Free Radical Production in CA1 Neurons Induces MIP-1α Expression, Microglia Recruitment, and Delayed Neuronal Death after Transient Forebrain Ischemia

Abstract

Several studies report microglial accumulation and activation in the CA1 area in response to transient forebrain ischemia (TFI). Here we examine the possibility that free radicals and chemokines mediate the transient activation of microglia. Free radicals are produced primarily in CA1 pyramidal neurons within 2 h of TFI. Administration of trolox, a vitamin E analog, led to the inhibition of free radical production and recruitment of microglia in the CA1 area. In addition, intrahippocampal injection of Fe 2ϩ triggered free radical production in CA1 neurons, followed by the recruitment and activation of microglial cells into this area. TFI-induced expression of macrophage inflammatory protein-1␣ (MIP-1␣) was increased in CA1 neurons before microglial recruitment, and blocked by trolox. Moreover, the MIP-1␣ level was upregulated in cultured hippocampal neurons exposed to Fe 2ϩ , suggesting an essential role of free radicals in TFIinduced expression of MIP-1␣. Intracerebroventricular injection of vMIP-2 (viral macrophage inflammatory protein-2), a broadspectrum peptide antagonist of chemokine receptors, attenuated microglial recruitment and delayed CA1 neuronal degeneration after TFI. Our data suggest that free radicals produced in CA1 neurons contribute to the recruitment and activation of microglia and neurodegeneration through MIP-1␣ expression.

Blood-derived iron mediates free radical production and neuronal death in the hippocampal CA1 area following transient forebrain ischemia in rat

“…Neutrophils and macrophages are recruited into injured brain areas after focal cerebral ischemia, which is significantly reduced in monocyte chemoattractant protein 1 (MCP-1)-deficient mice [52]. Expression of MCP-1 and macrophage inflammatory protein-1-alpha (MIP-1-alpha) is increased in CA1 neurons after TFI and thought to mediate the recruitment of iron-containing infiltrating leukocytes and possibly erythrocytes [57]. Iron can be released from these recruited blood cells and then iron- transferrin is taken up by and accumulates in CA1 neurons over-expressing TfR for a prolonged period of time after TFI.…”

“…Delayed neuronal degeneration was assessed by histological examination of Cresyl violet-stained brain sections at the level of the dorsal hippocampus collected from animals killed 3 or 7 days after ischemia as previously reported [57]. For quantitative analysis, surviving neurons in the CA1 layer within a 50 9 200 lm rectangular area were counted using an ocular grid within the microscope eyepiece (Olympus Optical Co., Tokyo, Japan).…”

“…Blockade of rising intracellular Zn 2? in CA1 neurons with the zinc chelators calcium EDTA or N,N,N 0 ,N 0 -tetrakis(2-pyridylmethyl)ethylenediamine attenuates DND [4,28]. Finally, the reduction of free radicals has been shown to protect hippocampal CA1 neurons from TFI [16,55], suggesting that free radicals comprise an additional route to DND [6,20,57].…”

Iron mediates endothelial cell damage and blood-brain barrier opening in the hippocampus after transient forebrain ischemia in rats

“…Iron-mediated free radical production mediates neuronal death and gliosis in the CA1 area after TFI (Kondo et al, 1995;Wang et al, 2008). Recent studies have shown that oxidative stress is a prominent feature of cerebral endothelial injury after cerebral ischemia (Maier et al, 2006;Jin et al, 2008).…”

“…Pharmacological treatments seeking to remove free radicals prevent BBB breakdown and neuronal death following focal cerebral ischemia (Kim et al, 2001;Ding-Zhou et al, 2002). Iron ions, serving as transition metal molecules catalyzing hydroxyl radical production via the Fenton reaction and the Haber-Weiss cycle, accumulate in neurons, astrocytes, and microglia in hippocampal CA1 areas, after occurrence of transient forebrain ischemia (TFI), and cause neuronal death and gliosis (Kondo et al, 1995;Wang et al, 2008). In the present study, we explored the possibility that iron-mediated free radical production mediates endothelial cell damage and BBB opening in the hippocampal CA1-2 regions, following TFI.…”