Oral glutamine supplementation increases seizure severity in a rodent model of mesial temporal lobe epilepsy.

Background: Glutamine synthetase (GS) is the only enzyme known to synthesize significant amounts of glutamine in mammals, and loss of GS in the hippocampus has been implicated in the pathophysiology of medication refractory mesial temporal lobe epilepsy (MTLE). Moreover, loss-of-function mutations of the GS gene causes severe epileptic encephalopathy, and supplementation with glutamine has been shown to normalize EEG and possibly improve the outcome in these patients. Here we examined whether oral glutamine supplementation is an effective treatment for MTLE by assessing the frequency and severity of seizures after supplementation in a translationally relevant model of the disease.Methods: Male Sprague Dawley rats (380-400 g) were allowed to drink unlimited amounts of glutamine in water (3.6% w/v; n = 8) or pure water (n = 8) for several weeks. Ten days after the start of glutamine supplementation, GS was chronically inhibited in the hippocampus to induce MTLE. Continuous video-intracranial EEG was collected for 21 days to determine the frequency and severity of seizures.Results: While there was no change in seizure frequency between the groups, the proportion of convulsive seizures was significantly higher in glutamine treated animals during the first three days of GS inhibition.Conclusion: The results suggest that oral glutamine supplementation transiently increases seizure severity in the initial stages of an epilepsy model, indicating a potential role of the amino acid in seizure propagation and epileptogenesis.

Circadian-Like Rhythmicity of Extracellular Brain Glutamate in Epilepsy.

Seizures often exhibit striking circadian-like (~24-h) rhythms. While chronotherapy has shown promise in treating epilepsy, it is not widely used, in part because the patterns of seizure rhythmicity vary considerably among patients and types of epilepsy. A better understanding of the mechanisms underlying rhythmicity in epilepsy could be expected to result in more effective approaches which can be tailored to each individual patient. The excitatory neurotransmitter glutamate is an essential modulator of circadian rhythms, and changes in the extracellular levels of glutamate likely affect the threshold to seizures. We used a reverse translational rodent model of mesial temporal lobe epilepsy (MTLE) combined with long-term intracerebral microdialysis to monitor the hourly concentrations of glutamate in the seizure onset area (epileptogenic hippocampus) over several days. We observed significant 24-h oscillations of extracellular glutamate in the epileptogenic hippocampus (n = 4, JTK_CYCLE test, p < 0.05), but not in the hippocampus of control animals (n = 4). To our knowledge, circadian glutamate oscillations have not been observed in a seizure onset region, and we speculate that the oscillations contribute to the rhythmicity of seizures in MTLE.

Branched-Chain Amino Acids and Seizures: A Systematic Review of the Literature.

BACKGROUND: Up to 40% of patients with epilepsy experience seizures despite treatment with antiepileptic drugs; however, branched-chain amino acid (BCAA) supplementation has shown promise in treating refractory epilepsy. OBJECTIVES: The purpose of this systematic review was to evaluate all published studies that investigated the effects of BCAAs on seizures, emphasizing therapeutic efficacy and possible underlying mechanisms. METHODS: On 31 January, 2017, the following databases were searched for relevant studies: MEDLINE (OvidSP), EMBASE (OvidSP), Scopus (Elsevier), the Cochrane Library, and the unindexed material in PubMed (National Library of Medicine/National Institutes of Health). The searches were repeated in all databases on 18 February, 2019. We only included full-length preclinical and clinical studies that were published in the English language that examined the effects of BCAA administration on seizures. RESULTS: Eleven of 2045 studies met our inclusion criteria: ten studies were conducted in animal models and one study in human subjects. Seven seizure models were investigated: the strychnine (one study), pentylenetetrazole (two studies), flurothyl (one study), picrotoxin (two studies), genetic absence epilepsy in rats (one study), kainic acid (two studies), and methionine sulfoximine (one study) paradigms. Three studies investigated the effect of a BCAA mixture whereas the other studies explored the effects of individual BCAAs on seizures. In most animal models and in humans, BCAAs had potent anti-seizure effects. However, in the methionine sulfoximine model, long-term BCAA supplementation worsened seizure propagation and caused neuron loss, and in the genetic absence epilepsy in rats model, BCAAs exhibited pro-seizure effects. CONCLUSIONS: The contradictory effects of BCAAs on seizure activity likely reflect differences in the complex mechanisms that underlie seizure disorders. Some of these mechanisms are likely mediated by BCAA's effects on glucose, glutamate, glutamine, and ammonia metabolism, activation of the mechanistic target of rapamycin signaling pathway, and their effects on aromatic amino acid transport and neurotransmitter synthesis. We propose that a better understanding of mechanisms by which BCAAs affect seizures and neuronal viability is needed to advance the field of BCAA supplementation in epilepsy.

Neurotoxicity of anesthetic drugs: an update.

PURPOSE OF REVIEW: This article reviews the most recently published evidence that investigated anesthesia-induced neurotoxicity in both animals and humans, especially as it pertains to the perinatal period. RECENT FINDINGS: Several recent studies have focused on better understanding the complex mechanisms that underlie intravenous and volatile anesthesia-induced neurotoxicity in animals. Adjuvant agents that target these pathways have been investigated for their effectiveness in attenuating the neuroapoptosis and neurocognitive deficits that result from anesthesia exposure, including dexmedetomidine, rutin, vitamin C, tumor necrosis factor α, lithium, apocynin, carreic acid phenethyl ester. Five clinical studies, including one randomized control trial, provided inconsistent evidence on anesthesia-induced neurotoxicity in humans. SUMMARY: Despite a growing body of preclinical studies that have demonstrated anesthesia-induced neurotoxic effects in the developing and aging brain, their effects on the human brain remains to be determined. The performance of large-scale human studies is limited by several important factors, and noninvasive biomarkers and neuroimaging modalities should be employed to define the injury phenotypes that reflect anesthesia-induced neurotoxicity. Ultimately, the use of these modalities may provide new insights into whether the concerns of anesthetics are justified in humans.

Recent trends in the anesthetic management of craniotomy for supratentorial tumor resection.

PURPOSE OF REVIEW: The article reviews the recent evidence on the anesthetic management of patients undergoing craniotomy for supratentorial tumor resection. RECENT FINDINGS: A rapid recovery of neurological function after craniotomy for supratentorial tumor allows for the prompt diagnosis of intracranial complications and possibly an early hospital discharge. Intraoperative esmolol infusion was shown to reduce the anesthetic requirements, and may facilitate a more rapid recovery of neurological function. Outpatient craniotomy for supratentorial tumor resection has been associated with several clinical and economic benefits, but has not gained widespread use because of skepticism and medical-legal concerns. Awake craniotomy is associated with advantageous outcomes compared with surgery under general anesthesia, and is regarded as the standard of care for tumors that reside in or in close proximity to the eloquent brain. Recent studies have demonstrated that intraoperative electroacupuncture, dexmedetomidine, pregabalin, and lidocaine may facilitate postcraniotomy pain management. The use of volatile anesthetic agents in cancer surgery is associated with a worse survival compared with intravenous anesthetics, possibly by hindering immunologic defenses against cancer cells. SUMMARY: Recent evidence has yielded valuable information regarding anesthetic management of patients undergoing supratentorial tumor craniotomy. Despite a plethora of studies that compare short-term outcomes using different anesthetic and analgesic regimens, randomized controlled trials that examine the long-term outcomes (i.e., neurocognitive function, quality of life, tumor recurrence, and survival) that are of particular interest to patients are needed.

Postoperative ICU management of patients after subarachnoid hemorrhage.

PURPOSE OF REVIEW: This article reviews recent advances in the postoperative ICU management of patients after subarachnoid hemorrhage (SAH), especially with regards to hemodynamic management, methods of improving neurological outcomes, and management of cardiac and pulmonary complications. RECENT FINDINGS: Several hemodynamic monitors and parameters may be useful for guiding volume therapy, including cardiac output, stroke volume variation monitoring, and global end-diastolic volume index. Early goal-directed hemodynamic therapy after SAH has recently been shown to improve clinical outcomes in patients with a poor clinical grade or coexisting cardiopulmonary complications. Recent laboratory and imaging modalities are being developed to identify patients at risk for developing vasospasm after SAH. Evidence for the use of various prophylactic adjuvant therapies to prevent vasospasm, including magnesium, phosphodiesterase 3 inhibitors, and therapeutic hypothermia, is emerging. Intrathecal administration of vasodilators or fibrinolytics may have offered advantages over systemic drug administration in the treatment of vasospasm. Pulmonary and cardiac complications are common after SAH, and are associated with an increased risk of mortality. SUMMARY: The postoperative ICU period after SAH is associated with a significant morbidity and mortality risk, and recent studies have greatly contributed to our understanding of how to optimally manage these patients.

Determination of factors affecting glutamate concentrations in the whole blood of healthy human volunteers.

BACKGROUND: Abnormally high concentrations of glutamate in brain fluids have been shown to be neurotoxic and correlate with a poor neurological outcome following traumatic brain injury (TBI). Since brain fluid glutamate can be reduced by scavenging blood glutamate, the purpose of this study was to investigate factors that may potentially influence levels of blood glutamate, glucose, and the enzymes glutamate-pyruvate transaminase (GPT) and glutamate-oxaloacetate transaminase (GOT) in healthy individuals. METHODS: Factors that were examined included age, gender, time of last meal or drink, and recent consumption of coffee. A total of 112 healthy volunteers between 18 and 70 years of age participated in the study. The average participant was 38 years old, and the sample consisted of 48 males and 64 females. Five milliliters of venous blood was collected from participants' cubital vein and blood glutamate, glucose, GOT and GPT levels were determined. Participants were then asked to complete a questionnaire addressing their gender, age, time of last meal, time of last drink, and whether coffee was consumed within the last 6 hours. RESULTS: Blood glutamate concentrations were significantly higher in males than in females (P < 0.001) and may be due to effects of estrogen and progesterone. Concentrations of GOT were significantly higher in males than in females (P < 0.01). Concentrations of GPT were significantly higher in males than in females (P < 0.01). There were no other significant differences demonstrated. CONCLUSIONS: Understanding the factors that affect blood glutamate levels may give new insight into mechanisms that protect the brain from excess glutamate and result in a better neurological outcome following TBI.