Is L-Glutamate Toxic to Neurons and Thereby Contributes to Neuronal Loss and Neurodegeneration? A Systematic Review

Abstract

L-glutamate (L-Glu) is a nonessential amino acid, but an extensively utilised excitatory neurotransmitter with critical roles in normal brain function. Aberrant accumulation of L-Glu has been linked to neurotoxicity and neurodegeneration. To investigate this further, we systematically reviewed the literature to evaluate the effects of L-Glu on neuronal viability linked to the pathogenesis and/or progression of neurodegenerative diseases (NDDs). A search in PubMed, Medline, Embase, and Web of Science Core Collection was conducted to retrieve studies that investigated an association between L-Glu and pathology for five NDDs: Alzheimer’s disease (AD), Parkinson’s disease (PD), multiple sclerosis (MS), amyotrophic lateral sclerosis (ALS), and Huntington’s disease (HD). Together, 4060 studies were identified, of which 71 met eligibility criteria. Despite several inadequacies, including small sample size, employment of supraphysiological concentrations, and a range of administration routes, it was concluded that exposure to L-Glu in vitro or in vivo has multiple pathogenic mechanisms that influence neuronal viability. These mechanisms include oxidative stress, reduced antioxidant defence, neuroinflammation, altered neurotransmitter levels, protein accumulations, excitotoxicity, mitochondrial dysfunction, intracellular calcium level changes, and effects on neuronal histology, cognitive function, and animal behaviour. This implies that clinical and epidemiological studies are required to assess the potential neuronal harm arising from excessive intake of exogenous L-Glu.

Glutamate Neurotoxicity and Destruction of the Blood–Brain Barrier: Key Pathways for the Development of Neuropsychiatric Consequences of TBI and Their Potential Treatment Strategies

“…There is well-established evidence that shows a relationship between glutamate neurotoxicity and neurodegeneration [ 29 ]. Glutamate excitotoxicity describes the process of excessive glutamate causing neuronal degeneration and dysfunction, resulting in neurotoxicity [ 29 , 84 , 85 ]. Its role in mood disorders has informed recent research into new therapeutic modalities, with drugs that target glutamatergic systems proposed as anti-depressants and related therapies [ 86 , 87 , 88 ].…”

“…Increased extracellular glutamate can prompt excitotoxicity, via overaction of ionotropic glutamate receptors, after acute brain insults such as ischemic stroke, cerebral ischemia, TBI, hypoglycemia, and epilepsy [ 85 , 89 , 90 , 91 , 92 , 93 , 94 ]. In addition to these acute conditions, a process of chronic glutamate neurotoxicity has also been suggested as a factor in many neurodegenerative diseases, such as amyotrophic lateral sclerosis, Alzheimer’s disease, and Huntington’s disease [ 92 ].…”

Metabolomics Reveals Nutritional Diversity among Six Coarse Cereals and Antioxidant Activity Analysis of Grain Sorghum and Sweet Sorghum

“…Considering the absence of species-specific metabolites in coix, L-glutamate and thiamine (vitamin B1), which have higher content in coix compared to in other grains, were selected to indicate the unique physiological function of coix. Further, although L-glutamate is a nonessential amino acid for the human body, it can also play a key role as a neurotransmitter in the human central nervous system in addition to its physiological functions such as preventing hair loss, enhancing blood circulation, and protecting the liver [ 32 , 33 ]. Thiamine is an essential vitamin for the production of adenosine triphosphate (ATP) in mitochondria, and a rate-limiting cofactor to multiple enzymes involved in the physiological processes [ 34 ].…”

The Time Sequence of Gene Expression Changes after Spinal Cord Injury

“…The role of L-glutamic acid in the CNS is controversial. It might regulate neuronal survival and neuroplasticity, whereas it is also associated with some neurodegenerative diseases through oxidative stress, neuroinflammation, or excitotoxicity [ 83 , 84 ]. Because there is no study on the effect of L-glutamic acid on SCI, it is necessary to clarify the mechanisms through further research.…”