Impaired axonal transport and neurofilament compaction occur in separate populations of injured axons following diffuse brain injury in the immature rat.
Diffuse brain injury is a leading cause of mortality in infants and children under 4 years of age and results in cognitive deficits in survivors. The anatomic basis for these behavioral deficits may be traumatic axonal injury (TAI), which manifests as impaired axonal transport (IAT) and neurofilament compaction (NFC), and may occur as a result of glutamate receptor activation. The extent of IAT and NFC was evaluated at 6, 24 and 72 h following non-contusive brain trauma in the 17 day-old rat to examine the causal relationship between these two pathologic entities; in addition, the effect of antagonists to the ionotropic glutamate receptors on TAI was evaluated. At 6 h post-injury, NFC was observed primarily in the cingulum, and appeared as swollen axons and terminal bulbs. By 24 h, swollen axons were additionally present in the corpus callosum and lateral white matter tracts, and appeared to increase in diameter. At 72 h, the extent of axonal swellings exhibiting compacted neurofilaments appeared to decrease, and was accompanied by punctate immunoreactivity within axon tracts suggestive of axonal degeneration. Although NFC was present in the same anatomical locations where axonal accumulation of amyloid precursor protein (APP) has been observed, double-label immunohistochemistry revealed no evidence of colocalization of compacted neurofilament and APP. Pre-injury treatment with either the NMDA receptor antagonist, ifenprodil, or the AMPA receptor antagonist, NBQX, had no significant effect on the extent of TAI, suggesting that excitotoxicity may not be a primary mechanism underlying TAI. Importantly, these data are indicative of the heterogeneity of mechanisms underlying TAI in the traumatically-injured immature brain.
Program in Neuroscience, Drexel University College of Medicine, Philadelphia, PA 19129, USA.
Ann Mae
AM
DiLeonardi
Jimmy W
JW
Huh
Ramesh
R
Raghupathi
D016564:Amyloid beta-Protein Precursor / Q000378:metabolism; D000818:Animals; D001370:Axonal Transport / Q000187:drug effects; D001369:Axons / Q000502:physiology* / Q000648:ultrastructure*; D001921:Brain / Q000473:pathology / Q000503:physiopathology; D001930:Brain Injuries / Q000473:pathology / Q000503:physiopathology*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D005260:Female; D007150:Immunohistochemistry; D007382:Intermediate Filaments / Q000648:ultrastructure*; D008297:Male; D009474:Neurons / Q000473:pathology / Q000502:physiology; D010784:Photomicrography; D010880:Piperidines / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
D016564:Amyloid beta-Protein Precursor; D018691:Excitatory Amino Acid Antagonists; D010880:Piperidines; D011810:Quinoxalines; C062865:2,3-dioxo-6-nitro-7-sulfamoylbenzo(f)quinoxaline; C010739:ifenprodil