5a-dihydroprogesterone: Potential Treatment for Complex Partial Seizures
By Frank Wang
At a recent epilepsy conference, Dr. Deborah Lonsdale and Dr. W. M. Burnham presented a study that explored the anticonvulsant effects of progesterone and its metabolites. The study utilized a kindling animal model that is thought to reflect the nature of epilepsy in humans. Results indicated that the primary metabolite of progesterone, 5a-dihydroprogesterone (5a-DHP), had a strong anticonvulsant effect on focal afterdischarges in female rats (1). The strong relationship between these focal afterdischarges in rats and complex partial seizures in humans is essential in this study.
Animal Models in Epilepsy Research
Animals are often preferred over humans in epilepsy research for ethical reasons (2). In scientific research, consistency in data collection is crucial. In come cases, to provide consistency in human epilepsy research, the investigators would need to induce seizures in an otherwise healthy human individual, which is unethical. Rats are often used as a substitute for humans. Although they differ greatly in shape and size, a rat brain shares many similarities with a human brain in terms of basic neurological functions. These similarities make rats ideal models to study epilepsy in humans (3).
In the study, female rats were elicited to experience focal epileptic discharges and afterdischarges in a process called kindling (1). Kindling refers to the process by which seizures are induced in an animal by repeated electrical stimulations to a specific part of the brain (4). The rats in the study were kindled in the amygdala, the part of the brain responsible for emotions. These rats exhibited persistent focal amygdaloid afterdischarges that had a similar profile to complex partial seizures in humans. Injections of 5a-DHP metabolite into these kindled rats produced a more potent anticonvulsant effect than progesterone. This anticonvulsant effect on afterdischarges in rats suggests a similar effect on complex partial seizures in humans (1).
Hormones and Drugs
Hormones, like progesterone, are chemical signals that allow cells, and ultimately organs, to communicate with each other. The target cells contain special receptors that, once activated by the presence of the hormone, cause a cascade of processes that elicit a cellular response. A hormone can also be bio-chemically converted into its metabolites for further signaling (5). Insulin, a famous hormone released by the pancreas, causes cells to store energy as glycogen from glucose. The total absence of insulin activity causes diabetes (6). Estrogen and progesterone, popularly known to be involved in the menstrual cycle, have been shown to have proconvulsant and anticonvulsant effects, respectively. The imbalance between these two antagonistic hormones is thought be the cause of catamenial epilepsy, seizures that cycle with the menstrual cycle (7).
Hormones and their metabolites are crucial in the regulation of bodily functions. Their importance in regulation makes hormones, their metabolites, and their derivatives potential drugs. Many drugs on the market are hormones or chemical compounds that mimic hormone function to cause a desired effect (8).
In the Clinic
The clinical implications of this study are profound. Progesterone is considered an effective anticonvulsant, especially in the treatment of catamenial (menstrual) epilepsy (7). However, the new results specifically point to the primary metabolite, 5a-DHP, as a more potent anticonvulsant. The increased potency of the metabolite means that it will require a smaller dosage of 5a-DHP to achieve the same anticonvulsant effects as the hormone progesterone (1). It also suggests that the metabolite may be more specific in anticonvulsant activity than the hormone. Side-effects can be caused by a drug's lack of specificity to trigger a particular cellular process; the drug affects a variety of processes that create undesired and unintended outcomes. The metabolite's higher specificity leads to a lower risk for side-effects (9). Pharmacologically, these implications are signs of a good drug. In the future, the metabolite may replace progesterone as an anti-epileptic drug. Clinically, and more importantly, this means
that 5a-DHP could be an effective drug for complex partial seizures – the most drug-resistant and most common type of seizures in adults.
Sources:
1. Lonsdale D, Burnham W M. The anticonvulsant effects of progesterone and 5a-dihydroprogesterone on amygdala-kindled seizures in rats. Epilepsia 2003 Dec;44(12): 1494-1499.
2. Animal Models of Disease. Online. Internet. University of Minnesota Academic Health Centre. Accessed May 28th, 2006. <
http://www.ahc.umn.edu/rar/MNAALAS/Models.html>
3. McNamara JO. Kindling Model of Epilepsy. Advances in Neurology 1986;44:303-18.
4. Gilbert ME. Does the kindling model of epilepsy contribute to our understanding of multiple chemical sensitivity? Ann N Y Acad Sci 2001 Mar;933:68-91
5. The Endocrine System. Online Internet. The Hormone Foundation. Accessed May 27th, 2006. <
http://www.hormone.org/endo101/index.html >
6. Insulin: Things You Should Know. Online. Internet. The Canadian Diabetes Association. Accessed May 27th, 2006. <
http://www.diabetes.ca/Section_About/insulin.asp#what>
7. Foldvary-Schaefer N, Falcone T. Catamenial epilepsy: pathophysiology, diagnosis, and management. Neurology 2003 Sep 1;61(6 Suppl 2):S2-15
