Free radical production in CA1 neurons induces MIP-1alpha expression, microglia recruitment, and delayed neuronal death after transient forebrain ischemia.
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 Fe2+ 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-1alpha (MIP-1alpha) was increased in CA1 neurons before microglial recruitment, and blocked by trolox. Moreover, the MIP-1alpha level was upregulated in cultured hippocampal neurons exposed to Fe2+, suggesting an essential role of free radicals in TFI-induced expression of MIP-1alpha. Intracerebroventricular injection of vMIP-2 (viral macrophage inflammatory protein-2), a broad-spectrum 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-1alpha expression.
Wang
Hyo Kyun
HK
Neuroscience Graduate Program, Brain Disease Research Center, Ajou University School of Medicine, Suwon 443-721, Korea.
Park
Ui Jin
UJ
Kim
Soo Yoon
SY
Lee
Jin Hwan
JH
Kim
Seung U
SU
Gwag
Byoung Joo
BJ
Lee
Yong Beom
YB
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002452:Cell Count; D016923:Cell Death; D054405:Chemokine CCL3 / Q000378:metabolism*; D002712:Chlorides; D002839:Chromans / Q000494:pharmacology; D005290:Ferric Compounds / Q000494:pharmacology; D005609:Free Radicals / Q000378:metabolism*; D002546:Ischemic Attack, Transient / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D016548:Prosencephalon / Q000098:blood supply*; D017966:Pyramidal Cells / Q000378:metabolism* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011999:Recruitment, Neurophysiological; D015424:Reperfusion; D015854:Up-Regulation
D000975:Antioxidants; D054405:Chemokine CCL3; D002712:Chlorides; D002839:Chromans; D005290:Ferric Compounds; D005609:Free Radicals; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid; C024555:ferric chloride