An In Vitro Paradigm for Diabetic Cerebral Oedema and its Therapy: A Critical Role for Taurine and Water Channels

Koves, Ildi H.; Russo, Vincenzo; Higgins, Sandra; Mishra, Avantika; Pitt, James; Cameron, Fergus; Werther, George A.

doi:10.1007/s11064-011-0598-8

Cited by 2 publications

(2 citation statements)

References 37 publications

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“…Previous research has suggested that osmotic disequilibrium in brain cells during DKA therapy is due in part to intracellular idiogenic osmoles that are elevated to compensate for the DKA-associated hyperosmolality (33). Given the cell swelling LT data were collected from a single region of interest over the course of an experiment.…”

Section: Resultsmentioning

confidence: 99%

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Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Rose

Watson

Drysdale

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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A common complication of type 1 diabetes mellitus is diabetic ketoacidosis (DKA), a state of severe insulin deficiency. A potentially harmful consequence of DKA therapy in children is cerebral edema (DKA-CE); however, the mechanisms of therapy-induced DKA-CE are unknown. Our aims were to identify the DKA treatment factors and membrane mechanisms that might contribute specifically to brain cell swelling. To this end, DKA was induced in juvenile mice with the administration of the pancreatic toxins streptozocin and alloxan. Brain slices were prepared and exposed to DKA-like conditions in vitro. Cell volume changes were imaged in response to simulated DKA therapy. Our experiments showed that cell swelling was elicited with isolated DKA treatment components, including alkalinization, insulin/alkalinization, and rapid reductions in osmolality. Methyl-isobutyl-amiloride, a nonselective inhibitor of sodium-hydrogen exchangers (NHEs), reduced cell swelling in brain slices elicited with simulated DKA therapy (in vitro) and decreased brain water content in juvenile DKA mice administered insulin and rehydration therapy (in vivo). Specific pharmacological inhibition of the NHE1 isoform with cariporide also inhibited cell swelling, but only in the presence of the anion transport (AT) inhibitor 4,4′-diisothiocyanatostilbene-2,2′-disulphonic acid. DKA did not alter brain NHE1 isoform expression, suggesting that the cell swelling attributed to the NHE1 was activity dependent. In conclusion, our data raise the possibility that brain cell swelling can be elicited by DKA treatment factors and that it is mediated by NHEs and/or coactivation of NHE1 and AT.

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Section: Resultsmentioning

confidence: 99%

“…In this study, we used an in vitro paradigm (33) to investigate the potential DKA therapies and membrane mechanisms contributing to cellular DKA-CE. DKA-CE occurs almost exclusively in children, typically within the first 24 h of DKA therapy (20,29).…”

Section: Discussionmentioning

confidence: 99%

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Rose

Watson

Drysdale

et al. 2015

American Journal of Physiology-Endocrinology and Metabolism

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Exendin-4 Reverses Biochemical and Functional Alterations in the Blood–Brain and Blood–CSF Barriers in Diabetic Rats

et al. 2016

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Diabetes mellitus (DM) is a metabolic disorder associated with micro- and macrovascular alterations that contribute to the cognitive impairment observed in diabetic patients. Signs of breakdown of the blood-brain barrier (BBB) and the blood-cerebrospinal fluid barrier (BCSFB) have been found in patients and animal models of DM. Breakdown of the BBB and BCSFB can lead to disruptions in cerebral homeostasis and eventually neural dysfunction and degeneration. However, our understanding of the biochemistry underlying barrier protein modifications is incomplete. Herein, we evaluated changes in the levels of specific proteins in the BBB (occludin, claudin-5, ZO-1, and aquaporin-4) and BCSFB (claudin-2 and aquaporin-1) in the hippocampus of diabetic rats, and we also investigated the functional alterations in these barriers. In addition, we evaluated the ability of exendin-4 (EX-4), a glucagon-like peptide-1 agonist that can cross the BBB to reverse the functional and biochemical modifications observed in these animals. We observed a decrease in BBB proteins (except ZO-1) in diabetic rats, whereas the EX-4 treatment recovered the occludin and aquaporin-4 levels. Similarly, we observed a decrease in BCSFB proteins in diabetic rats, whereas EX-4 reversed such changes. EX-4 also reversed alterations in the permeability of the BBB and BCSFB in diabetic rats. Additionally, altered cognitive parameters in diabetic rats were improved by EX-4. These data further our understanding of the alterations in the central nervous system caused by DM, particularly changes in the proteins and permeability of the brain barriers, as well as cognitive dysfunction. Furthermore, these data suggest a role for EX-4 in therapeutic strategies for cognitive dysfunction in DM.

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An In Vitro Paradigm for Diabetic Cerebral Oedema and its Therapy: A Critical Role for Taurine and Water Channels

Cited by 2 publications

References 37 publications

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Simulated diabetic ketoacidosis therapy in vitro elicits brain cell swelling via sodium-hydrogen exchange and anion transport

Exendin-4 Reverses Biochemical and Functional Alterations in the Blood–Brain and Blood–CSF Barriers in Diabetic Rats

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