No abstract

The role of microglia in the response to CNS injury is not fully understood. We characterized the temporal activation of microglia in the adult spinal cord following a lesion that severed the axons of the dorsal columns and corticospinal tract at T8. Two days after lesion, microglia in the severed T4-T5 fasciculus (f.) gracilis were ameboid and expressed intense OX42 and increased class I major histocompatibility complex (MHC) antigen (OX18) immunoreactivities. No activated microglia were seen in the intact f. cuneatus or the corticospinal tract. Five days postlesion, OX42 immunoreactivity was slightly decreased in the f. gracilis, and OX18 expression was slightly enhanced. By 12 days postlesion, OX42 and OX18 immunoreactivities were near control levels. At L1-L2, activated microglia with increased OX18 expression were restricted to the corticospinal tract and were maximal 5 days postlesion, returning to near control levels by 12 days postlesion. In the medulla, enhanced OX42 and OX18 immunoreactivities were seen in the nucleus (n.) gracilis, but not the n. cuneatus, at 2 days postlesion. At 5 days postlesion, OX42 immunoreactivity was markedly decreased, but class I MHC antigen expression was still enhanced. GFAP immunoreactivity increased only in the n. gracilis and remained elevated 2-12 days postlesion. Microglial activation is an early lesion-induced event in the CNS, and activated microglia may play a role in mediating the regenerative capacity of injured CNS axons.

In order to assess the role of circulating blood in early microglial activation after traumatic brain injury (TBI), controlled cortical impact injury was applied to adult rat brain slices (400 microm in thickness) and the microglial response was examined. The complement receptor (CR3) expression and morphological transformation of the microglia were evaluated by OX42 immunohistochemistry. At 5 min following injury, activated microglia with intense CR3 expression appeared throughout the hemisphere on the injured side. In contrast, the morphology and CR3 expression of the microglia on the contralateral side were indistinguishable from those of the resident ramified microglia seen in normal brains. At 30 min following injury, microglial activation was more pronounced on the injured side, while the microglia on the contralateral side still retained a ramified morphology. These results are consistent with our previous observations made in in vivo experiments, which indicate that, as the brain slice paradigm excludes variables arising from the circulating blood, the rapid and widespread microglial activation observed following TBI can not be attributed exclusively to the infiltration of blood-borne macrophages or molecules. Rather this activation is most likely caused by intrinsic mechanisms within the brain tissue, such as traumatic depolarization.

One major event taking place at the moment of traumatic brain injury in neuronal cells is the occurrence of massive ionic fluxes across the plasma membrane, which can be referred to as traumatic depolarization (TD). Unlike spreading depression, TD can occur over wide brain areas simultaneously. Furthermore, recovery from TD often takes far longer than recovery from ionic perturbation elicited by the passage of a single wave of spreading depression. Neuronal cell damage caused by ischemic brain injury is also initiated by massive ionic fluxes, termed anoxic depolarization. The occurrence of similar ionic events in these two forms of brain injury may account for the genesis of diffuse ischemia-like damage without actual episodes of hypoxia or ischemia in traumatic brain injury. We review the data indicating that excitatory amino acids (EAA) may play a vital role in producing TD, and that such EAA-mediated ionic perturbation is responsible for a number of posttraumatic events including subcellular metabolic dysfunction and cellular responses such as microglial activation and astrocytic transformation. TD may represent one of the most important mechanisms of diffuse neuronal cell dysfunction and damage associated with traumatic brain injury.

In this study, we examined the age-associated defect of stromal cells, which support B cell development, treated with 5-fluorouracil (5-FU) to induce severe perturbation of hematopoiesis, including B lymphocyte development, using SAMP1 mice exhibiting senescence-mimicking stromal-cell impairment after 30 weeks of age. Significant findings of this study are as follows: first, a marked and prolonged decrease in number of CFU-preB cells in non-SCI mice (58% of the steady-state level) associated with more markedly depressed number of CFU-preB cells in SCI mice (20% of the steady-state level), despite the absence of difference in the number of CFU-GMs during the period; second, in the non-SCI mice, a significant and prolonged up-regulation of GM-CSF and IL-6, positive regulators of myelopoiesis and suppressive factors of B lymphopoiesis, was observed. In SCI mice, greater and prolonged suppression of B lymphopoiesis was clearly demonstrated by the significant up-regulation of the negative regulator TNF-alpha associated with the concomitant marked down-regulation of the positive regulator SDF-1, although the increases of GM-CSF and IL-6 were limited. That is, 'negative complementation' makes preB recovery after 5-FU treatment impaired and prolonged. Principal component analysis clearly showed differences in the cytokine expression patterns in both early and later phases and the time course of the expression pattern of each cytokine between SCI and non-SCI mice without supervising information. An impaired regulation of the expressions of not only positive but also negative regulators after 5-FU treatment was, in part, the cause of the impaired regeneration of CFU-preB cells in SCI mice.