No abstract

-The effects of oxiracetam on the reduction of brain metabolism induced by focal cerebral ischemia were investigated by measuring local cerebral glucose uti lization (LCGU) in rats 24 hr after left middle cerebral artery occlusion. Focal cere bral ischemia reduced LCGU in the entire ipsilateral cortex, the greatest reduction being in the lateral parts of the frontoparietal cortex. LCGU was slightly reduced in the contralateral cortex; this reduction was considered to be caused by diaschisis. Ox iracetam was administered intraperitoneally for 3 days prior to middle cerebral artery occlusion. In the ipsilateral cortex, LCGU reduction was minimized in the ischemic center areas by oxiracetam at a dose of 400 mg/kg and in more extensive areas, by a dose of 800 mg/kg. Moreover, oxiracetam at a dose of 800 mg/kg enhanced metabo lism impaired by diaschisis in the caudal areas of the contralateral cortex. These find ings suggest that oxiracetam minimizes the reduction of brain function induced by ischemia and may therefore be useful in the treatment of cerebrovascular disease.The pharmacological actions of oxiracetam are similar to those of other pyrrolidone de rivatives, including piracetam, aniracetam and pramiracetam. Oxiracetam and other pyrroli done derivatives have been reported to im prove memory and learning ability in normal animals (1) and to prevent amnesia and the decrease in brain acetylcholine level induced by scopolamine and electroshock in rats (2 4). Oxiracetam and piracetam stimulate high affinity choline uptake in the rat hippocampus (5). Thus, the effects of pyrrolidone deriva tives may be related to the enhancement of brain cholinergic mechanisms. In addition, ox iracetam and other pyrrolidone derivatives have been shown to augment hippocampal long-term potentiation in rats (6) and guinea pigs (7,8). These investigations suggest that pyrrolidone derivatives enhance cerebral func tion in normal brain and protect it in impaired brain. Since we have recently found that ox iracetam protects rats and mice against cere bral hypoxia, we expected to find that ox iracetam had protective effects against cere bral ischemia in this experiment.Focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion (9) is a use ful model (9, 10) for studying ischemic brain damage, as well as cerebral blood flow (11, 12), energy metabolism (13), and neurotrans mitters (14,15). Sokoloff (16) showed that cerebral functional activity was closely coupled to energy metabolism, especially glucose con sumption. In this study, we investigated

No abstract

Macrophages are important components in modulating homeostatic and inflammatory responses and are generally categorized into two broad but distinct subsets: classical activated (M1) and alternatively activated (M2) depending on the microenvironment. Fibrosis is a chronic inflammatory disease exacerbated by M2 macrophages, although the detailed mechanism by which M2 macrophage polarization is regulated remains unclear. These polarization mechanisms have little in common between mice and humans, making it difficult to adapt research results obtained in mice to human diseases. Tissue transglutaminase (TG2) is a known marker common to mouse and human M2 macrophages and is a multifunctional enzyme responsible for crosslinking reactions. Here we sought to identify the role of TG2 in macrophage polarization and fibrosis. In IL-4-treated macrophages derived from mouse bone marrow and human monocyte cells, the expression of TG2 was increased with enhancement of M2 macrophage markers, whereas knockout or inhibitor treatment of TG2 markedly suppressed M2 macrophage polarization. In the renal fibrosis model, accumulation of M2 macrophages in fibrotic kidney was significantly reduced in TG2 knockout or inhibitor-administrated mice, along with the resolution of fibrosis. Bone marrow transplantation using TG2-knockout mice revealed that TG2 is involved in M2 polarization of infiltrating macrophages derived from circulating monocytes and exacerbates renal fibrosis. Furthermore, the suppression of renal fibrosis in TG2-knockout mice was abolished by transplantation of wild-type bone marrow or by renal subcapsular injection of IL4-treated macrophages derived from bone marrow of wild-type, but not TG2 knockout. Transcriptome analysis of downstream targets involved in M2 macrophages polarization revealed that ALOX15 expression was enhanced by TG2 activation and promoted M2 macrophage polarization. Furthermore, the increase in the abundance of ALOX15-expressing macrophages in fibrotic kidney was dramatically suppressed in TG2-knockout mice. These findings demonstrated that TG2 activity exacerbates renal fibrosis by polarization of M2 macrophages from monocytes via ALOX15.

No abstract