The response of the cerebral hemisphere of the rat to injury. I. The mature rat

Abstract

The response to injury of the cerebrum of the mature rat was studied chronologically in stereotactically placed knife wounds by using both light and electron microscopical, and immunohistochemical, techniques. Immediately after injury haematogenous cells fill the lesion and ischaemic necrosis occurs along the margins and a zone of cell swelling occupies the surrounding area. This phase is transformed by the appearance of large numbers of macrophages and fibroblasts, and some reactive astrocytes in the zone of cell swelling at 4 days. Blood vessels grow into the lesion at this time. Collagen deposition begins in the subpial region of the wound and, with time, scarring progresses into the deeper parts of the wound. By 8 days, the lesion contains a matrix of collagen fibrils, capillaries, fibroblasts, macrophages and astrocytes. The wound margins are better defined as astrocytes become aligned and secrete the basement membrane of the glia limitans, initially in the subpial regions of the scar. By 16 days, a glia limitans is complete along the margins of the entire lesion and the scar tissue between is reduced in area and contain fibroblasts, scattered macrophages, collagen fibrils and a few extra- parenchymatous astrocytes. Subsequently the scar condenses to a thin layer and becomes less vascularized; few cells remain. The persistence of astrocytes within mesenchymatous scar tissue excluded from the cerebral neuropile is a new finding. No further changes are seen in the scar after 30 days. The progressive development and maturation of scar tissue from the pial surface of the wound into the deeper regions of the cerebrum suggests that the major source of fibroblasts is from the meninges. The appearance of macrophages before fibroblasts in the wound may indicate that macrophages secrete a substance that is a trophic stimulus for fibroblasts. The organization of a glia limitans by astrocytes also proceeds inwards from the pial surface. Within the neuropile, degeneration of damaged neural elements is the prominent feature in the first 8 days after injury. Macrophages and reactive astrocytes also appear among the debris and are numerous by 4 days at the junctions of viable and necrotic neuropile. Signs of a regenerative response of neural processes is first seen at 4 days as growth cones appear in the viable neuropile at the edges of the necrotic zone. Growth cones are most numerous at 8 days. Evidence for new synapse formation is seen over the surface of dendritic swellings from 16 days onwards. Synapses of varying maturity are present, the most mature are adjacent to the dendritic shaft. This observation may suggest-that these swellings are true growth cones, in which case, this new synaptogenesis is similar to that over dendritic growth cones during development. It is not possible to judge the relative importance of either collateral sprouting or true regeneration in the reorganization of connections after injury, but neurite growth and the associated synaptogenesis described here could contribute to the recovery process. If the swellings on dendritic processes are true growth cones, then this is evidence for the regeneration of dendritic processes.

Differential effects of cysteamine on heat shock protein induction and cytoplasmic granulation in astrocytes and glioma cells

“…Reactive gliosis results in the formation of a gliotic scar at the site of injury. These scars are filled with GFAP filaments and encapsulated by the glia limitans (Maxwell et al, 1990;Reir et al, 1983). The glial scars may deter successful axonal regeneration (Rudge et al, 1990;Reir et al, 1990) and serve as epileptogenic foci (Fedoroff and Vernadakis, 1986b (Beach et al, 1989;Duffy et al, 1980;Kushner et al, 1991;.…”

Myelin inhibitors: does NO mean GO?

“…There are, however, other possibilities, such as an age change in the inherent regenerative capacity of axons 41,42 and the maturation of astrocytic reactivity [43][44][45] . An obvious adaptive advantage of myelin is the acceleration of axonal excitation by saltatory conduction, which enables information to span the increasing distances of the adult central and peripheral nervous system without increasing the transmission time.…”

Experimental strategies to promote axonal regeneration after traumatic central nervous system injury

“…Between 1 and 8 days after lesion the axoplasm begins to assume a more granular and dark appearance due to breakdown of cytoskeletal components. Shrinkage of axons, distension with multivesicular bodies as well as myelin retraction and disintegration are common pathological features after axonal lesion [Ramo n y Cajal (1928); Steward et al (1973); Richardson et al (1982) and Maxwell et al (1990a); for reviews see Povlishock et al (1992) and Povlishock and Christman (1995)]. These axonal changes spread in a centrifugal fashion into anterograde and retrograde directions.…”

“…Among the neuroglial cells, astrocytes and microglia/macrophages have received considerable attention in recent years. Both glial cell types exhibit a vigorous response to traumatic injury with marked hypertrophy, proliferation, migration and transition to a dierent morphological phenotype [for reviews see Maxwell et al (1990a); Hatten et al (1991); Landis (1994); Norenberg (1994); Moore and Thanos (1996); Ridet et al (1997)]. Reactive gliosis is the result of this very early response to injury and is characterized by a dense web of interlacing glial processes that forms within a lesioned area.…”

“…the rapidity of the glial response (Maxwell et al, 1990a,b;Matsumoto et al, 1992;Stichel and MuÈ ller, 1994a); 2. the spatial distribution (Takamiya et al, 1988;Schmidt-Kastner et al, 1990;Berry et al, 1996b); 3. the sequential activation of microglia/macrophages and subsequently astrocytes (Maxwell et al, 1990a;Schmidt-Kastner et al, 1990;Matsumoto et al, 1992;Stichel and MuÈ ller, 1994a); and 4. the transient absence of activated astrocytes in the perilesion area (Dusart and Schwab, 1994;Stichel and MuÈ ller, 1994a,b;Frank and Wolburg, 1996).…”