Plasma Albumin Induces Cytosolic Calcium Oscilations and DNA Synthesis in Human Cultured Astrocytes

Abstract

So far, a little is known about transition from normal to focal epileptic brain, although disruption in blood-brain barrier and albumin had recently involved. The main objective of this work is to characterize the response of cultured human astrocytes to plasma albumin, including induction of DNA synthesis. Cortical tissue was obtained from 9 patients operated from temporal lobe epilepsy. Astrocytes were cultured for 3-4 weeks and cytosolic calcium concentration ([Ca2+]c) was measured. Bovine and human plasma albumin were used. We observed that low albumin concentration decreases [Ca2+]c, while higher concentration, induces increase in [Ca2+]c. It was shown that increase in [Ca2+]c was mediated by inositol 1,4,5-trisphosphate and released from internal stores. Increase in [Ca2+]c was reduced to 19% by blocking the transforming growth factor-beta (TGF-βR) receptor. Albumin induces DNA synthesis in a dose-response manner. Finally, induction of DNA synthesis can be partially blocked by heparin and block of TGF-β; however, the combination of both incompletely inhibits DNA synthesis. Therefore, results suggest that mechanisms other than Ca2+ signals and TGF-β receptor activation might induce DNA synthesis in a lesser degree. These results may be important to further understand the mechanisms involved in the transition from normal to focal epileptic brain.

The Blood-Brain Barrier Breakdown During Acute Phase of the Pilocarpine Model of Epilepsy Is Dynamic and Time-Dependent

“…Astrocytes are particularly sensitive to SE-induced brain tissue damage. These cells can uptake albumin through TGF-β receptors, leading to increased intracellular calcium that results in downregulation of inward rectifying potassium (Kir 4.1) and aquaporin-4 (AQP4) channels (47–49), reducing the buffer of extracellular potassium and facilitating NMDA-mediated neuronal hyperexcitability and epileptiform activity (33, 44, 50, 51). Although the presence of albumin in neurons can lead to death (12), it seems that albumin per se is not neurotoxic; it can only be captured by damaged neurons (44).…”

Serum Albumin in Health and Disease: Esterase, Antioxidant, Transporting and Signaling Properties

“…Besides that, albumin induces the synthesis of DNA. These processes are partially blocked by heparin and TGF-β antagonists [ 268 ]. Thus, the use of SJN2511, which is a specific inhibitor of the ALK5/TGF-β pathway, prevents excitatory synaptogenesis and albumin-induced epilepsy [ 267 ].…”

“…Among these components, the vascular endothelium of the brain is of the greatest interest, since on the other side of the barrier there is the brain parenchyma, the “holy of holies” of the whole organism. The functional units of the parenchyma turned out to be extremely vulnerable to the action of albumin due to the presence of a special receptor on astrocytes, which until recently was considered specific to TGF-β, one of the minor cytokine proteins that regulate cell differentiation and apoptosis [ 267 , 268 ]. In the period at the beginning of or even in the heyday of studies of cytokine regulation, it was difficult to even imagine a common receptor for proteins, the difference in concentration of which in the blood serum is more than 9 orders of magnitude.…”

Albumin and multiple sclerosis

“…In the CNS, extravasated or exogenously administered albumin results in its presence in the parenchyma and uptake by microglia, astrocytes and neurons [ 73 – 76 ] leading to astrocyte gliosis and neuronal loss [ 185 ]. Mechanistically, albumin is thought to enter astrocytes after interacting with TGF-β receptors and this uptake affects calcium concentrations in the cytoplasm [ 186 ] and results in the downregulation of Kir4.1 in astrocytes [ 73 , 76 , 179 ]. Extracellular potassium homeostasis becomes disrupted [ 73 , 187 ] and neurons may become hyper-excitable to NMDA receptor activation [ 73 , 76 ].…”