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    • It is an aspiring task to

    2022-01-21

    It is an aspiring task to apply the glutamate biosensor for in vivo measurements in Chlorpromazine HCl tissue. Due to a relatively large size of the electrode used in this work, the biosensor fits only ex vivo applications. However, it is possible to apply platinum microelectrodes 50–100 μm in diameter for the biosensor construction and implant it into the living tissue [40]. The procedure of the biosensor preparation (deposition of PPD membrane and immobilization of GluOx) should be only slightly modified as the electrode material and detection principle would be similar. The creation of such microbiosensor for detection of glutamate release in certain brain and spinal cord regions needs more investigations. Our previous results demonstrated the principal necessity and perspectives of glutamate monitoring using the biosensor in practice. This statement is confirmed by the following facts: 1) the extracellular glutamate level is unique for each synapse [2,3,41]; 2) the alterations in extracellular glutamate in the nerve terminal preparations during therapeutic hypothermia are specific for each experimental animal, and they can be expected to be individual for a patient, and so the necessity of personal neuromonitoring in therapeutic hypothermia was demonstrated [4]; 3) the kinetics of glutamate uptake by nerve terminals can be measured using the glutamate biosensor [20]; and 4) the biosensor can be applied for glutamate release assessment in nerve terminals that was shown in this study. Blood platelets are of special interest and can be considered as a potential peripheral marker for the analysis of disturbance in the glutamate transport in brain nerve terminals [2,3]. Platelets express plasma membrane glutamate transporters EAAT 1–3, secretory granule vesicular glutamate transporters VGLUT 1 & 2, NMDA, AMPA, kainate and mGlu receptors. Recently, we have demonstrated similarity of glutamate transport process in nerve terminals and platelets. The latter, however, have restriction in application for neuromonitoring because they cannot be used directly for the assessment of the pathological glutamate transporter reversal, since this manner of glutamate release in platelets is rather ambiguous [4]. Glutamate is released from platelets exclusively by means of exocytosis [3]. In perspective, we plan to develop panels of glutamate-related biomarkers for comprehensive neuromonitoring, e.g. the glutamate concentration in the blood and cerebrospinal liquids, and the glutamate transport characteristics of platelets, etc. These glutamate-related diagnostic, prognostic and predictive biomarkers are necessary for standard clinical decision-making algorithms that could help to select optimal individual temperature regime for patients with prescribed therapeutic hypothermia in ischemic stroke, brain trauma and in cardiac surgery of the aortic arch. In this context, the glutamate biosensor can be applied in medical practice.
    Conclusions We propose a biosensor-based methodological approach for the analysis of effectiveness of tonic, exocytotic and transporter-mediated glutamate release from nerve terminals verified by the radiolabeled L-[14C]glutamate, spectrofluorimetric glutamate dehydrogenase and amino acid analyzer assays. Reliability of the biosensor measurements of the glutamate concentration in the blood plasma was also confirmed by the spectrofluorimetric glutamate dehydrogenase assay. The glutamate biosensor-based approach is suggested to be applied in clinics for neuromonitoring glutamate-related parameters in the brain samples, liquids and blood plasma in stroke, brain trauma, during therapeutic hypothermia treatment, etc., and also in laboratory work to record the glutamate release and uptake kinetics in nerve terminals.
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    Introduction Ionotropic glutamate receptors (iGluRs) transduce neurotransmitter signaling at synapses in the brain into electrical impulses. The release of neurotransmitters, such as glutamate, glycine, and d-serine, into the synaptic cleft is detected by iGluRs that reside in the plasma membrane of postsynaptic neurons and cause depolarization in those cells. These ligand-gated ion channels are essential for learning and memory, and they are drug targets for treating disorders and diseases such as epilepsy [1,2], depression [3], and Alzheimer’s disease [4]. The four protein subunits that comprise a receptor each include an extracellular amino-terminal domain (ATD, also called NTD), an extracellular ligand-binding domain (LBD), a transmembrane ion channel domain (TMD), and an intracellular, largely disordered carboxy-terminal domain (CTD) [5] (Fig. 1). Agonist binding to the LBDs activates the receptor, allowing an influx of cations into the postsynaptic neuron to trigger the generation of a nerve impulse.