Estradiol Facilitates Kainic Acid—Induced, but not Flurothyl‐Induced, Behavioral Seizure Activity in Adult Female Rats

Abstract

Summary:Purpose: This study was designed to determine whether previously demonstrated increases in hippocampal axospinous synapse density and NMDA receptor function induced by estradiol are paralleled by increased susceptibility to limbic (kainic acid induced) or generalized (flurothyl induced) behavioral seizures.Methods: Kainic acid was injected systemically to ovariectomized adult female rats treated with either estradiol or oil vehicle. The latencies to each of five stages of seizure-related behaviors (staring, wet-dog shakes, head waving and chewing, forelimb clonus, rearing, and falling) were recorded for each animal. Flurothyl was administered by inhalation to ovariectomized adult female rats treated with estradiol alone, estradiol followed by short-term progesterone, or oil vehicle. The latencies to each of three stages of seizure-related behaviors (first myoclonic jerk, forelimb clonus, wild running and bouncing) were recorded for each animal.Results: Estradiol treatment decreased the latency to seizurerelated behaviors induced by kainic acid, but neither estradiol alone nor estradiol followed by progesterone had any effect on flurothyl-induced seizure-related behaviors. Conclusions:The same estradiol treatment paradigm known to induce structural and functional changes in the excitatory circuitry of the hippocampus facilitates the progression of kainic acid-induced seizures, which are known to involve the hippocampus, but has no effect on flurothyl-induced seizures. The lack of an effect of estradiol alone or estradiol followed by progesterone on flurothyl-induced seizures indicates that estradiol's effects on seizure susceptibility do not result from increased neuronal excitability throughout the brain, but rather involve action within the limbic system. The data suggest that structural and functional changes in hippocampal circuitry induced by estradiol may contribute to increased susceptibility to limbic seizure activity. Key Words: Catamenial epilepsyLimbic seizures-Hippocampus-CAI pyramidal cellsDendritic spines.Numerous clinical and experimental studies have demonstrated that estrogen can be proconvulsant. Clinically, an association between seizure frequency and the menstrual cycle in women with epilepsy (termed catamenial epilepsy) has been recognized for over 100 years (1). Although the prevalence of catamenial epilepsy has been controversial, many studies have documented a significant relationship between seizure occurrence and menses (reviewed in 2, 3). For example, a study of 184 women with intractable partial complex seizures reported that approximately one third exhibited at least a doubling of average daily seizure frequency during one of three phases of the menstrual cycle: perimenstrual, Accepted December 20, 1999. Address correspondence and reprint requests to Dr. C. S. Woolley at Department of Neurobiology and Physiology, Northwestern University, Evanston, IL 60208, U.S.A. E-mail: cwoolley@nwu.edu preovulatory, or second half of cycles with an inadequate luteal phase ( 3 ) . Each of th...

Mass spectrometric assay and physiological–pharmacological activity of androgenic neurosteroids

“…We demonstrated that testosterone modulation of seizure susceptibility occurs through its conversion to neurosteroids with "anticonvulsant" and "proconvulsant" actions, and hence the net effect of testosterone on neural excitability and seizure activity depends on the levels of distinct testosterone metabolites within the brain (Reddy, 2004c). Unlike 17β-estradiol, which generally facilitates seizures (Backstrom, 1976;Hom and Buterbaugh, 1986;Buterbaugh, 1989;Woolley, 2000), 3α-androstanediol has been shown to produce powerful antiseizure effects (Reddy, 2004bc;Kaminski et al 2005), which are not mediated by the intracellular ARs (Cunningham et al, 1979;Roselli et al, 1987). To determine the pathways of neurosteroid synthesis (see Fig.1), the following agents were used: (i) Letrazole, an inhibitor of the aromatase enzyme (Bhatnagar et al, 1990;, was used to block conversion of testosterone to 17β-estradiol; (ii) Finasteride, an irreversible inhibitor of both type 1 (brain) and type 2 (peripheral tissues) 5α-reductase isozymes in rodents (Azzolina et al, 1997), was utilized to inhibit the conversion of testosterone into DHT; (iii) Indomethacin, a powerful blocker of 3α-HSOR enzyme activity 1983;, was used to inhibit reduction of DHT into 3α-androstanediol.…”

“…Generally, 17β-estradiol produces excitatory effects and thereby facilitates seizures (Woolley, 2000), while 3α-androstanediol has neuroprotective and antiseizure activity (Reddy, 2004b). Therefore, a detailed study of 3α-androstanediol and related neurosteroids as mediators of the physiological effects of testosterone is required to establish the pathophysiological role of androgenic neurosteroids in the brain function.…”

Seizure susceptibility in intact and ovariectomized female rats treated with the convulsant pilocarpine

“…Numerous studies over the last few decades have identified sex and cycle-dependent differences in seizure susceptibility in rodents. These studies have used various methods to induce seizures, including kindling, electroshock, and chemoconvulsant administration Buterbaugh, 1989;Edwards et al, 1999;Finn and Gee, 1994;Hoffman et al, 2003;Hom and Buterbaugh, 1986;Hudson and Buterbaugh, 1991;Kalkbrenner and Standley, 2003;Matejovska et al, 1998;Nicoletti et al, 1985;Pericic and Bujas, 1997;Persinger et al, 1988;Pesce et al, 2000;Schwartz-Giblin et al, 1989;Slamberova and Vathy, 2000;Tan and Tan, 2001;Tominaga et al, 2001;Valente et al, 2002;Velisek et al, 1999;Wahnschaffe and Loscher, 1992;Woolley, 2000). However, these studies have failed to provide a clear picture of the relationship between ovarian hormone levels and seizure susceptibility.…”

“…Subsequent work, however, has shown that proconvulsant effects of estrogen, as well as anticonvulsant effects of progesterone, may depend to a large extent on the specific experimental conditions used. For example, although there have been repeated demonstrations that estrogen is proconvulsant (Buterbaugh, 1989;Matejovska et al, 1998;Nicoletti et al, 1985), there is also evidence that this is not the case (Hoffman et al, 2003;Hom and Buterbaugh, 1986;Hudson and Buterbaugh, 1991;Slamberova and Vathy, 2000;Velisek et al, 1999;Woolley, 2000). Furthermore, while estradiol may protect neurons from seizureinduced neuronal damage (Azcoitia et al, 1998;Veliskova et al, 2000), this protective effect may not be mediated by a decrease in seizure severity (Hoffman et al, 2003;Reibel et al, 2000).…”

The increasingly plastic, hormone-responsive adult brain

“…Estrogen treatment can decrease the threshold for hippocampal seizures (15). The simultaneous excitation of two different CA1 cells by the same terminal bouton in estrogen-treated animals would be expected to increase the synchronization of firing that can lead to seizure (16). Perhaps steroid analogs could be developed to counteract these seizure-facilitating effects of estrogen without interfering with the beneficial effects of the steroid.…”