Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration

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.

Histamine Regulates the Inflammatory Profile of SOD1-G93A Microglia and the Histaminergic System Is Dysregulated in Amyotrophic Lateral Sclerosis

“…Because activation of H3R auto receptors inhibits histamine synthesis and release ( 1 ), its downregulation in the cortex of sALS patients might concur to boost the histaminergic signaling and its neuroprotective effects ( 53 ). Conversely, because histamine reduces excitotoxicity also via H2R activation ( 20 , 54 ), the decreased H2R mRNA that we observed in sALS, similar to what referred in mice, might be causative of neuronal damage sustained by increased excitotoxicity ( 7 , 9 ).…”

“…single dose) or vehicle (0.9% NaCl) groups ( n = 4/group). This dose provided detectable levels of histamine in CNS ( 17 – 19 ) and showed efficacy in models of cerebral ischemia ( 20 ). After 3 days, the mice were transcardially perfused with 50 ml of PBS and tissue processed as described for immunofluorescence (IF) or western blotting (WB) analysis.…”

Histaminergic transmission slows progression of amyotrophic lateral sclerosis

“…To overcome sex‐mixed results with low reproducibility, we used a single gender because of differences reported in male/female mice under pharmacological treatments. Female mice were randomly grouped into vehicle (0.9% NaCl) and histidine treatment groups at different doses (50, 100, and 250 mg/kg), based on previous results . Mice were injected i.p.…”

Potential of carnosine, a histamine precursor in rat model of bilateral common carotid artery occlusion‐induced vascular dementia

“…It is suggested to act as neuromodulator and neurotransmitter in CNS . Studies have reported significant protective role of histamine in various disorders such as ischemia ; stroke and many other disorders . Activation of histaminergic neurons is shown to enhance cognition and memory .…”