Overexpression of Human S100B Exacerbates Brain Damage and Periinfarct Gliosis After Permanent Focal Ischemia

Abstract

Background and Purpose-We have previously demonstrated that augmented and prolonged activation of astrocytes detrimentally influences both the subacute and chronic phases of cerebral ischemia. Furthermore, we have suggested that the astrocyte-derived protein S100B may be important in these pathogenic events. However, the causal relationship between S100B and exacerbation of brain damage in vivo remains to be elucidated. Methods-Using transgenic mice overexpressing human S100B (Tg huS100B mice), we examined whether S100B plays a cardinal role in aggravation of brain damage after permanent middle cerebral artery occlusion (pMCAO). Results-Tg huS100B mice had significantly larger infarct volumes and worse neurological deficits at any time point examined after pMCAO as compared with CD-1 background strain-matched control mice. Infarct volumes in Tg huS100B mice were significantly increased from 1 to 3 and 5 days after pMCAO (delayed infarct expansion), whereas those in control mice were not significantly altered. S100, glial fibrillary acidic protein, and Iba1 burdens in the periinfarct area were significantly increased through to 7 days after pMCAO in Tg huS100B mice, whereas those in control mice reached a plateau at 3 days after pMCAO. Conclusions-These results provide genetic evidence that overexpression of human S100B acts to exacerbate brain damage and periinfarct reactive gliosis (astrocytosis and microgliosis) during the subacute phase of pMCAO. (Stroke.

Autologous Bone Marrow Mononuclear Cells Exert Broad Effects on Short- and Long-Term Biological and Functional Outcomes in Rodents with Intracerebral Hemorrhage

“…Upon release, HMGB1 acts as an early proinflammatory cytokine within the NVU, which leads to exacerbation of proinflammatory responses, and blood-brain barrier breakdown in the ICH model [43,44]. S100B is released by activated astrocytes and is associated with enhanced reactive gliosis and further exacerbation of brain injury [45]. Increased S100B levels are also found after acute spontaneous ICH in patients, in association with acute worsening [46].…”

Transient Receptor Potential Canonical 3 (TRPC3) Mediates Thrombin-Induced Astrocyte Activation and Upregulates Its Own Expression in Cortical Astrocytes

“…Previous findings show that there is a significant correlation between S100B expression and the progression of neurodegenerative and other brain diseases, including cerebral ischemia, brain injury, Alzheimer's disease, Down syndrome, amyotrophic lateral sclerosis, schizophrenia, and depression (Rothermundt et al, 2003), so that astroglial S100B protein could be a sensitive marker of cerebral damage. Moreover, overexpression of S100B exacerbates brain damage and peri-infarct gliosis after focal ischemia (Mori et al, 2008), and arundic acid [(R)-(-)-2-propyloctanoic acid, ONO-2506], a novel agent that inhibits S100B synthesis in cultured astrocytes, and ameliorates ischemic brain damage (Tateishi et al, 2002) and cerebral amyloidosis and gliosis in a transgenic mouse model of Alzheimer's disease (Mori et al, 2006). TRPC3 could thus be a key upstream regulator of S100B expression and is a strong candidate protein for regulating the pathological activation of astrocytes induced by thrombin.…”

The Neuroprotective Effect of Picroside II and Its Best Therapeutic Dose and Time Window in Cerebral Ischemic Injury in Rats

“…In the experiment of cell culture, adding high concentration of S100B in nutrient solution could activate astrocytes and microglia to inhibit the expression of glial-derived nerve growth factor (GDNF) and reduce the neuroprotective effect of astrocytes, at the same time, promote inflammation factors releasing and exacerbate nerve cell damage [27]. Animal experiments showed that excessive expression of S100B could exacerbate brain ischemia injury in transgenic mice [28]. Clinical studies indicated that the concentration of S100B in CSF was highly correlated to the severity and prognosis of patients with acute ischemic stroke, the higher the concentration of S100B the worse the prognosis [29].…”