LE JOURNAL CANADIEN DES SCIENCES NEUROLOGIQUES
induced by electric stimulation, and that ZNS also suppressed
both interictal spikes and secondary generalized seizures induced
by cortical application of tungstic acid gel. These authors4
concluded that ZNS has a direct suppressive effect on the cortical
epileptogenic focus. In kindling models, Kamei et al5 reported
that ZNS was effective against neocortical and hippocampal
kindling but not amygdalar kindling. However, Hamada et al3
reported that ZNS retarded the development of amygdalar
kindling. In KA-induced amygdalar seizures, Takano et al7
previously demonstrated that ZNS suppressed seizure
propagation but did not suppress the epileptic activity of the
amygdala. Thus, despite various studies of the effects of ZNS,
the mechanism of its anticonvulsive action is still unclear.
In the present experiments, we investigated regional
accumulation of ZNS in the rat brain by an autoradiographic
method, and assessed the effects of ZNS on KA-induced limbic
seizures7-14 by EEG monitoring. In the present study, as soon as
the seizure attenuation was recognized by 14C-ZNS
administration, 14C-ZNS accumulation in the brain was studied.
14C-ZNS accumulated in the ipsilateral sensorimotor cortex and
parietal cortex, and focal suppression of epileptic discharges in
the sensorimotor cortex was seen a few minutes after intravenous
14C-ZNS administration. Regional 14C-ZNS accumulation was
also observed in the ipsilateral thalamus (lateral portion) and
hippocampal CA3 region.
Blood-brain barrier function is important in interpreting drug
distribution findings. In KA-induced amygdalar seizures, 14C-
aminoisobutyric acid autoradiography revealed severe disruption
of BBB function only in the hippocampal CA3 region and slight
damage in the amygdala on the KA-injected side.10 Additionally,
Tanaka et al11 studied local cerebral glucose utilization (LCGU)
and LCBF autoradiographically using 14C-2-deoxyglucose and
14C-iodoantipyrine during KA-induced limbic status epilepticus,
demonstrating relative hypoxia due to a high degree of
uncoupling of LCGU and LCBF in several limbic structures,
especially CA3. However, such uncoupling was not seen in the
cerebral cortex. Considering these results,11 disruption of the
BBB is likely to have induced the moderate uptake of 14C-ZNS
in CA3 in our study, but the cortical accumulation was not
caused by BBB dysfunction. We speculated that extravascular
ZNS was promptly transferred to the secondarily excited zone in
the cortex, maintaining a favorable extravascular/intravascular
ZNS gradient for further ZNS transport from the intravascular to
the extravascular space.
REFERENCES
1. Seino M, Okuma T, Miyasaka M. Efficacy evaluation of AD-810
(zonisamide).
Double-blind
study
comparing
with
carbamazepine. Clin Exp Med 1988; 144: 275-291.
2. Yagi K, Seino M. Methodological requirements for clinical trials in
refractory epilepsies – our experience with zonisamide. Prog
Neuropsychopharmacol Biol Psychiat 1992; 16: 79-85.
3. Hamada K, Ishida S, Yagi K, Seino M. Anticonvulsant effects of
zonisamide on amygdaloid kindling in rats. Neurosciences 1990;
16: 407-412.
4. Ito T, Hori M, Masuda Y, Yoshida K, Shimizu M. 3-
sulfamoylmethyl-1, 2-benzisoxazole,
a
new type of
anticonvulsant drug. Electroencephalographic profile.
Arzneimitterforschung 1980; 30: 603-609.
5. Kamei C, Oka M, Masuda Y, Yoshida K, Shimizu M. Effect of 3-
sulfamoylmethyl-1, 2-benzisoxazole (AD-810) and some
antiepileptics on the kindled seizures in the neocortex,
hippocampus and amygdala in rats. Arch Int Pharmacodyn 1981;
249: 164-176.
6. Masuda Y, Karasawa T, Shiraishi Y, et al. 3-sulfamoylmethyl-1, 2-
benzisoxazole,
a
new type of anticonvulsant drug.
Pharmacological profile. Arzneim-Forsch 1980; 30: 477-483.
7. Takano K, Tanaka T, Fujita T, Nakai H, Yonemasu Y. Zonisamide:
electrophysiological and metabolic changes in kainic acid-
induced limbic seizure in rats. Epilepsia 1995; 36: 644-648.
8. Imamura S, Tanaka S, Tojo H, et al. Kainic acid-induced perirhinal
cortical seizures in rats. Brain Res 1998; 800: 323-327.
9. Tanaka S, Kondo S, Tanaka T, Yonemasu Y. Long-term observation
of rats after unilateral intra-amygdaloid injection of kainic acid.
Brain Res 1988; 463: 163-167.
10. Tanaka S, Tanaka T, Fujita F, et al. Changes in blood-brain barrier
function in kainic acid-induced limbic status epilepticus in rats.
(Submitted for publication).
11. Tanaka S, Sako K, Tanaka T, Nishihara I, Yonemasu Y. Uncoupling
of local blood flow and metabolism in the hippocampal CA3 in
kainic acid-induced limbic seizure status. Neuroscience 1990; 36:
339-348.
12. Tanaka T, Kaijima M, Daita G, et al. Electroclinical features of
kainic acid-induced status epilepticus in freely moving cats.
Microinjection into the dorsal hippocampus. Electroenceph Clin
Neurophysiol 1982; 54: 288-300.
13. Tanaka T, Kaijima M, Yonemasu Y, Cepeda C. Spontaneous
secondarily generalized seizures induced by
a single
microinjection of kainic acid into unilateral amygdala in cats.
Electroenceph Clin Neurophysiol 1985; 61: 422-429.
14. Tanaka T, Tanaka S, Fujita T, et al. Experimental complex partial
seizures induced by a microinjection of kainic acid into limbic
structures. Prog Neurobiol 1992; 38: 317-334.
15. Paxinos G. The Rat Nervous System. Sydney: Academic Press.
1985.
16. Pellegrino LJ, Pellegrino AS, Cushman AJ. A Stereotaxic Atlas of
the Rat Brain. New York: Plenum. 1979.
17. Matsumoto K, Miyazaki H, Fujii T, et al. Absorption, distribution
and excretion of 3-(sulfamoyl[14C] methyl)-1,2-benzisoxazole
(AD-810) in rats, dogs and monkeys and of AD-810 in men..
Pharmacological profile Arzneim-Forsch, 1983; 33: 961-968.
18. Geary II WA, Wooten GF, Perlin JB, Lothman EW. In vitro and in
vivo distribution and binding of phenytoin to rat brain. J
Pharmacol Exp Ther 1987; 241: 704-713.
Why ZNS accumulates in the thalamus remains obscure. In
KA-induced limbic status epilepticus, Tanaka et al11 reported
increases of LCGU and LCBF in the ventrobasal complex,
including the ventroposteromedial nucleus of the thalamus and
the ventroposterolateral nucleus of the thalamus, that most likely
reflected retrograde input from the sensorimotor cortex to the
ventrobasal complex. This mechanism might favor ZNS
accumulation in the lateral portion of the thalamus. Further
experiments will be required to elucidate this point.
19. Mesdjian E, Ciesielski L, Valli M, et al. Sodium valproate: kinetic
profile and effects on GABA levels in various brain areas of the
rat. Prog Neuropsychopharmacol Biol Psychiat 1982; 6: 223-233.
20. Mimaki T, Tanoue H, Matsunaga Y, Miyazaki H, Mino M. Regional
distribution of 14C-zonisamide in rat brain. Epilepsy Res 1994;
17: 233-236.
21. Pantarotto C, Crunelli V, Lanzoni J, Frigerio A, Quattrone A.
Quantitative determination of carbamazepine and carbamaze-
pine-10,11- epoxide in rat brain areas by multiple ion detection
mass fragmentography. Ann Biochem 1979; 93: 115-123.
ACKNOWLEDGEMENTS
This work was supported by a grant from the Dainippon
Pharmaceutical Co., Osaka, Japan. The authors thank Mr. Masaru
Setoguchi (the Dainippon Pharmaceutical Co., Kagoshima, Japan) for
his kind assistance.
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