Search

In several models of traumatic brain injury in rodents, remarkably progressive tissue loss and neuron death has been observed accompanied by expanding ventricles. Here, we explored potential cell proliferation in the subventricular zone (SVZ) in response to this progressive posttraumatic neurodegeneration. Four-month-old rats (n = 57) were subjected to parasagittal fluid-percussion brain injury or sham treatment (no injury), and their brains were harvested at 2 weeks, 2 months, 6 months, and 1 year (n = 6-8/group) after injury or sham treatment. Brain sections (6 μm) were stained with markers of cell proliferation, Ki-67, and proliferative cell nuclear antigen (PCNA) to detect mitotically active cells. In sham animals, we found a typical age-dependent decrease in Ki-67- and PCNA-labelled cells in the SVZ over the course of 1 year. However, in brain-injured animals, this decrease was reversed culminating in a sixfold increase in the number of cells staining with Ki-67 and a threefold increase in cells staining with PCNA by 1 year following injury compared to age-matched controls. Using double labeling, we also determined that many of the cells staining with Ki-67 or PCNA expressed markers selective for neurons (neurofilament protein) and glia (GFAP). These data suggest that there is a persistent proliferation of neurons and glia in the SVZ following brain trauma that does not diminish during aging as found in non-injured animals.

AbstractN-acetylaspartate (NAA) is a plausible marker of neuronal viability which decreases in a variety of neurodestructive conditions. To elucidate the mechanism that leads to NAA decline in two different types of cerebral ischemia in rats, we simultaneously determined cortical concentrations of NAA and its hydrolytic metabolites, aspartate, and acetate by high-resolution 1H-NMR spectroscopy. NAA decreased almost linearly up to 24 h in both decapitation induced global cerebral ischemia, and in ischemic cortices of focal ischemia. Acetate was increased continuously for up to 24 h of global ischemia, while in focal cerebral ischemia it was increased transiently at 6 h. Aspartate did not show any change in global ischemia, while it was decreased in focal ischemia. Although NAA decreased similarly in the brain with global and focal ischemia, temporal changes of two NAA hydrolytic metabolites were different in each type of ischemia. The present results suggest hydrolytic degradation of NAA may be modified alternatively under each pathophysiologic condition. [Neurol Res 1999; 21: 771–774]

Growth inhibitory factor (GIF) is a small protein belonging to the metallothionein family that has the capacity to inhibit neuronal survival and neurite formation in vitro. This study was conducted to investigate the role of GIF in the brain afflicted with ischemic injury. We used the in situhybridization technique and Northern blot analysis to study the changes in GIF messenger RNA (mRNA) expression in a rat focal ischemia model. On the first day, the expression tended to decrease in the hemisphere ipsilateral to the injury. It returned to normal levels on the second day except for the central area of the middle cerebral artery (MCA) territory. On the third and fourth day, the expression increased diffusely in the hemisphere of the affected side, including the subcortical area. Two weeks after ischemia, the GIF mRNA expression increased again but only in the pert-infarcted area. Down-regulation of GIF on the first day in the cortex ipsilateral to the infarction might promote neurite sprouting. The subsequent increase in GIF mRNA expression on the third and fourth day might be a symptom of neurons attempting to inhibit excessive neurite outgrowth, or to protect themselves against toxicity caused by oxygen radicals. The later increase in the limited area around the infarction may be related to astroglial reaction. Growth inhibitory factor may play an important role in regulating the central nervous system after ischemic insults.

PLASMINOGEN activators (PAs) have been suggested to play a role in neuronal migration and glial cell proliferation in the developing CNS. Less is known, however, about the role of PAs in the mature nervous system. To elucidate the role of tissue type plasminogen activator (tPA) in the nervous system we used in situhybridization to study the expression of tPA mRNA within the rat facial nucleus after facial nerve transection. We also studied the effect of MK-801 on tPA mRNA expression in order to investigate whether the previously reported N-methyl-D-aspartate (NMDA) receptor activation is involved in this model. tPA mRNA was expressed in the ipsilateral facial motoneurones from 6 h after injury. This expression continued for at least 2 weeks after facial nerve transection. Administration of MK-801 before axonal injury did not affect the expression of tPA mRNA in the facial nucleus. These data suggest that tPA might be involved in the regenerative process without NMDA receptor activation in mature facial neurones.

Growth inhibitory factor / metallothionein III (GIF / MT-III) is reported to have the unique property of suppressing neuronal survival and neurite promotion in vitro. We investigated changes in the expression of GIF mRNA within the facial nucleus using in situ hybridization as well as changes in the function of the facial nerve after nerve injury. Following crushing injury just distal to the stylomastoid foramen, movement of the ipsilateral whiskers was eliminated but returned by the 7th day. GIF mRNA expression decreased at 3 days after injury and returned in 7 days. However, when the nerve was cut and sutured immediately, it took one month for the facial function to recover. In this case, GIF mRNA expression decreased 3 days after injury, remained at a low level for 14 days, and finally returned in 3-4 weeks. Thus, changes in the expression of GIF mRNA were found to be closely related to the facial nerve function.

Although accumulation of neurofilament (NF) proteins in axons has been recognized as a prominent feature of brain trauma, the temporal course of the accumulation of specific NF subtypes has not been well established. In the present study, 17 miniature swine were subjected to nonimpact inertial brain injury. At 3 hours (h), 6 h, 24 h, 3 days, 7 days, and 10 days post-trauma, immunohistochemical analysis was performed to determine axonal accumulation of NF-Iight (NF-L), the rod and sidearm domains and sidearm phosphorylation states of NF-medium (NF-M), and heavy (NF-H). We found that NF-L accumulation was easily identified in damaged axons by 6 h post-trauma, but NF-M and H accumulation was not clearly visualized until 3 days following injury. In addition, the axonal accumulation of NF-M and H appeared to be primarily comprised of the sidearm domains. While the accumulating NF was found to be predominantly dephosphorylated, we also detected accumulation of phosphorylated NR Finally, we found that developing axonal pathology may proceed either towards axotomy with discrete terminal bulb formation or towards the development of varicose swellings encompassing long portions ofaxons. These findings suggest that there is a differential temporal course in NF subtype disassembly, dephosphorylation, and accumulation in axons following initial brain trauma and that these processes occur in morphologically distinct phenotypes of maturing axonal pathology.