Histamine up-regulates astrocytic glutamate transporter 1 and protects neurons against ischemic injury.

Astrocytic glutamate transporter 1 (GLT-1) is responsible for the majority of extracellular glutamate clearance and is essential for preventing excitotoxicity in the brain. Up-regulation of GLT-1 shows benefit effect on ischemia-induced neuronal damage. In present study, we examined the effect of histamine, a neurotransmitter or neuromodulator, on GLT-1 expression and function. In acute hippocampal slices, histamine selectively increased GLT-1 expression independent of neuronal activities. Similar up-regulation of GLT-1 was also observed after histamine treatment in pure cultured astrocytes, which was abolished by H1 receptor antagonist or PKC inhibitor. Cell surface biotinylation and whole-cell patch recordings of glutamate transporter current confirmed the up-regulation of functional GLT-1 following histamine exposure. Histamine treatment decreased the extracellular glutamate content and alleviated neuronal cell death induced by exogenous glutamate challenge. Moreover, we found a significant neuroprotective effect of histamine in brain slices after oxygen-glucose deprivation (OGD). In addition, histidine, the precursor of histamine, also showed neuroprotection against ischemic injury, which was accompanied by reversion of declined expression of GLT-1 in adult rats subjected to middle cerebral artery occlusion (MCAO). These neuroprotective effects of histamine/histidine were blocked by GLT-1 specific inhibitor dihydrokainate or H1 receptor antagonist. In summary, our results suggest that histamine up-regulates GLT-1 expression and function via astrocytic H1 receptors, thus resulting in neuroprotection against excitotoxicity and ischemic injury.
AuthorsQi Fang, Wei-Wei Hu, Xiao-Fen Wang, Yang Yang, Guo-Dong Lou, Miao-Miao Jin, Hai-Jing Yan, Wei-Zheng Zeng, Yao Shen, Shi-Hong Zhang, Tian-Le Xu, Zhong Chen
JournalNeuropharmacology (Neuropharmacology) Vol. 77 Pg. 156-66 (Feb 2014) ISSN: 1873-7064 [Electronic] England
PMID23791559 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
CopyrightCopyright © 2013 Elsevier Ltd. All rights reserved.
Chemical References
  • Excitatory Amino Acid Transporter 2
  • Neuroprotective Agents
  • Histamine
  • Animals
  • Astrocytes (drug effects, metabolism)
  • Brain Ischemia (metabolism, prevention & control)
  • Cell Death (drug effects)
  • Excitatory Amino Acid Transporter 2 (metabolism)
  • Hippocampus (drug effects, metabolism)
  • Histamine (pharmacology)
  • Male
  • Neurons (drug effects, metabolism)
  • Neuroprotective Agents (pharmacology)
  • Rats
  • Rats, Sprague-Dawley
  • Up-Regulation (drug effects)

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