Abstract
The formation of glial scar impedes the neurogenesis and neural functional recovery following cerebral ischemia. Histamine showed neuroprotection at early stage after cerebral ischemia, however, its long-term effect, especially on glial scar formation, hasn’t been characterized. With various administration regimens constructed for histidine, a precursor of histamine, we found that histidine treatment at a high dose at early stage and a low dose at late stage demonstrated the most remarkable long-term neuroprotection with decreased infarct volume and improved neurological function. Notably, this treatment regimen also robustly reduced the glial scar area and facilitated the astrocyte migration towards the infarct core. In wound-healing assay and transwell test, histamine significantly promoted astrocyte migration. H2 receptor antagonists reversed the promotion of astrocyte migration and the neuroprotection provided by histidine. Moreover, histamine upregulated the GTP-bound small GTPase Rac1, while a Rac1 inhibitor, NSC23766, abrogated the neuroprotection of histidine and its promotion of astrocyte migration. Our data indicated that a dose/stage-dependent histidine treatment, mediated by H2 receptor, promoted astrocyte migration towards the infarct core, which benefited long-term post-cerebral ischemia neurological recovery. Therefore, targeting histaminergic system may be an effective therapeutic strategy for long-term cerebral ischemia injury through its actions on astrocytes.
Highlights
Astrocytes are critically involved in neuronal pathophysiological progresses following cerebral ischemia: as early as 6 h after onset of cerebral ischemia, astrocytes activates to facilitate the survival of neurons possibly via antioxidant defense, metabolic support and secretion of neuroprotective substances; those reactive astrocytes form a barrier to confine the spread of the lesion and the local immune response[5,6]
Intraperitoneal administration of histidine, a precursor of histamine, immediately and 6 h after reperfusion, remarkably alleviates the infarction induced by transient middle cerebral artery occlusion[11]
Under different treatment regimens, we evaluated the long term effects of histidine on neurological performance and cognitive abilities by using Morris water maze and fear conditioning test, for the memory related brain regions such as striatum, neocortex and amygdala are often compromised after tMCAO17–20
Summary
Astrocytes are critically involved in neuronal pathophysiological progresses following cerebral ischemia: as early as 6 h after onset of cerebral ischemia, astrocytes activates to facilitate the survival of neurons possibly via antioxidant defense, metabolic support and secretion of neuroprotective substances; those reactive astrocytes form a barrier to confine the spread of the lesion and the local immune response[5,6]. The glial scar, a barrier largely composed of astrocytes, may impede the neurogenesis at the late stage of ischemic neuronal injuries. The astrocytic H1-receptor-mediated up-regulation of glutamine synthetase and glutamate transporter 1 expressions contribute to the protective effect of histamine through the clearance of the redundant extracellular glutamate, which helps to alleviate the excitotoxicity at early stage of cerebral ischemia[9,10]. The long-term effect of histamine after cerebral ischemia has not been investigated, especially its effect on astrocytes at the late stage regarding the glial scar formation. Since histamine cannot penetrate the blood-brain barrier directly, histidine was used to test the long-term effects of histamine on behavioral and histological responses to cerebral ischemia and the potential mechanisms under different stage-related administration regimens
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