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Degenerative Diseases of the Nervous System
Published in Philip B. Gorelick, Fernando D. Testai, Graeme J. Hankey, Joanna M. Wardlaw, Hankey's Clinical Neurology, 2020
James A. Mastrianni, Elizabeth A. Harris
PD is a mostly sporadic disease which is likely multifactorial and heterogeneous in etiology. PD occurs due to a complex interaction among genetic, environmental, and other individual factors. PD is not one condition with a single cause for all patients, but is rather a downstream clinical syndrome resulting from different types of insults to the substantia nigra (e.g. hereditary, toxic, infectious, age-related). Despite continued expansion of scientific understanding, the cause of dopaminergic cell death in PD is not fully understood and probably heterogeneous and multifactorial, related to a probable self-propagating series of reactions including: Oxidative stress, reactive oxygen species production.Mitochondrial dysfunction.Excitotoxicity.A rise in intracellular free calcium.Protein aggregation.Inflammation.
A Neurochemical Approach to Elucidate Metabotropic vs. Ionotropic Glutamate Receptor Activities in Rat Hippocampal Slices
Published in Avital Schurr, Benjamin M. Rigor, BRAIN SLICES in BASIC and CLINICAL RESEARCH, 2020
Darryle D. Schoepp, Manisha A. Desai
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
Published in Sahab Uddin, Rashid Mamunur, Advances in Neuropharmacology, 2020
Shalini Mani, Chahat Kubba, Tanya Sharma, Manisha Singh
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).
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].
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].
Delivery of neurotrophic factors in the treatment of age-related chronic neurodegenerative diseases
Published in Expert Opinion on Drug Delivery, 2020
Smrithi Padmakumar, Maie S. Taha, Ekta Kadakia, Benjamin S. Bleier, Mansoor M. Amiji
Neuroprotection aims to limit neuronal damage by intercepting the underlying pathogenenic causes. The use of antioxidants to reverse the oxidative stress accompanied with mitochondrial dysfunction has shown to alleviate neurons damage and positively impacted disease symptoms [61]. Anti-excitotoxic agents block glutamate receptors, alleviate glutamate-mediated excitotoxicity, and relieve neurodegenerative symptoms [62]. Anti-inflammatory drugs are proposed for neuroprotection; however, due to early implication of inflammation in the neurodegeneration process, anti-inflammatory agents might not be sufficient to suppress neuron loss [63]. Apoptotic nerve cell death is the eventual pathophysiological outcome in neurodegeneration, thus anti-apoptotic agents are investigated for their potential neuroprotective effect. However, to exert a clinical benefit they need to be supplemented with other therapeutic modalities. Given the physiological role of NTFs, they are explored for their therapeutic neuroprotective effects through different approaches, such as cell therapy, gene therapy, etc., which will be discussed further.