Estrone, but not 17β-estradiol, attenuates kainate-induced seizures and toxicity in male mice

Summary:

Estrogens change the susceptibility to seizures in humans and experimental animals. In this study, the effect of estrone and 17β-estradiol on kainate-induced seizures and neurotoxicity was investigated in male mice. Pre-treatment with estrone (250-1000 μg/kg) at 24 and 2 hours before kainate (40 mg/kg) administration significantly decreased both the percentage of animals with clonic seizures and their mortality (the latter at a dose of 1000 μg/kg only). On the other hand, 17β-estradiol (10-500 μg/kg) had no effect on seizures, and its dose of 10 μg/kg increased mortality. When given alone at a dose of 1 mg/kg, tamoxifen, an antagonist at estrogene receptors, did not affect the kainate-induced seizures, but prevented the anticonvulsant effect of estrone. A histological analysis showed that 73% of mice injected with vehiculum and kainate incurred hippocampal damage. Estrone (2000 μg/kg) decreased the percentage of animals with hippocampal neuronal loss down to 43%, and that effect was not antagonized by tamoxifen. Pretreatment of mice with 17β-estradiol had no effect on the kainate-induced neuronal loss. Additionally, we found that kainate injected i.p. had a profound effect on the immune system of mice, as reflected by a decrease in the thymus weight and an increased metabolic activity of splenocytes. The anticonvulsive dose of estrone (1000 μg/kg) did not change the immunoreactivity of either control or kainate-treated mice. In conclusion, the obtained data indicate that estrone, but not 17β-estradiol, attenuates the kainate-induced seizures, mortality and excitotoxicity in male mice. Moreover, it is suggested that the suppressive effect of estrone on clonic seizures involves intracellular receptors, whereas its antineurotoxic activity seems to depend on a non-genomic mechanism.

Key words:

Estrone - 17β-estradiol - kainate - seizures - neurotoxicity - immunoreactivity - mice

References

• 1 Azcoitia I, Sierra A, Garcia-Segura L M. Estradiol prevents kainic acid-induced neuronal loss in the rat dentate gyrus.  NeuroReport. 9 3075-3079 1998; 
• 2 Backstrom T. Epileptic seizures in women related to plasma estrogen and progesterone during the menstrual cycle.  Acta Neurol Scand. 54 321-347 1976; 
• 3 Behl C, Widmann M, Trapp T, Holsboer F. 17beta-estradiol protects neurons from oxidative stress-induced cell death in vitro.  Biochem Biophys Res Commun. 216 473-482 1995; 
• 4 Ben-Ari Y, Tremblay E, Ottersen O P, Naquet R. Evidence suggesting secondary epileptogenic lesions after kainic acid: Pretreatment with diazepam reduced distant but not local damage.  Brain Res. 165 632-635 1979; 
• 5 Bostantjopoulou S, Hatzizisi O, Argyropoulou O, Andreadis S, Deligiannis K, Kantaropoulou M, Kazis A, Kyrazis G, Routsonis K. Immunological parameters in patients with epilepsy.  Funct Neurol. 9 11-15 1994; 
• 6 Buterbaugh G G, Hudson G M. Estradiol replacement to female rats facilitates dorsal hippocampal but not ventral hippocampal kindled seizure acquisition.  Exp Neurol. 111 55-64 1991; 
• 7 Eriksson C, Van Dam A M, Lucassen P J, Bol J G, Winbald B, Schultzberg M. Immunohistochemical localisation of interleukin-1beta, interleukin-1 receptor antagonist and interleukin-1beta converting enzyme/caspase-1 in the rat brain after peripheral administration of kainic acid.  Neuroscience. 93 915-930 1999; 
• 8 Gu Q, Korach K S, Moss R L. Rapid action of 17beta-estradiol on kainate-induced currents in hippocampal neurons lacking intracellular estrogen receptors.  Endocrinology. 140 660-666 1999; 
• 9 Hayashi T, Ishikawa T, Yamada K, Kuzuya M, Naito H, Hidaka A. Biphasic effect of estrogen on neuronal constitutive nitric oxide synthase via Ca2+-calmodulin dependent mechanism.  Biochem Biophys Res Commun. 203 1013-1019 1994; 
• 10 Kendall M D. Have we underestimated the importance of the thymus in man?.  Experientia. 40 1181-1185 1984; 
• 11 Kubera M, Basta-Kaim A, Skowron-Cendrzak A, Mazur-Kolecka B, Roman A, Borycz J. Effect of repeated amitriptyline administration to mice on the T lymphocyte proliferative activity and natural killer cell cytotoxicity.  Pol J Pharmacol. 47 321-326 1995; 
• 12 Lanthier A, Patwardhan V V. Sex steroids and 5-en-3β-hydroxysteroids in specific regions of the human brain and cranial nerves.  J Steroid Biochem. 25 445-449 1986; 
• 13 Logothetis J, Harner R. Electrocortical activation by estrogens.  Arch Neurol. 3 290-297 1960; 
• 14 Logothetis J, Harner R, Morrell F, Torres F. The role of estrogens in catmenial exacerbation of epilepsy.  Neurology. 9 352-360 1959; 
• 15 Mazur-Kolecka B, Grigoriev V A, Kubera M, Basta-Kaim A, Shani J. Effect of hypothalamic lesion or chemical axotomy on restitution of immunoreactivity in mice after cyclophosphamide administration.  Int J Immunopharmacol. 18 289-294 1996; 
• 16 Mermelstein P G, Becker J B, Surmeier D J. Estradiol reduces calcium currents in rat neostriatal neurons via a membrane receptor.  J Neurosci. 16 595-604 1996; 
• 17 Nance D M, Rayson D, Carr R I. The effects of lesions in the lateral septal and hippocampal areas on the humoral immune response of adult female rats.  Brain Behav Immun. 1 292-305 1987; 
• 18 Nicoletti F, Speciale C, Sortino M A, Summa G, Caruso G, Patti F, Canonico P L. Comparative effects of estradiol benzoate, the antiestrogen clomiphene citrate, and the progestin medroxyprogesterone acetate on kainic acid-induced seizures in male and female rats.  Epilepsia. 26 252-257 1985; 
• 19 O'Shaughnessy D, Gerber G J. Damage induced by systemic kainic acid in rats is dependent upon seizure activity - a behavioral and morphological study.  NeuroToxicology. 7 187-202 1986; 
• 20 Regan R, Guo Y. Estrogens attenuate neuronal injury due to hemoglobin, chemical hypoxia and excitatory amino acids in murine cortical cultures.  Brain Res. 764 133-140 1997; 
• 21 Reibel S, André V, Chassagnon S, André G, Marescaux C, Nehlig A, Depaulis A. Neuroprotective effects of chronic estradiol benzoate treatment on hippocampal cell loss induced by status epilepticus in the female rat.  Neurosci Lett. 281 79-82 2000; 
• 22 Schumacher M, Coirini H, McEwen B S. Regulation of high-affinity GABA_A receptors in the dorsal hippocampus by estradiol and progesterone.  Brain Res. 487 178-183 1989; 
• 23 Schwartz-Giblin S, Korotzer A, Pfaff D W. Steroid hormone effects on picrotoxin-induced seizures in female and male rats.  Brain Res. 476 240-247 1989; 
• 24 Singer C A, Rogers K L, Strickland T M, Dorsa D M. Estrogen protects primary cortical neurons from glutamate toxicity.  Neurosci Lett. 212 13-16 1996; 
• 25 Smith S S, Waterhouse B D, Woodward D J. Sex steroid effects on extrahypothalamic CNS I. Estrogen augments neuronal responsiveness to iontophoretically applied glutamate in the cerebellum.  Brain Res. 422 40-51 1987; 
• 26 Velisek L, Veliskova J, Etgen A M, Stanton P K, Moshe S L. Region-specific modulation of limbic seizure susceptibility by ovarian steroids.  Brain Res. 842 132-138 1999; 
• 27 Weiland N G. Estradiol selectively regulates agonist binding sites on the N-methyl-D-aspartate receptor complex in the CA1 region of the hippocampus.  Endocrinology. 131 662-668 1992; 
• 28 Werboff J, Corcoran J B. Effects of sex hormone manipulation on audiogenic seizures.  Am J Physiol. 201 830-832 1961; 
• 29 Wetmore L, Green-Johnson J, Gartner J G, Sanders V, Nance D. The effect of kainic acid-induced lesions in the lateral septal area on cell-mediated immune function.  Brain Behav Immun. 8 341-354 1994; 
• 30 Wooley D E, Timiras P S. The gonad-brain relationship: Effects of female sex hormones on electroshock convulsions in the rat.  Endocrinology. 70 196-209 1962; 
• 31 Zaulyanov L L, Green P S, Simpkins J W. Glutamate receptor requirement for neuronal death from anoxia-reoxygenation: an in vitro model for assessment of the neuroprotective effects of estrogens.  Cell Mol Neurobiol. 19 705-718 1999;