The considerable damage that epilepsy inflicts to an individual's social development aside, recurrent seizures result in neuron death in the brain and progressive loss of cognitive function. Why seizures kill brain neurons is not entirely known however there is evidence that free radicals play an important role in the process. Free radicals (atoms, molecules, or ions with unpaired electrons) are both necessary and detrimental to life. Every living cell continually generates free radicals and it has become clear that organisms have evolved complex systems to help check the production of free radicals. Although the science of free radical biology is still very young, these reactive species have been linked to myriad human diseases. Excessive free radicals have been blamed for aging and almost all major human maladies including cancer, atherosclerosis, stroke, emphysema, and neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease. A recent paper by Neganova et al (Neurochem J. 2011;5(3):208-214) has reminded us that free radicals may also contribute to brain damage and persistent seizures in epilepsy. This fascinating paper suggests that antioxidants may someday emerge as a novel anticonvulsive and neuroprotective treatment strategy against epilepsy.
In this paper, scientists from Russia chose to study a derivative of a naturally-occurring plant metabolite called securinine. This tryptamine derivative of securinine (TDS) was synthesized in their lab (Figure ). The group hypothesized that TDS may have anticonvulsant activity secondary to its previously demonstrated antioxidant properties. TDS was studied in vitro using rat brain homogenates and in vivo with 2 different mouse models of epilepsy. The antioxidant properties of securinine and TDS were studied in rat brain homogenate by measuring lipid peroxidation, Fe+2 chelation, and antiradical activity. Unlike the plant alkaloid securinine, its tryptamine derivate, TDS was shown have significant antioxidant activity.
Figure: The molecular structure of clazosentan, a selective endothelin receptor antagonist. (With kind permission from Springer Science + Business Media: Neurochemical Journal, Investigation of the antioxidant characteristics of a new tryptamine derivative of ?securinine and its influence on seizure activity in the brain in experimental epilepsy, Vol. 5, No. 3, 2011, 208-214, M.E. Neganova.)
Next, TDS was studied in 2 different mouse epilepsy models: the pentylenetetrazole (PTZ) model of seizures and the lithium-pilocarpine model of status epilepticus. Seizure activity in mice was analyzed using a 5-point scale. Administration of TDS intraperitoneally for 10 days prior to giving PTZ was found to reduce the latent period of PTZ-induced seizures. Moreover, in the lithium-pilocarpine model of status epilepticus, intraperitoneal TDS was also shown to positively influence the dynamics of status epilepticus progression in the mice. Intracerebroventricular administration of TDS was also shown to significantly reduce the duratio?n of seizures in the lithium-pilocarpine model. In addition, EEG analysis of animals in status epilepticus revealed that there was a significant decrease in the proportion of high amplitude irregular activity in the TDS-treated animals as compared to controls. Thus, in these animal models, TDS was able to not only reduce the duration of severe seizures but also delay the onset of seizures. In addition, the clinical improvements observed in TDS-treated animals correlated with normalization of EEG activity.
This study has several important implications. First, it brings to light the fact that epilepsy is another brain disease that has been linked with abnormal brain oxidation processes. Long after a seizure is over excessive free radicals may continue to damage the brain and lead to cognitive dysfunction. Although there is a wide spectrum of anticonvulsant therapies aimed at stopping abnormal electrical activity in the brain, this study suggests that antioxidants may someday be used to control seizures. Future studies are needed to discover whether commonly available antioxidants such as vitamin E and C may be able to act synergistically with anticonvulsant medications to better control epilepsy. It is also interesting to speculate whether the well-known ability of a ketogenic diet to suppress epilepsy may be linked to energy metabolism and free radical formation in the brain. Since we have the privilege of direct access to the brain and spinal cord, neurosurgeons are well poised to participate in the future of therapeutic brain redox manipulation. The ultimate cure for epilepsy will require not only stopping seizures but also preventing the smoldering loss of neurons in the brain.
