Abstract

Purpose: Adrenocorticotrophic hormone (ACTH) suppresses several types of childhood seizures, but it has many side effects. The mechanism of ACTH’s anticonvulsant actions is not known. ACTH, however, releases deoxycorticosterone (DOC) – as well as cortisol – from the adrenal cortex and it has been suggested that DOC may mediate, at least in part, ACTH’s anticonvulsant actions. The present study assessed DOC’s anticonvulsant actions in infant rats. Age-related changes in DOC’s anticonvulsant actions were also studied. Methods: DOC’s anticonvulsant actions were assessed against hippocampal-kindled, maximal pentylenetetrazol test (MMT) and maximal electroshock (MES) seizures in 15-day-old rats. Age-related changes in responsiveness to DOC were also assessed using the MMT model. Results: DOC suppressed generalized convulsions in all three of the seizure models. Focal spiking in the hippocampal-kindling model, however, was not fully suppressed, even at high doses. Ataxia increased proportionally with the dose, with the time of peak seizure suppression roughly correlating with the time of peak ataxia in all models. DOC was anticonvulsant in both infant and adult rats. ED50s, however, were much higher in adults. Young rats showed ataxia at the time of testing (15 min), whereas adult rats did not, although ataxia was seen at later times. Conclusions: DOC is a potent anticonvulsant against generalized seizures, particularly in infants. It deserves a clinical test against generalized seizures in infants.

Keywords: ACTH; Deoxycorticosterone (DOC); Kindled seizure; MES seizure; MMT seizure

Abbreviations: ACTH, adrenocorticotriphic hormone; AD, afterdischarge; ADT, afterdischarge threshold; CO₂, carbon dioxide; CORT, corticosterone; DHDOC, dihydrodeoxycorticosterone; DOC, deoxycorticosterone; EEG, electroencephalograph; ED50, a dose that produced 50% of the maximal effect; FLC, forelimb clonus; FLE, forelimb extension; FLF, forelimb flexion; MES, maximal electroshock seizure; min, minutes; MMT, maximal pentylenetetrazol seizure; PTZ, pentylenetetrazol; THDOC, tetrahydrodeoxycorticosterone

Article Outline

1. Introduction

2. Results

2.1. Experiment 1: dose– and time–response studies

2.1.1. Kindled seizures

2.1.2. MES seizures

2.1.3. MMT seizures

2.2. Experiment 2: age–response studies

2.2.1. Age–response study

3. Discussion

4. Experimental procedures

4.1. Subjects

4.2. Drugs and injections

4.3. Procedures for the kindling experiments (Experiment 1)

4.3.1. Implantation of electrodes

4.3.2. Threshold determination

4.3.3. Kindling procedure

4.3.4. Dose–response studies in kindled subjects

4.3.5. Time–response studies in kindled subjects

4.3.6. Histological validation of electrode placement

4.4. Procedures for maximal electroconvulsive shock (MES) seizure tests (Experiment 1)

4.4.1. MES procedure

4.4.2. Dose–response studies in MES subjects

4.4.3. Time–response studies in MES subjects

4.5. Procedures for maximal pentylenetetrazol (MMT) seizure tests (Experiments 1 and 2)

4.5.1. MMT procedure

4.5.2. Dose–response studies in MMT subjects

4.5.3. Time–response studies in MMT subjects

4.5.4. Age–response studies in MMT subjects

4.6. Procedure for the scoring of ataxia

4.7. Data analysis

Acknowledgements

References