Neurochemistry Of Epilepsy
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Neurochemistry of Epilepsy
Epileptic seizures have been described and recognized for millennia. One of the earliest descriptions of a secondarily generalized tonic-clonic seizure was recorded over 3000 years ago in Mesopotamia. The first book about epilepsy was written by Hippocrates about 2500 years ago. His ideas of seizures caused by excessive phlegm and abnormal brain consistency have been rejected, and at the turn of the century, even things such as excessive masturbation was considered a cause of epilepsy. This hypothesis is credited as leading to the use of the first effective anticonvulsants known as bromides (William et al).
In 1929, Berger discovered that electrical brain signals could be recorded from the brain by using scalp electrodes attached to the head, and this discovery led to the use of electroencephalography (EEG) to study and classify epileptic seizures. In 1981, the International League Against Epilepsy (ILAE) developed an international classification of epileptic seizures that divides seizures into two major classes: partial seizures and generalized seizures. Partial seizures begin in one focal area of the cerebral cortex, whereas generalized seizures have an onset recorded simultaneously in both cerebral hemispheres. Some seizures are difficult to fit into one class, and they are considered unclassified seizures. The ILAE uses EEG patterns, among other characteristics of the history of the seizures to classify epilepsy (epilepsy.com).
Epilepsy is a disorder characterized by the occurrence of at least 2 unprovoked seizures. Seizures are abnormal and temporary discharges of cortical neurons. The clinical signs or symptoms of seizures depend on the location and extent of the firings. That seizures are a common, nonspecific manifestation of neurologic injury and disease should not be surprising because the main function of the brain is the transmission of electrical impulses. The lifetime likelihood of experiencing at least one epileptic seizure is about 9%, and the lifetime likelihood of receiving a diagnosis of epilepsy is almost 3% (Gilman et al). Epilepsy contains no discrimination against race, gender, or age, although there are higher incidence of seizure activity among the very young and the very old.
Because seizures affect so many areas of the brain, and involve so many different neurotransmitters, it is hard to pinpoint one reason or cause of epileptic activity. There is much research being done about seizures and sodium channels. However, most anti-epileptic drugs (AED) target GABA pathways in the brain. Mechanisms leading to decreased inhibition include defective gamma-aminobutyric acid (GABA)-A inhibition, defective GABA-B inhibition, and defective activation of GABA neurons (Matthews).
GABA is the main inhibiting neurotransmitter in the brain. GABA binds to two of three major classes of receptors: GABA-A and GABA-B. GABA-C has no physiological activity that is known. Studies have shown that repeated and intense seizures cause a loss of GABA mediated inhibition of dentate granule cells in vitro. Detailed immunohistcohemical studies of sclerotic hippocampus from humans and models provide potential mechanisms of hyperexcitability. GABA neurons are actually more resistant to seizure induced neuronal death than were other hippocampal neurons. However, mossy cells are located in the dentate hilus (a part of the hippocampus) and were found to be extremely sensitive to seizure induced neuronal death (Goodkin). Mossy cells are the most common type of neuron in the dentate hilus. Functionally, mossy cells are excitatory on the granule cells. They are damaged following intense synaptic activation, probably through excitotoxic mechanisms of activation of N-methyl-D-aspartate (NMDA) subtype of glutamate receptors, or seizure activity.
These series of findings lead to the dormant basket cell hypothesis which suggests that the seizure induced death of excitatory neurons in the hilus (probably mossy cells) removes an excitatory projection to GABA neuron, resulting in disinhibition. Once initiated, the cycle continues in which a partial loss of this inhibition, combined with excitatory synaptic input, could lead to excessive firing of granule cells, more mossy cell death, further loss of GABAergic inhibition and so on, resulting in an epileptic condition long after the first seizure. Studies such as these show that GABA plays a very important role in seizure activity, and AEDs working with these pathways can help improve the symptoms of epilepsy (Merlo et al).
In one recent study, a mutation in the gamma 2-subunit of GABAA receptor passed down among genetically caused epilepsy has caused seizures in its patients continually. The Ala322Asp mutation of GABAA receptor is another factor that adds to this disorder. The HEK-293 cells, which contain receptors for the GABAA, show slow receptor deactivation and