A Neurochemical Approach to Elucidate Metabotropic vs. Ionotropic Glutamate Receptor Activities in Rat Hippocampal Slices
Avital Schurr, Benjamin M. Rigor in BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Endogenous excitatory amino acids, including L-glutamate, are considered to be the major excitatory neurotransmitter substances in the mammalian central nervous system (CNS). l-Glutamate exerts its physiological actions by acting on multiple populations of receptor proteins that are clearly distinguished by their pharmacological and molecular characteristics.1–4 In addition to transducing the physiological actions of the transmitter glutamate, excessive or inappropriate activation of glutamate receptors can lead to neuronal degeneration through the process of excitotoxicity. The phenomenon of excitotoxicity may be relevant to a variety of disease states such as cerebral ischemia, brain and spinal cord trauma, Parkinson’s disease, Huntington’s chorea, and Alzheimer’s disease.5–7 Thus, the discovery and development of compounds that act at the receptor level to modify glutamatergic neuronal transmission are approaches that may provide neuroprotection from glutamate excitotoxicity.
Pharmacological Management of Amyotrophic Lateral Sclerosis
Sahab Uddin, Rashid Mamunur in Advances in Neuropharmacology, 2020
Glutamate communicates with an assortment of definite receptor and system for transportation to create a functional synapse during the excitatory action in the CNS. Excitotoxicity is a phenomenon caused due to excessive stimulation of glutamate receptors shown in both acute as well as chronic neurodegenerative diseases. Extreme and deregulated activation of glutamate receptors is the primary cause of excitotoxicity. When these receptors are exposed to high or steadily increasing concentrations of glutamate for lengthened periods of time, the cells expressing these receptors begin to die (Choi, 1994). In physiologic circumstances, glutamate level are retained at nanomolar concentration range (Herman and Jahr, 2007), which is insufficient to cause high-affinity glutamate receptor activation. However, glutamate concentration can rise upto millimolar amounts during synaptic discharge events (Beato and Scimemi, 2009). Ca2+-permeable receptors primarily cultivate excitotoxicity. Incursion of Ca2+ is buffered by the endoplasmic reticulum (ER) and the mitochondria are responsible for the moderation of Ca2+, and disturbance of intracellular compartmentalization of Ca2+ or its surplus can lead to cell death (Bonda et al., 2011).
Brain Development and Its Relationship to Patterns of Injury
Richard A. Jonas, Jane W. Newburger, Joseph J. Volpe, John W. Kirklin in Brain Injury and Pediatric Cardiac Surgery, 2019
In summary, the nervous system—especially the immature nervous system—needs stimulation which is normally maintained by excitatory amino acid neurotransmitters. However, too much excitement is not a good thing. In infants, excitatory amino acid receptors play important roles in brain plasticity, that is, stabilizing some circuits and pruning others. Excessive activation of the excitatory mechanism is capable of producing what might be referred to colloquially as a “synaptic power surge” analogous to a power surge in a computer. In a computer, the electricity is carried by electrons. In the brain, much of the electricity is carried by ions such as calcium. In the brain, as in the computer, the power surge is capable of destroying neurons in a regionally selective fashion.40 These concepts suggest that therapeutic interventions that block glutamate receptors might be efficacious, but that care must be taken because reduced activation of these receptors for a prolonged time is also capable of producing developmental abnormalities.41 The theory of excitotoxicity has clarified a number of issues related to the pathogenesis of brain injury and supplied hypotheses for therapeutic studies.
Dietary omega-3 fatty acids prevent neonatal seizure-induced early alterations in the hippocampal glutamatergic system and memory deficits in adulthood
Published in Nutritional Neuroscience, 2022
Júlia D. Moreira, Letícia Vicari Siqueira, Alexandre P. Müller, Lisiane O. Porciúncula, Lúcia Vinadé, Diogo O. Souza
The fundamental role of glutamate for brain development, maturation and functions related to memory / learning processes and synaptic plasticity is well known, in addition to being involved in brain aging [5,6,9]. However, glutamate can become toxic to brain cells in a process named ‘excitotoxicity’ [6,9]. Glutamatergic excitotoxicity occurs when excess glutamate is release in the synaptic cleft and it overcomes the capacity of glial glutamate transporters to remove it from the synapse, which leads to NMDA receptor hyperactivation, excess calcium influx and the loss of neuronal homeostasis, culminating with cell death and loss of function [10,11]. Excitotoxicity is involved in pathological processes associated with neurological diseases such as Alzheimer's disease, Parkinson's disease, and epilepsy [10–12].
Ketogenic diet: overview, types, and possible anti-seizure mechanisms
Published in Nutritional Neuroscience, 2021
Mohammad Barzegar, Mohammadreza Afghan, Vahid Tarmahi, Meysam Behtari, Soroor Rahimi Khamaneh, Sina Raeisi
The role of seizure in neuronal damage and the involved underlying mechanisms have been discussed for decades. It has been revealed that isolated slight seizures probably could not kill neurons; however, severe and prolonged seizures not only can cause neuronal damage, but also may cause neuronal death [84]. The cognitive impairments and seizure severity in DRE patients, both can be affected by the amount of neuronal damage caused by seizures [85]. This damage may be mediated mainly by excitotoxicity. In this pathological process, the prolonged seizures lead to extreme presynaptic glutamate release which activates an excessive number of postsynaptic NMDA receptors and opens their cationic sodium and calcium channels. Excessive sodium influx can cause osmotic stress leading to neuronal swelling and rupture. The increased intraneuronal calcium amount enhances the activation of calcium-dependent proteases, phospholipases, and nitric oxide synthase elevating free radicals that all lead to DNA degradation and organelles destruction culminating in necrosis of the postsynaptic neurons [85,86].
Nutraceutical induction and mimicry of heme oxygenase activity as a strategy for controlling excitotoxicity in brain trauma and ischemic stroke: focus on oxidative stress
Published in Expert Review of Neurotherapeutics, 2021
A practical nutraceutical strategy for opposing excitotoxicity might be of particular interest, inasmuch as it could be employed in a preventive mode for individuals at high risk for brain trauma or ischemic stroke. In particular, those who participate regularly in contact sports likely to induce head trauma (e.g. football, boxing, soccer), as well as soldiers at risk for blast injuries, might be candidates for such supplementation. In light of the above discussion, a regimen comprised of PhyCB, high-dose biotin, astaxanthin, and a phase 2-inductive agent with good pharmacokinetics and brain permeability might be useful in this regard. Phase 2 inducers that might be considered include lipoic acid, sulphoraphane, and ferulic acid. The latter is of particular interest in light of numerous rodent studies demonstrating its protective efficacy in rodent models of brain trauma and brain ischemia-reperfusion damage [145–155]. It also protects the brains of mouse fetuses from excitotoxicity when their mothers are gavaged with monosodium glutamate [145]. Unlike many phytochemicals, ferulic acid is well absorbed in its native form. Moreover, the clinical efficacy of sodium ferulate for cardiovascular applications is well documented in the Chinese literature [156]. Ferulic acid exerts anti-inflammatory effects independent of its phase 2-inductive activity, and it is conceivable that these contribute to its utility in excitotoxicity [157,158].
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