Neuroprotection in Epilepsy

epilepsy pic

Epilepsy is a neurological disease characterized by recurrent, spontaneous seizures of neurological origin [1]. Epilepsy is generally detected through extensive EEG recording and video EEG testing. Those suffering with epilepsy are usually prescribed anticonvulsant medications to control the frequency and duration of their seizures. Recently, research has examined the use of antiepileptogenic drugs to prevent neuronal loss and alter the cognitive impairment commonly seen with the progression of epilepsy [2].

An increasing body of literature has focused on the development of epilepsy as a disease. Along with the presence of seizures with a neuronal cause, epilepsy is also characterized by progressive neuronal loss and cognitive impairment brought on by the disease itself. Research has found that neuronal loss can occur not only from sustained seizures, but also from single brief episodes [3]. Consequently, treatments have started to emphasize the importance of neuroprotection, which can be subcategorized into two main types: primary and secondary.

Primary neuroprotection consists of preventative and symptomatic approaches to the disease including measures to avert the progression of seizures and protect the brain during an active seizure. It has been hypothesized that the rise in potassium—a necessary ion that plays a role in whether a neuron would “fire”—in the extracellular environment following a seizure, which results in excess discharge and further potassium increase, may elicit future seizures [1]. This explains the self-sustaining cycle created by an initial seizure.

Secondary neuroprotection involves the etiopathogenic course of the disease, which is mainly the neuronal death caused by seizures and other changes in neuronal function due to the natural progression of the disorder. Neuronal loss from seizures is due to energy depletion within the neuronal cell. Mitochondria are organelles found in the neuron, which produce adenosine triphosphate (ATP). Most living cells depend largely on the supply of ATP the mitochondria produces to carry out necessary cellular processes. Mitochondrial dysfunction in this case, is brought on by a series of processes occurring due to glutamate surges brought on by repeated seizures [4].

Seizures are not caused solely by excessive neuronal discharge; synchronization of neuronal networks is also a key factor. One mechanism for neuronal synchronization involves glutamatergic interconnections, which are generally found between pyramidal cells in the cortex. Gap junctions are another mechanism of synchronization, found between many of the nervous systems neurons. Additionally, the cortex contains GABA-ergic inhibitory neurons that innervate pyramidal cells. When a discharge occurs, a network of pyramidal cells become depolarized due to the inactivation of the inhibitory properties of the GABA-ergic neurons [1].

Naturally occurring changes in the brain of epileptics can stimulate progressive synchronization, indicating that seizures lead to self-propagating neuronal changes. Growth of axon collaterals between excitatory neurons is one of the main ways in which synchronization is propagated in the nervous system due to epilepsy. The new axon collaterals generally do not terminate in same locations as “healthy” collaterals. These types of neuronal connections are believed to increase recurrent excitatory circuits, which facilitate in the propagation of seizures throughout the nervous system, and are not seen in healthy brains [1].

Experiments have also shown that epilepsy can cause rearrangement of receptors on neuronal cell surface. These changes are seen in both ionotropic receptors such as AMPA and NMDA as well as metabotropic receptors such as glutamate and GABA. One change involves the up-regulation of AMPA receptor subunits GluR2 and GluR1. This causes rearrangement in postsynaptic densities of NMDA and AMPA binding sites, hyperexcitable seizure focus, and increased axonal sprouting as well as several other neuronal level changes. Changes in the GABA receptors following a seizure have also been shown to reduce the amplitude and duration of evoked inhibitory postsynaptic currents [5]. This change is especially detrimental, because it is the mechanism through which seizures induce future seizures; by diminishing the inhibitory currents, it becomes even easier for the propagation and maintenance of future seizures.

Research has pointed to the fact that neuronal damage in epileptics is generally found in certain brain regions, signifying that certain neurons are more susceptible to the damage of seizures than others. Specifically neurons found in hippocampal histological divisions CA1, CA2, and CA3 (among others) have been found to suffer particular damage following a seizure. Furthermore, the damage to specific sub regions was correlated with the number of past seizures. For example, damage to CA3 was only seen in cases of thirty or more past seizures [4].

A single seizure is capable of inducing significant change in the human brain, and progressive seizures lead to increased neuronal damage. What is even more important is that many of these changes themselves increase the susceptibility for future seizures, thus creating a self-sustaining system for the progression of epilepsy. It is for these reasons that neuroprotection has been indicated as a top priority in the treatment of epilepsy.

The damage seen due to the progression of epilepsy shows that the process of neuronal damage is a gradual one. The human body has certain mechanisms for protecting the brain following a seizure that are referred to as endogenous neuroprotection. Generally, protective metabolites and ligands including antioxidant enzymes, growth factors, neuropeptides, and adenosine, among others, are created within the nervous system in an attempt to limit the spread of epileptic discharge during subsequent seizures. These substances also aid in reducing calcium entry as well as decreasing neuronal excitability in succeeding seizures. This process by which the brain develops a system for reducing brain injury following a seizure is known as epileptic tolerance [4].

Unfortunately, epileptic tolerance is not enough to protect epileptics from the cognitive impairments seen with epilepsy, resulting in neuroprotection being incorporated as an intricate part of treatment. Neuroprotection seen with treatment includes not only preventative measures such as administration of benzodiazapines during prolonged seizures to reduce neuronal loss, but also administration of antiepileptic drugs (AED) which have also been shown to aid in neuroprotection [2].

Use of AED’s for the treatment of epilepsy has been shown to have neuroprotective qualities if administered during the acute phase of the disease. Little to no neuroprotective advantages are seen if the drugs are administered during the latency/chronic phase of the disease. They work through the blockage of voltage dependent ion channels and mediation of excitatory and inhibitory neurotransmitters. Certain AED’s such as Topiramate aid in protecting the mitochondria of hippocampal cells from calcium overload. Others, such as Felbamate, work as NMDA antagonists to induce an anti-apoptotic state [4]. Unfortunately, AED’s only have minimal neuroprotective properties that are limited by the stage at which they are administered. Thus, AED’s are not enough to wholly protect the brain against epileptogenesis.

Increasingly, nutritional alterations have been shown to be beneficial for neuroprotection. Antioxidants for example, reduce ROS, which are produced during mitochondrial strain. Similarly, ketogenic diet’s, high in fats and low in carbohydrates have been beneficial not only for epilepsy, but other neurological disorders such as Alzheimer’s and Parkinson’s disease. Although the mechanism behind their action has yet to be elucidated, ketone bodies have been found to reduce the occurrence and duration of seizures as well as the neuronal damage associated with them [5].

Currently, research is looking into the possibility of using glutamate receptor blockers for the purpose of neuroprotection in epilepsy. Glutamate receptor blockers function as mediators to the propagation of a seizure by reducing the amount of available glutamate within the neuronal network. Some research has shown remarkable advantages for the use of receptor blockers however they are generally only effective in the early stages of the disease. Additionally, use of this type of treatment is limited by the fact that at higher doses, glutamate blockers can cause a slowly progressing neurodegenerative process all on their own [5]. Thus, this intervention can be potentially harmful if not administered in the correct amounts.


[1] Scharfman, H. E. (2007). The Neurobiology of Epilepsy. Current Neurology and Neuroscience Reports, 7, 348-354.

[2] Sloviter, R. S. (2011). Progress on the Issue of Excitotoxic Injury Modification VS. Real Neuroprotection; Implications for Post-Traumatic Epilepsy. Neuropharmacology, 61, 1048-1050.

[3] McDonald, C. R., Taylor, J., Hamberger, M., Helmstaedter, C., Hermann, B., & Schefft, B. (2011). Future Directions in the Neuropsychology of Epilepsy. Epilepsy & Behavior, 22, 69-76.

[4] Hamed, S. A. (2010a). The Multimodel Prospects for Neuroprotection and Disease Modification in Epilepsy: Relationship to its Challenging Neurobiology. Restorative Neurology and Neuroscience, 28, 323-348.

[5] Hamed, S. A. (2010b). The Rationale for Neuroprotection in Epilepsy: Steps Forward for New Therapeutic and Preventative Strategies. Journal of Integrative Neuroscience, 9(1), 65-102.

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[1] Retrieved April 10, 2014, from:


Maria Cimporescu recently graduated with a B.A. in Psychology and is currently conducting research at The George Washington University. Follow The Triple Helix Online on Twitter and join us on Facebook.

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