Abstracts

INHIBITORY AND PROTECTIVE EFFECTS OF THE SELECTIVE ESTROGEN RESPONSE MODULATOR (SERM) RALOXIFENE

Abstract number : 2.247
Submission category :
Year : 2003
Submission ID : 2524
Source : www.aesnet.org
Presentation date : 12/6/2003 12:00:00 AM
Published date : Dec 1, 2003, 06:00 AM

Authors :
Thomas Mercurio, Jeffrey Goodman, Russell Berger, Cynthia Harden, Neil MacLusky, Helen Scharfman CNRRR, Helen Hayes Hosp., W. Haverstraw, NY; Depts. Pharmacol. & Neurol., Columbia Univ., NY, NY; Comprehensive Epi. Ctr., Dept. Neurol.& Neurosci., Weill Cor

Reproductive hormones such as estrogen are known to influence seizures, both [italic]in vivo[/italic] and [italic]in vitro[/italic]. We tested the hypothesis that raloxifene, a member of the class of drugs known as SERMs, which are currently used to treat bone loss after menopause, would influence seizures.
Raloxifene was tested [italic]in vitro[/italic] and [italic]in vivo[/italic]. [italic]In vitro[/italic] studies used 400 [mu]m-thick horizontal hippocampal slices of adult female (60-120 days old), or male (over 30 days old) Sprague-Dawley rats. Female rats were examined at a particular stage of the estrus cycle (based on vaginal cytology), or they were examined 2-3 weeks after ovariectomy. Slices were maintained in an interface recording chamber at 32[deg]C and perfused with oxygenated (95% O[sub]2[/sub], 5% CO[sub]2[/sub]) artificial cerebrospinal fluid (containing, in mM: 125 NaCl, 5 KCl, 2 CaCl[sub]2[/sub], 2 MgSO[sub]4[/sub], 1.25 Na[sub]2[/sub]HPO[sub]4[/sub], 10 d-glucose) at approximately 1 ml/min. [italic]In vitro[/italic] experiments tested 1, 5, or 10 [mu]M raloxifene (in 0.05% DMSO; Sigma) for effects on spontaneous epileptiform burst discharges of area CA3 neurons evoked by bath-application of the GABA[sub]A [/sub]receptor antagonist bicuculline (10 [mu]M). [italic]In vivo[/italic] experiments tested the effects of 5 mg/kg raloxifene (in DMSO, i.p. or s.c.), administered 30 min before pilocarpine injection (350 mg/kg, i.p.) in ovariectomized rats. Atropine methylbromide (1 mg/kg, s.c.) was injected immediately after raloxifene. Diazepam (5 mg/kg, i.p.) was injected 1 hr after the onset of status epilepticus.
[italic]In vitro[/italic] experiments showed that 10 [mu]M raloxifene blocked afterdischarges of spontaneous bursts recorded in area CA3 (n=3), and vehicle had no effect (n=3). Burst duration and frequency were less influenced (5 [mu]M, n=5; 10 [mu]M, n=5). Pretreatment with 1 [mu]M raloxifene for 30 min prior to bicuculline exposure led to burst discharges with a short duration and no afterdischarges (n=5); 10 [mu]M produced no further effects. Pressure-application of raloxifene (20 mM) to the area CA3 cell layer had similar effects as bath-application (n=5). Effects of raloxifene appeared independent of the hormonal state of the animal that was used for slices. Intracellular recordings from CA3 neurons after [gt]1 hr exposure to raloxifene (10 [mu]M) demonstrated similar intrinsic properties and firing behavior as untreated neurons (n=5). [italic]In vivo[/italic] experiments showed mortality after status was low after raloxifene treatment (0/4 deaths) relative to vehicle treatment (3/5) or untreated (3/4) rats.
The results suggest that raloxifene decreases spontaneous epileptiform activity in area CA3 of hippocampus that is induced by disinhibition. This effect is primarily on afterdischarges. The effects of raloxifene [italic]in vitro[/italic] appear to be more potent if it is added before epileptiform activity occurs. These effects do not appear to be due to a nonspecific depression of neuronal function. The [italic]in vivo[/italic] data suggest that raloxifene may be protective.
[Supported by: NIH grant 37562.]