Preventing flow-metabolism uncoupling acutely reduces axonal injury after traumatic brain injury.
We have previously presented evidence that the development of secondary traumatic axonal injury is related to the degree of local cerebral blood flow (LCBF) and flow-metabolism uncoupling. We have now tested the hypothesis that augmenting LCBF in the acute stages after brain injury prevents further axonal injury. Data were acquired from rats with or without acetazolamide (ACZ) that was administered immediately following controlled cortical impact injury to increase cortical LCBF. Local cerebral metabolic rate for glucose (LCMRglc) and LCBF measurements were obtained 3 h post-trauma in the same rat via ¹⁸F-fluorodeoxyglucose and ¹⁴C-iodoantipyrine co-registered autoradiographic images, and compared to the density of damaged axonal profiles in adjacent sections, and in additional groups at 24 h used to assess different populations of injured axons stereologically. ACZ treatment significantly and globally elevated LCBF twofold above untreated-injured rats at 3 h (p<0.05), but did not significantly affect LCMRglc. As a result, ipsilateral LCMRglc:LCBF ratios were reduced by twofold to sham-control levels, and the density of β-APP-stained axons at 24 h was significantly reduced in most brain regions compared to the untreated-injured group (p<0.01). Furthermore, early LCBF augmentation prevented the injury-associated increase in the number of stained axons from 3-24 h. Additional robust stereological analysis of impaired axonal transport and neurofilament compaction in the corpus callosum and cingulum underlying the injury core confirmed the amelioration of β-APP axon density, and showed a trend, but no significant effect, on RMO14-positive axons. These data underline the importance of maintaining flow-metabolism coupling immediately after injury in order to prevent further axonal injury, in at least one population of injured axons.
Department of Neurosurgery, David Geffen School of Medicine at UCLA, Box 957039, Los Angeles, CA 90095-7039, USA. ngharris@mednet.ucla.edu
Neil G
NG
Harris
Yevgeniya A
YA
Mironova
Szu-Fu
SF
Chen
Hugh K
HK
Richards
John D
JD
Pickard
D000086:Acetazolamide / Q000494:pharmacology; D000818:Animals; D001930:Brain Injuries / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism*; D002560:Cerebrovascular Circulation / Q000187:drug effects* / Q000502:physiology; D020833:Diffuse Axonal Injury / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000378:metabolism; D004734:Energy Metabolism / Q000187:drug effects* / Q000502:physiology; D008297:Male; D011877:Radionuclide Imaging; D051381:Rats; D017207:Rats, Sprague-Dawley
D000086:Acetazolamide