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Brain Res. 2013 Aug 21;1527:246-54. doi: 10.1016/j.brainres.2013.07.004. Epub 2013 Jul 11.

Role of histidine/histamine in carnosine-induced neuroprotection during ischemic brain damage.

Author information

1
Division of Cerebrovascular Diseases and Department of Neurology and Ophthalmology, Michigan State University, East Lansing, MI, USA.

Abstract

Urgent need exists for new therapeutic options in ischemic stroke. We recently demonstrated that carnosine, an endogenous dipeptide consisting of alanine and histidine, is robustly neuroprotective in ischemic brain injury and has a wide clinically relevant therapeutic time window. The precise mechanistic pathways that mediate this neuroprotective effect are not known. Following in vivo administration, carnosine is hydrolyzed into histidine, a precursor of histamine. It has been hypothesized that carnosine may exert its neuroprotective activities through the histidine/histamine pathway. Herein, we investigated whether the neuroprotective effect of carnosine is mediated by the histidine/histamine pathway using in vitro primary astrocytes and cortical neurons, and an in vivo rat model of ischemic stroke. In primary astrocytes, carnosine significantly reduced ischemic cell death after oxygen-glucose deprivation, and this effect was abolished by histamine receptor type I antagonist. However, histidine or histamine did not exhibit a protective effect on ischemic astrocytic cell death. In primary neuronal cultures, carnosine was found to be neuroprotective but histamine receptor antagonists had no effect on the extent of neuroprotection. The in vivo effect of histidine and carnosine was compared using a rat model of ischemic stroke; only carnosine exhibited neuroprotection. Taken together, our data demonstrate that although the protective effects of carnosine may be partially mediated by activity at the histamine type 1 receptor on astrocytes, the histidine/histamine pathway does not appear to play a critical role in carnosine induced neuroprotection.

KEYWORDS:

Carnosine; DIV; Histamine; Histidine; Ischemic stroke; LDH; N-methyl-d-aspartate; NMDA; Neuroprotection; OGD; PI; days in vitro; lactate dehydrogenase; oxygen–glucose deprivation; pMCAO; permanent middle cerebral artery occlusion; propidium iodide; tPA; tissue plasminogen activator

PMID:
23850642
DOI:
10.1016/j.brainres.2013.07.004
[Indexed for MEDLINE]

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