Histidine provides long-term neuroprotection after cerebral ischemia through promoting astrocyte migration.
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.
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Ru-jia
RJ
Liao
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Lei
L
Jiang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.|Department of Pharmacology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Rong-rong
RR
Wang
Department of Pharmacology, Children's Hospital of Zhejiang University, Hangzhou 310006, China.
Hua-wei
HW
Zhao
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Ying
Y
Chen
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Ya
Y
Li
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Lu
L
Wang
Department of Radiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310009, China.
Li-Yong
LY
Jie
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.
Yu-dong
YD
Zhou
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.|Department of Pharmacology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Xiang-nan
XN
Zhang
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.|Department of Pharmacology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Zhong
Z
Chen
Department of Pharmacology, Key Laboratory of Medical Neurobiology of the Ministry of Health of China, School of Basic Medical Sciences, School of Medicine, Zhejiang University, Hangzhou, 310058, China.|Department of Pharmacology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, the First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310003, China.
Wei-wei
WW
Hu
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D002545:Brain Ischemia / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects; D002921:Cicatrix / Q000473:pathology; D003071:Cognition / Q000187:drug effects; D004195:Disease Models, Animal; D006639:Histidine / Q000378:metabolism* / Q000494:pharmacology; D008297:Male; D000066829:Neuroprotection / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D051381:Rats; D011970:Receptors, Histamine H2 / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects; D014945:Wound Healing / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000378:metabolism
D018696:Neuroprotective Agents; D011970:Receptors, Histamine H2; D006639:Histidine; D020830:rac1 GTP-Binding Protein