Simulated Diabetic Ketoacidosis Therapy In Vitro Elicits Brain Cell Swelling

نویسندگان

  • Charles H. Lang
  • Andrew J. Watson
  • Thomas A. Drysdale
  • Melissa Chan
  • Anthony Rupar
چکیده

25 A common complication of type-1 diabetes mellitus is diabetic ketoacidosis (DKA), a state of 26 severe insulin deficiency. A potential harmful consequence of DKA therapy in children is 27 cerebral edema (DKA-CE); however, the mechanisms of therapy-induced DKA-CE are 28 unknown. Our aims were to identify the DKA treatment factors and membrane mechanisms that 29 might contribute specifically to brain cell swelling. To this end, DKA was induced in juvenile 30 mice with the administration of the pancreatic toxins streptozocin and alloxan. Brain slices were 31 prepared and exposed to DKA-like conditions in vitro. Cell volume changes were imaged in 32 response to simulated DKA-therapy. Our experiments showed that cell swelling was elicited 33 with isolated DKA treatment components, including alkalinization, insulin/alkalinization or rapid 34 reductions in osmolality. Methyl-isobutyl-amiloride, a non-selective inhibitor of sodium35 hydrogen exchangers (NHEs), reduced cell swelling in brain slices elicited with simulated DKA36 therapy (in vitro) and decreased brain water content in juvenile DKA mice administered insulin 37 and rehydration therapy (in vivo). Specific pharmacological inhibition of the NHE1 isoform with 38 Cariporide also inhibited cell swelling, but only in the presence of the anion transport (AT) 39 inhibitor 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid. DKA did not alter brain NHE1 40 isoform expression, suggesting that the cell swelling attributed to the NHE1 was activity41 dependent. In conclusion, our data raises the possibility that brain cell swelling can be elicited by 42 DKA treatment factors and that it is mediated by NHEs and/or co-activation of NHE1 and AT. 43 44

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

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تاریخ انتشار 2015