Reactive microglia in cerebral ischaemia: an early mediator of tissue damage?

Abstract

Microglial cell activation is a rapidly occurring cellular response to cerebral ischaemia. Microglia proliferate, are recruited to the site of lesion, upregulate the expression of several surface molecules including major histocompatibility complex class I and II antigens, complement receptor and the amyloid precursor protein (APP) as well as newly expressed cytokines, e.g. interleukin-1 and transforming growth factor beta 1. The ischaemia-induced production of APP may contribute to amyloid deposition in the aged brain under conditions of hypofusion. Ultrastructurally, microglia transform into phagocytes removing necrotic neurons but still respecting the integrity of eventually surviving neurons even in the close vicinity of necrotic neurons. Microglial activation starts within a few minutes after ischaemia and thus precedes the morphologically detectable neuronal damage. It additionally involves a transient generalized response within the first 24 hours post-ischaemia even at sites without eventual neuronal cell death. In functional terms, the microglial reaction appears to be a double-edged sword in ischaemia. Activated microglia may exert a cytotoxic effector function by releasing reactive oxygen species, nitric oxide, proteinases or inflammatory cytokines. All of these cytotoxic compounds may cause bystander damage following ischaemia. Pharmacological suppression of microglial activation after ischaemia has accordingly attenuated the extent of cell death and tissue damage. However, activated microglia support tissue repair by secreting factors such as transforming growth factor beta 1 which may limit tissue damage as well as suppress astroglial scar formation. In line with ultrastructural observations microglial activation in ischaemia is a strictly controlled event. By secreting cytokines and growth factors activated microglia most likely serve seemingly opposed functions in ischaemia, i.e. maintenance as well as removal of injured neurons. Post-ischaemic pharmacological modulation of microglial intervention in the cascade of events that lead to neuronal necrosis may help to improve the structural and functional outcome following CNS ischaemia.

Nano neuro knitting: Peptide nanofiber scaffold for brain repair and axon regeneration with functional return of vision

“…These obstacles are: (i) scar tissue formation after tissue injury (1-7); (ii) gaps in nervous tissue formed during phagocytosis of dying cells after injury (3,(8)(9)(10)(11)(12)(13)(14); (iii) factors that inhibit axon growth in the mature mammalian CNS (1,3,(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20); and (iv) failure of many adult neurons to initiate axonal extension (3, 8-12, 15, 17, 21, 22). In this paper, we describe the creation of a permissive environment for axonal regrowth using a synthetic biological nanomaterial that self assembles in vivo, with components that break down into beneficial building blocks and produce no adverse effects on the CNS.…”

Increased Expression of IL-1β Converting Enzyme in Hippocampus after Ischemia: Selective Localization in Microglia

“…It is well known that microglia play an important role in inflammation and repair by acting as scavengers of cellular debris (Killackey, 1984;Giulian, 1987). Several reports also suggest that microglia produce and release neurotoxic substances, such as glutamate and free radicals (Colton and Gilbert, 1987;Thery et al, 1991), and contribute to tissue damage after cerebral ischemia (Gehrmann et al, 1995).…”

Estrogen stimulates microglia and brain recovery from hypoxia-ischemia in normoglycemic but not diabetic female mice

“…The present study is, to our knowledge, the first report of bfl-1 expression in the brain, and the localization of bfl-1 to microglia is consistent with its expression in cells of the monocyte/macrophage lineage. The early (8 hours) appearance of bfl-1, especially in the less damaged brains, which would be expected to have less breakdown of the blood-brain barrier, supports primary expression in resident microglia (44). Flow cytometric analysis of bfl-1-positive cells (Figure 9) confirms the early microglial expression in postischemic brain from +/?…”