Clinical pharmacology and therapeutics: drugs for neuropathic pain in cancer
Nigel Sykes, Michael I Bennett, Chun-Su Yuan in Clinical Pain Management, 2008
Glutamate is the main excitatory neurotransmitter in the central nervous system (CNS).67, 68 Activation of one of the receptors for glutamate, the NMDA receptor, found in the spinal cord seems to be a critical step in the generation of a number of pain states, including prolonged pain states.68 After initial activation of the alpha-amino-3-hydroxy-5-methylisoxazole-4-proprionic acid (AMPA) receptors in the dorsal horn, repeated stimulation may allow activation of the NMDA receptors with the consequent conversion of a small to large amplitude response and a corresponding increase in pain intensity.67 The C fiber-induced activity of the dorsal horn nociceptive neurons is enhanced and prolonged – the “wind up” phenomenon. This phenomenon converts simple touch into painful sensation – allodynia. It means that a pain response to any given painful stimulus is magnified – hyperalgesia – and prolonged.
Pain Sensitization
Peter Kam, Ian Power, Michael J. Cousins, Philip J. Siddal in Principles of Physiology for the Anaesthetist, 2020
Activation of NMDA receptors results in a cascade of secondary events in the cell, which lead to changes within the cell to increase the responsiveness of the nociceptive system. The NMDA receptor channel in its resting state is ‘blocked’ by a magnesium ‘plug’. Priming of the NMDA receptor by co-release of glutamate and the peptides acting on neurokinin receptors removes the magnesium plug and results in the subsequent calcium influx into the cell, leading to secondary events such as immediate early gene induction; production of nitric oxide (NO) and activation or production of a number of second messengers including phospholipases, polyphosphoinositides (IP3 and diacylglycerol [DAG]), cyclic guanosine monophosphate, eicosanoids and protein kinase C (Figure 71.3). These second messengers then directly change the excitability of the cell or induce the production of oncogenes, which may result in long-term alterations in the responsivity of the cell. Prolonged stimulation, through sustained and excitotoxic release of glutamate, may result in cell death. It has been experimentally demonstrated that interference with the function of second messenger systems such as protein kinase C results in normal responses to acute painful stimuli (‘good pain’) and attenuation of the development of neuropathic pain states (‘bad pain’).
Effect of Monosodium Glutamate (MSG) on spatial memory in rats (Rattus norvegicus)
Robert Hofstra, Noriyuki Koibuchi, Suthat Fucharoen in Advances in Biomolecular Medicine, 2017
However, the presence of excessive glutamate can lead to overstimulation of receptors that leads to irreversible cell damage or even cell death (Murrah, 2011). Various studies in the early life period have shown that administration of high concentrations of MSG may act as a neurotoxic or excitotoxic agent. Furthermore, it causes damage to the cells in the central nervous system, resulting in various abnormal histological patterns of the cerebral cortex and hippocampus, cerebral cortex layer depletion, damage to neurons in the primary sensory area of neonatal rat cerebral cortex, damage to the paraventricular nucleus of the hypothalamus arcuatus, and the nucleus of neonates whose parents are fed with MSG. MSG has the ability to penetrate the placenta–blood barrier and the brain–blood barrier (Cekic et al., 2005; Zarate et al., 2001; Yuliana, 2012; Briliantina, 2012).
Progress in the development of kynurenine and quinoline-3-carboxamide-derived drugs
Published in Expert Opinion on Investigational Drugs, 2020
Further types of ionotropic glutamate receptors in the CNS are the AMPA and the kainate receptors. As kynurenines can alter glutamate levels by several mechanisms modifying both uptake and conversion, one would expect that under specific conditions, they have effects on these receptors as well. Indeed, KYNA is a competitive inhibitor of AMPA receptors at millimolar concentrations; in nanomolar to micromolar levels, however, KYNA induces their facilitation through allosteric modulation [6]. KYNA has also been reported to inhibit presynaptic α7nAChRs, and by doing so, to decrease presynaptic glutamate release and extracellular Gamma Amino Butyric Acid (GABA) levels [11,12]. However, as some of the later studies reported no such effects recently T.W. Stone reviewed published data on KYNA and α7nAChRs interactions and concluded that critical reevaluation of previous experimental results does not support the claim that KYNA is a ligand of α7nACh receptors [14].
Potential of Müller Glia for Retina Neuroprotection
Published in Current Eye Research, 2020
Karen Eastlake, Joshua Luis, G Astrid Limb
Müller cells are considered the main regulators of neuronal signalling within the retina, a function that they accomplish through the recycling of neurotransmitters. The main excitatory neurotransmitter in the retina is glutamate, which is released by photoreceptors, bipolar cells and retinal ganglion cells at their synapses. Although glutamate modulates neuronal excitability and synaptic transmission, excessive glutamate can cause over-excitation of neurons, leading to cell death. To protect neurons, Müller glia takes up excess glutamate from the extracellular environment and converts it into glutamine, a function that is exerted through the expression of the enzyme glutamine synthetase.13 Consequently, the uptake of glutamate by Müller glia is considered to be an important neuroprotective function, as inhibition of glutamate transporter uptake or inhibition of glutamine synthetase in Müller glia can rapidly lead to neuronal toxicity, even at very low concentrations.14 Müller glia are therefore important regulators of the neurotransmitter pool, where bipolar and retinal ganglion cells rely on the glutamine released from Müller glia to synthesize glutamate.15 It has been suggested that Müller glia contribute to visual resolution signalling in the outer retina, by preventing glutamate from diffusing from the synaptic area.16
Oleuropein isolated from Fraxinus rhynchophylla inhibits glutamate-induced neuronal cell death by attenuating mitochondrial dysfunction
Published in Nutritional Neuroscience, 2018
Mi Hye Kim, Ju-Sik Min, Joon Yeop Lee, Unbin Chae, Eun-Ju Yang, Kyung-Sik Song, Hyun-Shik Lee, Hong Jun Lee, Sang-Rae Lee, Dong-Seok Lee
Glutamate, which is one of the main neurotransmitters of the CNS, is engaged in neuronal transmission, development, differentiation, and plasticity. However, excessive glutamate accumulation can cause abnormal depolarization of neurons, excitotoxicity; it leads to neuronal cell death.17 Especially, excitotoxicity causes many neurodegenerative disease, including Huntington's disease, Alzheimer's disease, lateral amyotrophic sclerosis, Parkinson's disease, and stroke or traumatic brain injury. Glutamate excitotoxicity is induced through activation of NMDA, AMPA receptor or non-glutamate receptor. HT-22 cell line, which is an immortalized mouse hippocampal cell line, is widely used to study the non-receptor mediated oxidative glutamate toxicity through GSH depletion and ROS accumulation.18 In addition, several studies suggest that mitochondrial oxidative stress and dysfunction play crucial role in promoting glutamate-induced cell death in HT-22.19–21 Therefore, Glutamate-mediated excitotoxicity, which is associated with ROS accumulation, is hypothesized to be a major contributor to pathological cell death in the mammalian CNS and to be involved in many acute and chronic brain diseases. In this study, we showed that Ole, isolated from FR, protected HT-22 hippocampal neuronal cells from glutamate-induced oxidative stress. In addition, as the protective molecular mechanism, this study showed that Ole inhibits glutamate-induced neuronal cell death through attenuating mitochondrial dysfunction with mitochondrial fragmentation and characteristic apoptosis.
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