Seizures

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This is not a comprehensive list, simply some articles I have found along the way.

“Epilepsy, a paroxysmal disorder characterized by abnormal neuronal discharges, is common in children. While the causes of epilepsy are many, the fundamental disorder is secondary to abnormal synchronous discharges of a network of neurons. Whether or not a seizure occurs in a child depends upon the balance between excitability and inhibition. Central nervous system neurotransmitters have significant effects on neuronal excitability and play a pivotal role in brain excitability. The most common excitatory neurotransmitter in the brain, glutamate, has been implicated in both the initiation and propagation of seizures as well as brain damage that can occur following prolonged or repeated seizures. Gammaaminobutyric acid, the most common inhibitory neurotransmitter, usually suppresses seizure activity, although in absence seizure drugs that enhance GABA may exacerbate seizures. Experience with GABA indicates that certain neurotransmitters may have either anticonvulsant or proconvulsant effects depending on the neuronal networks involved. While other neurotransmitters also have effects on neuronal excitability, their function in epilepsy remains to be defined.” http://onlinelibrary.wiley.com/doi/10.1002/mrdd.1410010309/abstract

“Glutamate is the principal excitatory neurotransmitter in the brain and, as such, it inevitably plays a role in the initiation and spread of seizure activity. It also plays a critical role in epileptogenesis. The process of “kindling” limbic seizures in rodents by repeated electrical stimulation is dependent on activation of N-methyl-D-aspartate (NMDA) receptors. The function of these receptors is enhanced in the hippocampus of kindled rats and in the cerebral cortex of patients with focal epilepsy. Microdialysis studies show an increase in the extracellular concentration of glutamate and aspartate before or during seizure onset, suggesting that either enhanced amino acid release or impaired uptake contributes to seizure initiation. Glutamate antagonists selective for NMDA or non-NMDA receptors are potent anticonvulsants when given systemically in a wide variety of animal models of epilepsy. They are of limited efficacy against kindled seizures in rats and (on the basis of preliminary evidence) in patients with drug-refractory complex partial seizures. Cognitive side effects appear to be a significant problem with competitive, as well as noncompetitive, NMDA antagonists. Glutamate receptor antagonists provide significant protection against brain damage following global or focal cerebral ischemia or acute traumatic injury in rodent models. Anticonvulsant compounds of the lamotrigine type, which act on sodium channels and reduce ischemia-induced glutamate release, are cerebroprotective in rodent ischemia models and are free from the cognitive side effects of NMDA-receptor antagonists.” https://www.ncbi.nlm.nih.gov/pubmed/7970002

“This neuroinflammation upsets the balance between excitatory and calming neuro-transmitters, causing the glutamate system to become overexcited and GABA production to be curtailed.  This results in the development of autistic symptoms and other neurological disturbances such as seizures.” “Two biomarkers of this glutatmate excitotoxicity are mitochondrial dysfunction involving 1) viral exposures which damages the mitochondrial membrane resulting in formation of swellings (dendritic beading) along the nerve dendrites and 2) the formation of lipid rafts, ceramides within the cells impairing mebrane function.” http://www.ageofautism.com/2009/07/solving-the-autism-puzzle-the-fatty-acid-question-and-big-fat-neurons.html

“Epileptic syndromes have very diverse primary causes, which may be genetic, developmental or acquired. In rodent models, altering glutamate receptor or glutamate transporter expression by knockout or knockdown procedures can induce or suppress epileptic seizures. Regardless of the primary cause, synaptically released glutamate acting on ionotropic and metabotropic receptors appears to play a major role in the initiation and spread of seizure activity” http://jn.nutrition.org/content/130/4/1043S.full

“There is a growing list of neurologic disorders are now understood to share a final common destructive metabolic pathway called excitotoxicity, which has been the focus of intense investigative efforts in the neurosciences over the past several decades (3–31). Excitotoxicity refers to an excessive activation of neuronal amino acid receptors. The specific type of excitotoxicity triggered by the amino acid glutamate is the key mechanism implicated in the mediation of neuronal death in many disorders. Glutamate excitotoxicity is the final common pathway resulting in neuronal injury for many seemingly unrelated disorders, including ischemia, trauma, seizures, hypoglycemia, hypoxia, and even some neural degenerative disorders. Familiarity with this process is important for neuroradiologists because of its central position in many of the disorders encountered in daily practice. This area has been one of the most intensely investigated fields in the neurosciences over the past several decades, and the information generated from this work will clearly influence our basic understanding of many neurologic disorders.” https://www.ncbi.nlm.nih.gov/pubmed/11733308

“Epilepsy is a broad range of neurological conditions that are manifested as seizures. Two major hypotheses—glutamate and potassium—have been proposed for the mechanism of epilepsy development (Fisher et al., 1976; During and Spencer, 1993). Although both hypotheses have some evidence to support, the relative contribution of potassium and glutamate to epilepsy has not been determined. Glutamate is a major excitatory neurotransmitter in the brain and an immediate precursor for GABA in neurons and glutamine in astrocytes. Glutamate is differentially compartmentalized and metabolized via different enzymes by astrocytes and neurons and exogenous and endogenous glutamate is handled distinctively by them (McKenna, 2007). Elevated levels of glutamate have been reported in human brain tissues and animal models of epilepsy, and it is known that glutamate-induced excitotoxicity causes the neuronal death in epilepsy (Haglid et al., 1994; Coulter and Eid, 2012 for detail).” https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3741557/

“Another graphic demonstration of the connection between seizures, glutamate accumulation and cognitive deterioration is seen in the case of pyrodoxine-sensitive seizure in newborns. It has been shown that in the untreated child, CSF glutamate levels are 200X normal and seizures are uncontrollable.19 When given an intermediate dose of 5mg/kg/BW/day of pyrodoxine, the seizures cease, but mental deterioration continues. Glutamate levels at this dose were still 10X higher than normal. When using pyrodoxine at 10 mg/kg/BW/day there were no seizures, no cognitive deterioration, and glutamate levels are normal. It is interesting to note that some reported cases of pyridoxine-dependent seizures also had features of autism.” (http://dorway.com/doctors-speak-out/dr-blaylock/the-role-of-excitotoxicity-in-autism-spectrum-disorders/)

“This neuroinflammation upsets the balance between excitatory and calming neuro-transmitters, causing the glutamate system to become overexcited and GABA production to be curtailed.  This results in the development of autistic symptoms and other neurological disturbances such as seizures.” http://www.ageofautism.com/2009/07/solving-the-autism-puzzle-the-fatty-acid-question-and-big-fat-neurons.html

Both clinical and subclinical seizures are known to occur in relatively high rates in autism spectrum disorders.’^” Likewise, a number of studies have shown that MSG given systemically can lower seizure threshold and prolong seizures, with the immature brain being significantly more susceptible.'” ‘”http://www.encognitive.com/files/A%20POSSIBLE%20CENTRAL%20MECHANISM%20IN%20AUTISM%20SPECTRUM%20DISORDERS.pdf

“Glutamate receptors have been discovered to have a role in the onset of epilepsy. NMDA and metabotropic types have been found to induce epileptic convulsions. Using rodent models, labs have found that the introduction of antagonists to these glutamate receptors helps counteract the epileptic symptoms.[70] Since glutamate is a ligand for ligand-gated ion channels, the binding of this neurotransmitter will open gates and increase sodium and calcium conductance. These ions play an integral part in the causes of seizures. Group 1 metabotropic glutamate receptors (mGlu1 and mGlu5) are the primary cause of seizing, so applying an antagonist to these receptors helps in preventing convulsions.[71]” https://en.wikipedia.org/wiki/Glutamate_receptor#Seizures

“The specific decrease in GLU uptake in the cortex of GAERS linked to synaptic changes suggests impairment of the glutamatergic terminal network. These data support the idea that a change in glutamatergic neurotransmission in the cortex could contribute to hyperexcitability in absence epilepsy.” https://bmcneurosci.biomedcentral.com/articles/10.1186/1471-2202-8-69

“High-speed glutamate biosensor imaging showed that glutamate signaling was significantly increased in the injured cortex. Elevated glutamate responses correlated with epileptiform activity, were highest directly adjacent to the injury, and spread via deep cortical layers. Immunoreactivity for markers of GABAergic interneurons were significantly decreased throughout CCI cortex. Lastly, spontaneous inhibitory postsynaptic current frequency decreased and spontaneous excitatory postsynaptic current increased after CCI injury. Our results suggest that specific cortical neuronal microcircuits may initiate and facilitate the spread of epileptiform activity following TBI. Increased glutamatergic signaling due to loss of GABAergic control may provide a mechanism by which TBI can give rise to post-traumatic epilepsy.” Traumatic Brain Injury Increases Cortical Glutamate Network Activity by Compromising GABAergic Control. https://www.ncbi.nlm.nih.gov/pubmed/24610117

 “Growing evidence indicates that there is a close correlation between brain inflammation (by microglial released inflammatory cytokines and glutamate) and seizures, just as we see with excessive brain immune stimulation with vaccines. Using lipopolysacchride as a vaccine-based immune stimulant, scientists have induced seizures in experimental animals of various species.57,58 A considerable amount of evidence links excitotoxicity and seizures. In addition, a number of the newer anti-seizure medications work by blocking glutamate receptors or preventing glutamate release. One of the central mechanisms linking excessive immune stimulation with seizures, as with vaccines, is the induced release of the excitotoxin glutamate and quinolinic acid from immune stimulated microglia and astrocytes.59-61 In many cases these seizures are clinically silent or manifest as behavioral problems, often not recognized by pediatricians as seizures. Yet, they can alter brain function and eventually result in abnormal brain development. Even the CDC and American Academy of Pediatrics recognize that infants and children with a history of seizure should not be vaccinated. It is also known that autistic children who regress, that is begin to show a sudden worsening of mental development, have a significantly higher incidence of seizures, both clinical and subclinical, than those who do not regress. Interestingly, studies have shown that during early brain development after birth the number of glutamate receptors (that trigger the seizures) increase steadily until the age of two when it peaks.62 Thereafter they decline in number. This means that the immature brain is significantly more susceptible to seizures than the more mature brain and this is when your child is being given 24 vaccine inoculations, many of which are associated with a high incidence of seizure.” Growing evidence indicates that there is a close correlation between brain inflammation (by microglial released inflammatory cytokines and glutamate) and seizures, just as we see with excessive brain immune stimulation with vaccines. Using lipopolysacchride as a vaccine-based immune stimulant, scientists have induced seizures in experimental animals of various species.57,58 http://articles.mercola.com/sites/articles/archive/2008/03/14/the-danger-of-excessive-vaccination-during-brain-development.aspx

Studying the mechanisms underlying glutamate excitotoxicity and inflammatory responses provides hints to the pathology of neurological diseases such as epilepsy. In this dissertation I investigated the expression and function of Krüppel-like factor 4 (KLF4) in glutamate excitotoxicity. I also studied the distribution and the role of progranulin (PGRN) in inflammatory stimulation, in epilepsy and in astrocytes subjected to glutamate excitotoxicity. Our findings suggest that PGRN may be involved in glutamate-evoked increase of glycolysis in cultured astrocytes. In conclusion, our findings provide insights into factors involved in glutamate excitotoxicity, inflammation, and epilepsy. https://open.library.ubc.ca/media/download/pdf/24/1.0072497/1

“Glutamate transporters are operative at an early developmental stage well before synapse formation, but their functional significance has not been determined. We now report that blockade of glutamate transporters in the immature neocortex generates recurrent NMDA receptor-mediated currents associated with synchronous oscillations of [Ca2+]i in the entire neuronal population. Intracerebroventricular injections of the blocker to pups generate seizures that are prevented by coinjections of NMDA receptor blockers. Therefore, the early expression of glutamate transporters plays a central role to prevent the activation by local glutamate concentrations of NMDA receptors and the generation of seizures that may alter the construction of cortical networks. A dysfunction of glutamate transporters may be a central event in early infancy epilepsy syndromes.” http://www.jneurosci.org/content/24/13/3289

Glutamatergic Mechanisms Associated with Seizures and Epilepsy

http://perspectivesinmedicine.cshlp.org/content/5/8/a022863.full.pdf