Those who have difficulty accepting the fact that no one is entirely sure how many anti-epileptic drugs work will find solace in research published in the last two months, which gives us several insights into why certain medications such as stiripentol and CBD might help control seizures. Two studies on STP and one on CBD show that scientists are working on understanding these mechanisms more completely. A fourth study introduces us to a new line of induced pluripotent stem cells (iPSC’s) from a patient mosaic for an SCN1A mutation, and lastly a clinical study offers a new description of the neuropsychological characteristics of Dravet.
1. Verrotti, A., et. al. (Feb. 2016). Pharmacological considerations in the use of stiripentol for the treatment of epilepsy.
Expert Opinion on Drug Metabolism and Toxicology, Volume 12, Issue 3. Retrieved from http://www.tandfonline.com/doi/full/10.1517/17425255.2016.1145657
Stiripentol has proven effective in treating seizures, but its mechanism of action has not been well understood. Recent research suggests that in addition to affecting metabolism of other AEDs, it has GABAergic properties and inhibits the entry of both sodium and calcium ions, which can be helpful when a neurons are overexcited. (Remember that GABAergic properties are inhibitory, while glutamergic properties are excitatory, a bad thing in Dravet syndrome.) Researchers are also investigating its effects on the lactate dehydrogenase pathway, a key energy pathway in the brain.
2. Verleye, M., et. al. (Feb. 2016). Neuroprotective activity of stiripentol with a possible involvement of voltage-dependent calcium and sodium channels.
Journal of Neuroscience Research, 94(2). Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/26511438
Stiripentol has been shown to have GABAergic properties. Using samples of rat neurons, the authors subjected the cells to two lab models of brain injury: Oxygen/glucose deprivation and exposure to glutamate. Stiripentol increased survival of neurons in both models, suggesting a neuroprotective effect, possibly due to the fact that stiripentol blocked sodium and calcium ion entry into the neurons during excess stimulation.
3. Rubio, M., et. al. (April 2016). Analysis of endocannabinoid signaling elements and related proteins in lymphocytes of patients with Dravet syndrome.
Pharmacology Research and Perspectives, Volume 4, Issue 2. Retrieved from http://onlinelibrary.wiley.com/doi/10.1002/prp2.220/full
According to recent studies, CBD appears to have some effectiveness in treating seizures in Dravet syndrome. The mechanism of action, however, is unknown. This study examined how the body’s endocannabinoid system, which consists of two primary receptors, CB1 and CB2, and is involved in several physiological processes, differs in Dravet patients compared to controls. They studied lymphocytes (white blood cells) and found that there were signs of CB2 receptor upregulation among Dravet patients, as well some markers of possible inflammation. While most of the CBD targets they analyzed did not differ between DS and control patients, these findings suggest a potential mechanism of action.
4. Maeda, H., et. al. (Feb. 2016). Establishment of isogenic iPSCs from an individual with SCN1A mutation mosaicism as a model for investigating neurocognitive impairment in Dravet syndrome.
Journal of Human Genetics, Volume 5. Retrieved from http://www.nature.com/jhg/journal/vaop/ncurrent/full/jhg20165a.html
Using cells from a patient with a mosaic SCN1A mutation, the authors created two lines of neuronal cells: one with no SCN1A mutation, and one with a mutation. Because the cells contain the same DNA aside from the SCN1A mutation, the non-mutated cells serve as an almost perfect control group against which the mutated cells can be studied. The group found increased levels of certain types of mRNA and dopamine in the mutated cells compared to the non-mutated cells, which could contribute to the behavioral abnormalities seen in Dravet syndrome.
5. Battaglia, D., et. al. (Feb. 2016). Outlining a core neuropsychological phenotype for Dravet syndrome.
Epilepsy Research, Volume 120. Retrieved from http://www.epires-journal.com/article/S0920-1211(15)30081-4/abstract
The authors reviewed existing literature on the neuropsychological phenotypes in Dravet. Neuropsychology is a field of psychology that studies not just the structure and function of the brain, but how they influence cognition and behavior. It uses a scientific approach to understand how neurological disorders impact the patient in terms of understanding, response, and information processing. The findings suggest an original set of neuropsychologic symptoms common to patients with Dravet including defects in sensorimotor integration (input from the senses, coupled with muscle movement), particularly visuoconstructive abilities (the ability to interpret and reconstruct visual patterns, especially fine motor activities like writing, math, etc.).