Impaired axonal transport and neurofilament compaction occur in separate populations of injured axons following diffuse brain injury in the immature rat

Abstract

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 hours 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 hours post-injury, NFC was observed primarily in the cingulum, and appeared as swollen axons and terminal bulbs. By 24 hours, swollen axons were additionally present in the corpus callosum and lateral white matter tracts, and appeared to increase in diameter. At 72 hours, 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.

Time-related morphometric studies of neurofilaments in brain contusions

“…In humans as well as in animals morphologic changes in NF occur in DAI following TBI. In animals those changes are observed in sites of contusions, accompanied by selective necrosis of neurons in the brain cortex, especially in the hippocampus which is exceptionally susceptible to hypoxia and several other damaging factors [3,5,10,16,19,20,[22][23][24][25][26].…”

“…In majority of studies, NF-H and NF-L were researched [3][4][5]7,10,12,15,16,19,20,23,28]. Neurofilaments at the site of the brain contusion disintegrate, their complete disappearance was observed 1 to 2 weeks following trauma [10,20,22,26].…”

Combination Therapies for Traumatic Brain Injury: Retrospective Considerations

“…We had based our study design on previous in vitro and in vivo preclinical studies in adults. [62][63][64][65] In our initial ageappropriate monotherapy conformational studies with FK506, however, we found that when FK506 was administered IP as a monotherapy immediately and 6 h after TBI at doses of 10 or 25 mg/kg, the signature dephosphorylation of neurofilaments and axonal degeneration 66 was significantly reduced, but benefits were achieved only at doses that were 2-5 times greater than in the adult [62][63][64]67 ; there was no amelioration of impaired axonal transport or CAP deficits. 59 Ultimately, because FK506 failed to improve functional outcome associated with persistent CAP deficits in the white matter tracts after diffuse trauma to the immature brain, we abandoned the idea of using this medication for our combination therapy; instead, we evaluated minocycline and GPE.…”

Neurofilaments and traumatic brain injury

“…U ludzi i zwierząt z TBI zmiany morfologiczne w obrębie NF występowały w przypadkach wspomnianego już powyżej rozlanego uszkodzenia aksonów, a u zwierząt także w ogniskach stłuczenia mózgu, współistniejących z wybiórczą martwicą neuronów w korze mózgu, a zwłaszcza w hipokampie, okolicy szczególnie wrażliwej zarówno na epizody hipoksji, jak i szerokie spektrum czynników uszkadzających [10][11][12][13][16][17][18][19][20][21][22][23][24].…”

“…In people and animals with TBI, morphological changes within NF have been found to occur in cases of the above-mentioned diffuse axonal injury, an in animals also in brain contusion foci, coexisting with selective neuronal necrosis in the brain cortex and, particularly, in the hippocampus -a region which is especially sensitive both to hypoxic episodes and to a wide spectrum of damaging factors [10][11][12][13][16][17][18][19][20][21][22][23][24].…”