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.2010 Dec;59(7-8):573-81.
doi: 10.1016/j.neuropharm.2010.08.017. Epub 2010 Sep 8.

Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis

Affiliations

Disease-modifying activity of progesterone in the hippocampus kindling model of epileptogenesis

Doodipala Samba Reddy et al. Neuropharmacology.2010 Dec.

Abstract

Progesterone (P) is an endogenous anticonvulsant hormone. P is being evaluated as a treatment for epilepsy, traumatic brain injury, and other complex neurological conditions. Preclinical and clinical studies suggest that P appears to interrupt epileptogenic events. However, the potential disease-modifying effect of P in epileptogenic models is not widely investigated. In this study, we examined the effects of P on the development of hippocampus kindling in female mice. In addition, we determined the role of progesterone receptors (PR) in the P's effect on the kindling epileptogenesis utilizing PR knockout (PRKO) mice. P, at 25 mg/kg, did not affect seizures and did not exert sedative/motor effects in fully-kindled mice. P treatment (25 mg/kg, twice daily for 2 weeks) significantly suppressed the rate of development of behavioral kindled seizure activity evoked by daily hippocampus stimulation in wild-type (WT) mice, indicating a disease-modifying effect of P on limbic epileptogenesis. There was a significant increase in the rate of 'rebound or withdrawal' kindling during drug-free stimulation sessions following abrupt discontinuation of P treatment. A washout period after termination of P treatment prevented such acceleration in kindling. PRKO mice were kindled significantly slower than WT mice, indicating a modulatory role of PRs in seizure susceptibility. P's effects on early kindling progression was partially decreased in PRKO mice, but the overall (˜2-fold) delay in the rate of kindling for the induction of stage 5 seizures was unchanged in PRKO mice. Moreover, the acute anticonvulsant effect of P was undiminished in fully-kindled PRKO mice. These studies suggest that P exerts disease-modifying effects in the hippocampus kindling model at doses that do not significantly affect seizure expression and motor performance, and the kindling-retarding effects of P may occur partly through a complex PR-dependent and PR-independent mechanism.

Copyright © 2010 Elsevier Ltd. All rights reserved.

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Figures

Fig. 1
Fig. 1. Study design
In protocol #1, animals were treated with P (25 mg/kg, s.c., twice daily) for 2 weeks, followed by a P-free (withdrawal) period. In protocol #2, animals were treated with P for 2 weeks, followed by a 1 week washout period. In both studies, animals were kindled daily (except during washout period) until they exhibited three consistent stage 5 seizures.
Fig. 2
Fig. 2. Effect of P on behavioral seizures (A), afterdischarge duration (B), and motor activity in fully-kindled WT mice
Animals were stimulated daily and were used when they exhibited fully kindled (stage 5) seizures on three consecutive days. P (25 and 100 mg/kg) was injected subcutaneously 30 min before stimulation. The motor effects of P are measured by the inverted screen test. Each bar represents the mean ± SEM of data from six to eight animals. *p<0.05 vs. control.
Fig. 3
Fig. 3. Inhibition of hippocampus kindling epileptogenesis in WT and PRKO mice by P
P (25 mg/kg, sc) was given twice daily from day 1 to day 14 (dotted line) and animals were stimulated daily (30 min after morning dosing) until they had consistent stage 5 seizures. (A) WT mice treated with P displayed marked retardation of kindling development as expressed by lower mean seizure stage during P treatment and post-drug stimulation sessions. (B) AD duration was similar between control and P groups. (C) PRKO mice treated with P displayed inhibition of kindling development as expressed by lower mean seizure stage during post-drug session. (D) AD duration was similar between control and P groups. Each data point represents the mean of the seizure stage or AD duration of six to eight animals. Small filled squares indicate that the mean value is significantly (p<0.05) different from that in control.
Fig.4
Fig.4. Rate of kindling epileptogenesis in control and P-treated WT and PRKO mice
Rate of kindling (# of stimulations required to elicit third stage 5 seizures) was significantly delayed in P-treated WT and PRKO mice. P (25 mg/kg, sc) was given 30-min prior to stimulation sessions as described in Fig.3. Values represent the mean ± SEM (n = 6–8 mice per group). *p<0.01 vs. control;#p<0.01 vs. control WT mice.
Fig.5
Fig.5. Comparison of the rate of kindling development during P-treatment and P-free periods in WT and PRKO mice
Mean seizure stage values with stimulations 1 through 14 or stimulation 14 through stage 5 kindling (Fig. 3A and 3C) were fit to the linear functionSn=Rn+A, whereSn is the mean seizure stage value for thenth stimulation,R is the rate of kindling, andA is set equal to either 0 (stimulations 1 through 14) or S14 (stimulations 14 to stage 5 kindling). Correlation coefficients (r) were >0.95 for WT groups. Values represent the mean ± SEM. *p<0.01 vs. control group.
Fig.6
Fig.6. Comparison of the rate of kindling development during P-treatment and following a one week washout period in WT mice
The rate of kindling was calculated as described in Fig.5. Values are shown as the mean ± SEM of six to eight animals.
Fig.7
Fig.7. Plasma P levels in control mice and that had been chronically treated with P (25 mg/kg, s.c., twice daily) for 7 days
Plasma samples were taken 30 min after administration of P on the morning after the 7-day chronic treatment period. In control animals, plasma samples were collected 30 min after vehicle injection. Each value represents the mean ± SEM of the levels in four to six animals.
Fig. 8
Fig. 8. Inhibition of fully kindled seizures and afterdischarge duration by P in WT (A) and PRKO mice (B)
Animals were stimulated daily and were used when they exhibited fully kindled (stage 5) seizures on three consecutive days. Vehicle or P was injected subcutaneously 30 min before stimulation. Percent inhibition of seizure stage was calculated as 100 × (1−S/5), whereS is the seizure stage following drug treatment. Percentage inhibition of afterdischarge was calculated as 100 × (1−D/Dc), whereD is the afterdischarge duration after drug treatment andDc is the average control afterdischarge duration without any drug treatment. The overall mean control AD duration was 31±4 and 26 ±4 s in WT and PRKO mice, respectively. Each bar represents the mean ± SEM (n = 6–8 mice per group). *p<0.01 vs. control.
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