression (red) in astrocytes and the neuronal induction of cyclo-oxygenase-2
(green) in piriform cortex of a Wistar rat 24 hours after the last pentylenetetrazole-induced
The latter may also explain why certain other changes affecting seizure episode in a sequence of repeatedly induced seizures for two weeks.
EUROPEAN NEUROLOGICAL REVIEW 79