Aminoguanidine inhibits caspase‐3 and calpain activation without affecting microglial activation following neonatal transient cerebral ischemia

Abstract

Microglial cells, the resident macrophages of the CNS, can be both beneficial and detrimental to the brain. These cells play a central role as mediators of neuroinflammation associated with many neurodegenerative states, including cerebral ischemia. Because microglial cells are both a major source of inducible nitric oxide synthase (iNOS)/nitric oxide (NO) production locally in the injured brain and are activated by NO-mediated injury, we tested whether iNOS inhibition reduces microglial activation and ischemic injury in a neonatal focal ischemiareperfusion model. Post-natal day 7 rats were subjected to a 2 h transient middle cerebral artery (MCA) occlusion. Pups with confirmed injury on diffusion-weighted magnetic resonance imaging (MRI) during occlusion were administered 300 mg/kg/dose aminoguanidine (AG) or vehicle at 0, 4 and 18 h after reperfusion, and animals were killed at 24 or 72 h post-reperfusion. The effect of AG on microglial activation as judged by the acquisition of ED1 immunoreactivity and proliferation of ED1-positive cells, on activation of cell death pathways and on injury volume, was determined. The study shows that while AG attenuates caspase 3 and calpain activation in the injured tissue, treatment does not affect the rapidly occurring activation and proliferation of microglia following transient MCA occlusion in the immature rat, or reduce injury size.

Does Inflammation after Stroke Affect the Developing Brain Differently than Adult Brain?

“…Compared to the adults, macrophage accumulation in neonates is more rapid following transient MCAO. A 3-to 8-fold increase in the number of CD68-positive macrophages in the injured cortex and basal ganglia occurs by 24 h after reperfusion [85] . Based on CD45 expression, which is relatively low on resting microglia and microglia which undergo gradual activation, but is high on central monocyte lineage cells, in ischemic-reperfused neonatal brain, macrophages derive from resident microglia rather than invading monocytes within 24 h after reperfusion [86] .…”

The Yin and Yang of Microglia

“…Oligodendrocyte-microglial communication could be one of the mechanisms underlying selective white matter damage and hypomyelination in periventricular leukomalacia. Similarly, activated microglia-macrophages are seen in abundance following both neonatal hypoxia-ischemia [91,92] and focal stroke [93,94], producing inflammatory cytokines, high levels of NO, complement molecules and matrix metalloproteinases (MMP). By proteolytic cleavage, the MMP control the components of the extracellular matrix proteins, such as adhesion, membrane receptors and soluble proteins.…”

Mechanisms of Perinatal Arterial Ischemic Stroke

“…Varying the length of tMCAO has allowed production of injuries of different severity. [73][74][75] The presence of recirculation in the tMCAO model 76,77 also serves to mimic reperfusion, which frequently occurs in arterial stroke in term babies.…”