Amiloride increases neuronal damage after traumatic brain injury in rats.
OBJECTIVE
It is well known that traumatic brain injury (TBI) decreases brain free magnesium (Mg) concentration, and that administration of Mg salts after TBI restores concentration of Mg in brain and improves functional outcome. In the presence of hemorrhage, administration of Mg salts exacerbates the injury process and worsens outcome. An alternative to administration of Mg salts may be to prevent cellular loss of Mg with use of amiloride, which inhibits the Na(+)/Mg(2+) exchange.


METHODS
In the present study, male, adult Sprague-Dawley rats were injured using the impact acceleration model of diffuse TBI and administered either 100 mols/kg i.v. amiloride, or an equal volume of 50% DMSO/saline, 30 minutes (min) after injury.


RESULTS
Amiloride did not improve functional outcome (motor or cognitive outcome) after TBI relative to vehicle treated controls. Histologically, treatment with amiloride significantly increased hippocampal caspase-3 expression (apoptosis), axonal swellings in the medulla and the degree of dark cell change (cell stress) in the cortex. Phosphorus NMR demonstrated that amiloride did not increase free Mg concentration after injury.


CONCLUSIONS
Thus, amiloride is ineffective in preventing Mg loss after TBI when administered 30 min after trauma. Moreover, by administering amiloride after the TBI-related Mg decline has already been initiated, it may exacerbate injury by, in part by inhibiting Na(+)/Mg(2+) antiport and preventing entry of Mg back into the cell, and also by inhibiting other Na(+) linked transporters.
Department of Pathology, University of Adelaide, Adelaide, SA, Australia.
Renee J
RJ
Turner
Corinna
C
Van den Heuvel
Robert
R
Vink
D000584:Amiloride / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001921:Brain / Q000378:metabolism; D001930:Brain Injuries / Q000378:metabolism*; D003071:Cognition / Q000187:drug effects; D004232:Diuretics / Q000494:pharmacology*; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley
D004232:Diuretics; D000584:Amiloride; D008274:Magnesium