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1.
Nat Commun ; 11(1): 5073, 2020 10 08.
Article in English | MEDLINE | ID: mdl-33033238

ABSTRACT

Brain cells continuously produce and release protons into the extracellular space, with the rate of acid production corresponding to the levels of neuronal activity and metabolism. Efficient buffering and removal of excess H+ is essential for brain function, not least because all the electrogenic and biochemical machinery of synaptic transmission is highly sensitive to changes in pH. Here, we describe an astroglial mechanism that contributes to the protection of the brain milieu from acidification. In vivo and in vitro experiments conducted in rodent models show that at least one third of all astrocytes release bicarbonate to buffer extracellular H+ loads associated with increases in neuronal activity. The underlying signalling mechanism involves activity-dependent release of ATP triggering bicarbonate secretion by astrocytes via activation of metabotropic P2Y1 receptors, recruitment of phospholipase C, release of Ca2+ from the internal stores, and facilitated outward HCO3- transport by the electrogenic sodium bicarbonate cotransporter 1, NBCe1. These results show that astrocytes maintain local brain extracellular pH homeostasis via a neuronal activity-dependent release of bicarbonate. The data provide evidence of another important metabolic housekeeping function of these glial cells.


Subject(s)
Astrocytes/metabolism , Bicarbonates/metabolism , Brain/metabolism , Extracellular Space/metabolism , Acetazolamide/pharmacology , Adenosine Triphosphate/metabolism , Animals , Astrocytes/drug effects , Carbonic Anhydrases/metabolism , Cells, Cultured , Electric Stimulation , Fluorescence , Hippocampus/metabolism , Hydrogen-Ion Concentration , Mice, Inbred C57BL , Models, Biological , Neurons/drug effects , Neurons/metabolism , Purinergic Antagonists/pharmacology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Receptors, Purinergic/metabolism , Signal Transduction , Sodium-Bicarbonate Symporters/metabolism
2.
S D Med ; 61(3): 105, 2008 Mar.
Article in English | MEDLINE | ID: mdl-18491464
3.
Eur J Nucl Med Mol Imaging ; 30(10): 1371-7, 2003 Oct.
Article in English | MEDLINE | ID: mdl-12856155

ABSTRACT

Iodine kinetics were studied in patients with differentiated thyroid cancer while euthyroid under exogenous thyroid stimulating hormone (TSH) and while hypothyroid to detect differences in radioiodine uptake, distribution and elimination. Nine patients with total or near-total thyroidectomy on thyroid hormone suppressive therapy received two or three daily doses of 0.9 mg recombinant human TSH (rhTSH) followed by administration of a diagnostic activity of 2 mCi (74 MBq) iodine-131. After the biokinetics assessments had been performed, patients stopped taking thyroid hormones to become hypothyroid. A second 2 mCi (74 MBq) diagnostic activity of 131I was administered, followed by a second set of biokinetics assessments. One week later the patients underwent remnant ablation with a therapeutic activity of 131I. A comparison of the 131I kinetics in the patients while euthyroid and while hypothyroid showed major differences in the doses to the remnant as well as in residence times and radiation exposure to the blood. In the first diagnostic assessment the remnant dose was higher in eight of the nine patients and clearance of the activity from the blood was faster in all of them. The data from this study suggest that radioiodine administration is potent and safe when administered to euthyroid patients following rhTSH administration. Enhanced residence time in the remnant and decreased radiation exposure to the blood were noted when patients were euthyroid compared to when they were rendered hypothyroid. However, all patients received diagnostic activities in the same order: first while euthyroid, followed by hypothyroidism. It is quite possible that "stunning" from the radioiodine administered in the initial uptake study inhibited the subsequent uptake of radioiodine by the remnant lesions in the second uptake study.


Subject(s)
Carcinoma/metabolism , Iodine Radioisotopes/blood , Iodine Radioisotopes/pharmacokinetics , Neoplasm Recurrence, Local/metabolism , Thyroid Gland/metabolism , Thyroid Neoplasms/metabolism , Thyrotropin/administration & dosage , Adult , Carcinoma/blood , Carcinoma/drug therapy , Carcinoma/radiotherapy , Dose-Response Relationship, Drug , Female , Humans , Iodine Radioisotopes/therapeutic use , Kinetics , Male , Metabolic Clearance Rate/drug effects , Middle Aged , Neoplasm Recurrence, Local/blood , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/radiotherapy , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/therapeutic use , Recombination, Genetic , Thyroid Gland/drug effects , Thyroid Gland/radiation effects , Thyroid Neoplasms/blood , Thyroid Neoplasms/drug therapy , Thyroid Neoplasms/radiotherapy
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