Tacrolimus (FK506) Limits Accumulation of Granulocytes and Platelets and Protects against Brain Damage after Transient Focal Cerebral Ischemia in Rat

Abstract

Cerebral ischemia is one of the most frequent causes of disability and death in later life. The primary aim of therapeutic intervention for cerebral ischemia is to reduce the volume of brain damage and thus to minimize the neurological impairment. Because neuronal degeneration after cerebral ischemia can progress rapidly and is often irreversible, the benefit of effective pharmacological intervention is quite limited at present. The only medication proven to be effective and widely used at the acute stage of human stroke is tissue plasminogen activator (tPA). 1)

Ischemic–hypoxic mechanisms leading to hippocampal dysfunction as a consequence of status epilepticus

“…Immunoreactivity for pimonidazole was characterized by three different patterns of distribution [65]: firstly, we observed a diffuse immunostaining in various cerebral regions, including the hippocampus (Fig. 3B), similar to that reported in the penumbra of cerebral ischemic lesions in rat models [59][60][61]; secondly, we found previously unreported Golgi-like stained cells in various hippocampal and extrahippocampal regions; and thirdly, darkly stained neuronal somas were detected in specific brain regions, resembling the distribution described in a model of cerebral malaria [66]. Notably, pimonidazole-immunopositive cells increased and became more widespread by prolonging the duration of SE.…”

“…Note the presence of a diffuse immunoprecipitate around the lesion core (arrows); this latter was not reached by pimonidazole probably because of limited blood flow. The pattern of immunostaining was similar to that which is known to occur in regions of cerebral ischemia [59][60][61]. C, immunoreactivity for hypoxia-inducible factor 1α (HIF-1α) [65] was found to be intense around the lesion core (arrows).…”

“…In an effort to clarify the role of hypoxia in SE and also in chronic epilepsy, we performed a series of experiments by testing two markers that consistently localized to or in brain areas exposed to hypoxia in models of cerebral ischemia, namely pimonidazole and hypoxiainducible factor 1α (HIF-1α) [59][60][61][62][63]. Additionally, we investigated another marker affected by ischemia or hypoxia: high-mobility group box 1 (HMGB1) [64].…”

FAK regulates platelet extravasation and tumor growth after antiangiogenic therapy withdrawal

“…However, lowering platelet numbers in patients with cancer requires careful titration, as thrombocytopenia can easily lead to life-threatening bleeding complications. Although platelet function and numbers can change under hypoxic conditions (27)(28)(29)55), their role in tumor hypoxia, especially with regard to antiangiogenic therapy-induced hypoxia, is not well understood. We showed that increased platelet infiltration after withdrawal of antiangiogenic therapy was dependent on expression of FAK in platelets.…”

Combination therapy with bone marrow stromal cells and FK506 enhanced amelioration of ischemic brain damage in rats

“…Our recent studies have also shown that hypothermia or transductive anti-death FNK protein in combination with FK506 enhances neuroprotection against brain damage with focal transient ischemia in rats, the two treatments acting additively or synergistically against ischemic damage (Nito et al, 2004;Katsura et al, 2008). Although the precise mechanism producing the neuroprotective effects of FK506 is still unclear, previous studies have shown that FK506 exerts anti-apoptotic and anti-inflammatory effects on cerebral ischemic injury (Furuichi et al, 2004;Noto et al, 2007). Taking into account the extra-neurogenic effect of MSCs, we speculate that FK506 may act additively or synergistically with MSC transplantation.…”