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Maturation, Barrier Function, Aging, and Breakdown of the Blood–Brain Barrier
Published in Shamim I. Ahmad, Aging: Exploring a Complex Phenomenon, 2017
Elizabeth de Lange, Ágnes Bajza, Péter Imre, Attila Csorba, László Dénes, Franciska Erdő
Glutamate transporters: The transporters, EAAT1, EAAT2, and EAAT3, at the BBB determine the levels of brain extracellular glutamate and are essential to prevent excitotoxicity (Lipton 2005), prompting the question whether changes in these transporters may contribute to glutamate excess and excitotoxicity. It has been suggested that glutamate excitotoxicity plays a role in the neurodegenerative processes in AD (Lipton 2005). Strict control l-glutamate concentration in the brain ISF is important to maintain neurotransmission and avoid excitotoxicity. The role of astrocytes in handling l-glutamate transport and metabolism is well known, however, ECs may also play an important role through mediating brain-to-blood l-glutamate efflux. These can account for high affinity concentrative uptake of l-glutamate from the brain ISF into the capillary ECs. The mechanisms in between l-glutamate uptake in the ECs and l-glutamate appearing in the blood may involve a luminal transporter for l-glutamate, metabolism of l-glutamate, and transport of metabolites, or a combination of the two (Cederberg et al. 2014).
Neurotransmitters and pharmacology
Published in Mark J. Ashley, David A. Hovda, Traumatic Brain Injury, 2017
Ronald A. Browning, Richard W. Clough
High-affinity uptake across the cell membrane is responsible for terminating the synaptic actions of glutamate. This uptake across the cell membrane is mediated by a sodium-dependent, high-affinity transporter that has been studied in synaptosomes and brain slices. It does not distinguish between l-glutamate, l-aspartate, and d-aspartate.170,174,175 This transporter, referred to as the excitatory amino acid transporter (EAAT), is present in both neurons and glial cells and has an uneven brain regional distribution consistent with a role in neurotransmission. Five subtypes of EAAT have been identified, some of which have a distinct anatomical distribution in the brain and a specific sensitivity to pharmacological agents.1 Both the neuronal and glial EAATs are believed to play an important role in terminating the action of glutamate following its release from nerve endings as was discussed previously for GABA. It is of interest that some glial cells also possess receptors for glutamate, which, when activated, lead to a transient increase in intracellular calcium (i.e., a Ca2+ wave) and which may pass from one glial cell to another and function as a form of intercellular communication.176 Molecular cloning studies have been used to study the different EAATs.58 These EAATs can transport glutamate as well as aspartate in a high-affinity sodium-dependent manner. They are believed to be responsible for the majority of the glutamate inactivation in the CNS.58 All five EAATs (EAAT1–EAAT5) have been cloned and studied in some detail. EAAT1 is expressed mainly in glial cells of the cerebellum whereas EAAT2 is expressed in astrocytes throughout the brain and EAAT3 is the main neuronal transporter throughout the brain.1,58,168 EAAT4 is found primarily in Purkinje cells of the cerebellum, and EAAT5 is found in several types of cells in the retina.58
The research advances in the mechanism of manganese-induced neurotoxicity
Published in Toxin Reviews, 2019
Autophagy is regulated by various molecular mechanisms such as mTOR signaling pathway, autophagy-related gene (Atg), Beclin-1 and bcl-2 family genes. The autophagy substrate protein p62 can bind to the substrate protein modified by ubiquitin, and binds to the microtubulin-3 (LC3) of the autophagy membrane to induce ubiquitin substrate and itself to be degraded by lysosomes. LC3 is associated with autophagosome, so LC3 can be used as an indicator of autophagy. After the SH-SY5Y cells treated with Mn, the levels of intracellular ROS increased. This enhanced lipid peroxidation, and the amount of lipid peroxidation product such as malondialdehyde (MDA) generation increases. It will damage the cell membrane structure and function. Meanwhile, the expression and activation of LC3 protein increases. These show that Mn activated autophagy and cause oxidative stress (Feng and Feng 2010). On the other hand, the appropriate level of ROS can activate Keapl-Nrf2-ARE pathway, this signaling pathway is one of the important antioxidant pathways in the body. It regulates the expression of EAAT3 through the nerve cells, coordinates of astrocyte release reduced glutathione (GSH) and neuron GSH synthesis. But, overproduction of ROS leads to cell death (Bahar et al.2017).
Everolimus attenuates glutamate-induced PC12 cells death
Published in International Journal of Neuroscience, 2023
Mohaddeseh Sadat Alavi, Sahar Fanoudi, Azar Hosseini, Mohammad Jalili-Nik, Amirbehzad Bagheri, Hamid R. Sadeghnia
It has been shown that glutamate exposure results in mTOR activation and S6 kinase phosphorylation. Dysregulation of mTOR signaling axis contributes to the neurodegenerative disease states [43–45]. Kimura et al. indicated that the phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) signaling pathway exist in PC12 cells [46]. While the PI3K/Akt/mTOR pathway regulates various physiological processes of neurons and glia, its abnormal sustained activation may underlie various pathological conditions [47, 48]. Studies have shown that prolonged exposure to high concentrations of glutamate (24-72 h), by means of complex activation of ionotropic and metabotropic glutamate receptors and glutamate transporters, induce significant toxicity by sustained activation of the PI3K/Akt/mTOR pathway [10]. Other signaling [such as MEK/ERK or PI3K/Akt/Glycogen synthase kinase (GSK)3β] pathways are also participated in the glutamate-induced toxicity [49–52]. It was shown that pharmacological antagonism of metabotropic glutamate receptor 5 (mGluR5) abolished the enhanced PI3K/Akt/mTOR signaling observed in Huntington’s disease mice model [53]. In the same way, inhibition of mGluR1, significantly and dose-dependently, decreased the viability of U87 glioma cells by abolishing the PI3K/Akt/mTOR pathway [54]. Zhu et al. also showed that glutamate activates PI3K/Akt/mTOR signaling pathway, through the insulin receptors, in the intestinal stem cells [55]. Besides, glutamate deficiency or inhibition of excitatory amino acid transporter 3 (EAAT3) were shown to markedly suppress mTOR activity [56, 57]. Interestingly, a recent study by Swiatkowski et al. indicated that glutamate toxicity and neuronal dysfunction mediated via mTOR and GSK3β signaling, independent on Akt activity [58]. They observed that inhibition of mTOR and GSK3β (by everolimus and lithium chloride, respectively), but not Akt, improved neuronal function after glutamate injury [58].
Efflux proteins at the blood–brain barrier: review and bioinformatics analysis
Published in Xenobiotica, 2018
Massoud Saidijam, Fatemeh Karimi Dermani, Sareh Sohrabi, Simon G. Patching
In terms of individual functionalised amino acids, the ABC transporters all had a lower content of cysteine residues (down to 0.5% in P-gp) than the overall average content in human secondary transport proteins (2.1%). Of the SLC transporters, the OATPs had exceptionally high contents of cysteine residues (4.3%, 4.2%, 3.7%, 3.4% and 4.6%), reflecting the conserved cysteine-rich extracellular loop between the ninth and 10th putative transmembrane domains. The distribution of cysteine residues in OATP1A2 is shown in Figure 16. EAAT1 had a noticeably low content of cysteine residues (0.6%). The content of histidine residues in the ABC transporters was relatively non-variable and similar to the overall average value in human secondary transport proteins (1.8%). One exception was MRP5 with a histidine content of 2.6%. The content of histidines in the SLC transporters was much more variable, ranging from 0.4% in EAAT3 to 3.4% in PMAT. The distribution of histidine residues in PMAT is shown in Figure 16. The relatively high content of histidines in PMAT presumably provides favourable interactions for binding of its monoamine and organic cation substrates. The content of proline residues in the proteins showed some variability with the highest contents in OATP2B1, OAT3 and PMAT (6.9%, 6.5% and 5.8%, respectively), which compares with an overall average of 5.1% in human secondary transport proteins. Tryptophan residues were generally present with higher contents in ABC transporters than in SLC transporters with the highest content in MRP6 (2.3%). A large majority of the SLC transporters had tryptophan contents that were lower than the overall average content in human secondary transporters (1.6%). One exception was OAT3 with a tryptophan content of 2.2%. The content of tyrosine residues in the ABC transporters was relatively non-variable and similar to the overall average value in human secondary transport proteins (3.2%). One exception was MRP6 with a tyrosine content of 1.8%. The content of tyrosines in the SLC transporters was more variable, ranging from 1.6% in EAAT2 to 4.9% in OATP1C1. The distribution of tyrosine residues in OATP1C1 is shown in Figure 16.