Diseases and Disorders

Glutamatergic Neurotransmission In Epilepsy

Rachel Klick


Abstract

    Epilepsy is a neurological condition identified by recurrent seizures. Glutamate, an excitatory neurotransmitter in the brain, has a correlation to epilepsy symptoms and epileptogenesis, the process by which epilepsy develops in a patient. With this knowledge, experts are conducting research to develop anticonvulsant drugs that use glutamate antagonists to target seizures and eliminate the difficulties that epilepsy causes in the daily lives of patients. In addition, new advances in neurosurgery have been particularly useful when treating seizures in pediatric patients.

The Nature of Epilepsy and Epileptogenesis

    In the brain, high levels of neuronal excitability cause recurrent involuntary seizures [1, 2]. In half of all epileptic patients to date, the epileptogenic causes, or the causes of an otherwise healthy brain developing epileptic seizures, have been unidentifiable. Without a certain etiology, the diagnosis of the patient is defined as cryptogenic [3].

    Epilepsy is typically diagnosed through an electroencephalogram (EEG). Electrodes are attached to the scalp to monitor neurological levels of electrical activity. Blood tests, magnetic resonance imaging (MRI), computed tomography (CAT) scans, and lumbar punctures are procedures used to assist and corroborate the diagnosis [4]. A patient must have had at least two seizures to be formally diagnosed [1]. Although no cure has been discovered, current treatments include medication, ablative surgery, and vagus nerve stimulation (VNS) with 70% of treatments resulting in successful management [4}{5}.

    A seizure occurs when a burst of unusually strong electrical signals in the brain interrupts regular brain function. There are multiple causes of seizures including, but not limited to high fever, progressive brain disease, brain tumors, low blood sugar, concussions, and withdrawal from alcohol and drugs.

    Seizures fall into two general categories, either focal or generalized, with each further divided into subtypes. Focal seizures, otherwise known as partial seizures, occur when an irregular burst of electrical activity takes place at one or more locations on one side of the cerebrum. Specific examples of focal seizures include simple focal seizures and complex focal seizures. Generalized seizures result from abnormal electrical activity on both sides of the brain. Specific examples of generalized seizures are absence seizures (“petit mal” seizures), atonic (drop attacks), generalized tonic-clonic seizures (GTC or “grand mal” seizures), myoclonic seizures, infantile spasms, and febrile seizures [5].

 

Glutamatergic Neurotransmission

    Glutamate is an excitatory neurotransmitter in the mammalian brain, and in any animal with a rudimentary nervous system, strongly associated with epilepsy and other central nervous system disorders [7, 8, 9]. Glutamate was initially believed to be simply a factor in metabolic function in the central nervous system due to its ubiquitous nature and presence in intracellular compartments. This includes involvement in the mitochondria and cytosol of all central nervous system cell types [9, 10, 11].

    Glutamate was first identified in 1984  as a neurotransmitter after research corroborated the existence of intense regulation of glutamate by the CNS [6]. Glutamate, an amino acid, is synthesized via glucose outside of the CNS through the Krebs Cycle, producing pyruvate. Joint activity of the enzymes pyruvate dehydrogenase and pyruvate carboxylase have an essential influence. Via α-ketoglutarate, the citrate is converted to glutamate. Glutamine synthetase then converts the glutamate to glutamine which enters the glutamine–glutamate (GABA) cycle [1,11].

    After crossing the blood-brain barrier to arrive at the neuronal astrocytes, intracellular glutamate is transaminated to accept an amino group from a branched chain amino acid donor such as leucine and valine, y-aminobutyric acid (GABA), and alanine. Glutamate release refers to the process by which cytosolic glutamate uses vesicular glutamate transporters to cross the vesicular membrane.

    Glutamate clearing and cycling are essential to the prevention of excitotoxic damage due to high concentrations of extracellular glutamate and extrasynaptic glutamate that form due to dysregulated excitatory neurotransmission. The clearance of extracellular glutamate must transpire within the boundaries of a millisecond timescale to prevent excitotoxic damage and protect neuronal health. The central nervous system tightly regulates glutamate in order to account for glutamate metabolism, release, transport, and clearance [11].

    Glutamatergic synapses provide communications between postsynaptic dendritic spikes (axodendritic synapses) or adjacent nerve endings (axo-axonal synapses) and presynaptic nerve terminals. Glutamate receptors are divided into two categories: metabotropic and ionotropic:

    (1) Ionotropic receptors are categorized into N-methyl-D-aspartate (NMDA), a-amino-3- hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and kainate (KA) [11, 12]. To generalize, these receptors are ligand-gated ion channels that function to flux cations (Ca2+, Na+).

    (2) Metabotropic glutamate receptors initialize or restrain second messenger systems through the use of cognate G-proteins. Metabotropic receptors are divided into three groups. Group I consists of mGluR1 and mGluR5, group II involves mGluR2 and mGluR3 and group III is composed of mGluR4-8. Both general categories of receptors use their intracellular C-termini to establish an interaction with postsynaptic proteins [8, 11].

    The process by which glutamate receptors, glutamate transporters, and glutamate interact with the cerebral environment is referred to as glutamatergic neurotransmission [6, 11, 12].

 

The Pathology Between Glutamate and Epilepsy

    Pathology between glutamate and epilepsy has been proven to contribute to epileptogenesis. Through microdialysis studies, it has been identified that extracellular concentrations of glutamate and aspartame increase before and/or during seizures [7]. Therefore, it can be concluded that seizures induce elevations of extracellular glutamate, leading to issues with the clearance of extracellular glutamate, the excitotoxic damage of neurons in the brain, and further epileptogenesis.

    In addition, a 1974 study revealed that an antihelminthic called kainic acid caused seizure-like convulsions in small mammals [7]. Kainate is a potent agonist towards AMPA and kainate receptors [7]. It elicits the assumption that there is an association between seizures and biological processes, and structures directly or indirectly related to glutamate.

 

Anticonvulsant Drugs

    In an effort to develop anticonvulsant drugs and further treatments for epilepsy, research has been conducted on the mammalian brains of rats through the use of glutamate antagonists [7, 8]. Antagonists for N-methyl-D-aspartate (NMDA) and non-NMDA receptors have been used as models of anticonvulsant drugs and have been found to have limited efficacy when treating seizures in small mammals, in addition to human patients with drug-refractory complex seizures.

    Negative cognitive effects from competitive and non-competitive NMDA antagonists have been found to exist. However, anticonvulsant compounds of the lamotrigine variety were found to be free of any side effects associated with NMDA antagonists.

    Lamotrigine anticonvulsant compounds use channels of sodium and diminish glutamate release caused by ischemia, a condition in which the blood supply to tissues is reduced. Glutamate receptor antagonists were discovered to be cerebroprotective from forms of brain damage following acute brain trauma or global or focal cerebral ischemia [7].


 

The Future of Epilepsy Research and Treatments

    In order for new anticonvulsant drugs to be produced and distributed by the pharmaceutical industry, it is essential that there be further research into the properties of glutamate, glutamate antagonists, and the association between glutamatergic neurotransmission and epileptogenesis. It is necessary to discover and comprehend the relevance between NMDA antagonists and the cognitive dispositions that develop as a result of biologically targeting NMDA receptors. It is of critical importance that there be an understanding of the pathology between the numerous factors of epilepsy, not limited to the human genome, and this disease that affects over 50 million individuals every day.

    According to the National Institutes of Health, approximately 60% of all patients with epilepsy suffer from focal epilepsy syndromes. For approximately 15% of these patients (an estimated 4.5 million patients), the seizures are not adequately controlled with antiepileptic drugs. The majority of this group are pediatric patients (18 years old or less), potential candidates for surgical ablation of the epileptic foci in the brain [15].

    Surgery in carefully selected epileptic children with intractable seizures has been demonstrated in approximately two-thirds of children to either eliminate or significantly reduce (>90%) the frequency of seizures. While further research is necessary, current advances in structural and functional neuroimaging, neurosurgery, and neuroanaesthesia seem to have improved the outcomes of surgery for children with intractable epilepsy [15].

    Early surgery can improve the quality of life and cognitive and developmental outcomes. These remarkable breakthroughs, and more which can come of future research and treatments, can finally allow many of children to lead more normal lives free from these debilitating seizure patterns.


References


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Rachel Klick

Rachel Klick


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