Modulation of astrocytic glutamine synthetase expression and cell viability by histamine in cultured cortical astrocytes exposed to OGD insults.

Histamine, a neurotransmitter or neuromodulator has been demonstrated to be neuroprotective in cerebral ischemia. However, few reports concern its function on astrocytes during cerebral ischemia. The purpose of this study was to investigate the effects of histamine on astrocytic cell damage and glutamate signaling, especially on glutamine synthetase (GS) expression in primary cultured cortical astrocytes exposed to oxygen-glucose deprivation (OGD) insult. OGD for 6h caused a severe damage of astrocytic mitochondrial function, and decreased GS expression and then increased the extracellular glutamate level. Pretreatment with histamine significantly prevented the cell damage and rescued the expression of GS in a concentration-dependent manner. The protective effect of histamine on astrocytic cell damage could be partly reversed either by H1 receptor antagonist pyrilamine or H2 receptor antagonist cimetidine. However, the regulatory effect of histamine on GS expression was antagonized only by pyrilamine. In addition, bisindolylmaleimide II, a broad-spectrum inhibitor of PKC, reversed the regulatory action of histamine on GS expression. These results indicate that histamine can effectively protect against OGD-induced cell damage in astrocytes through H1 and H2 receptors, and its regulatory effect on astrocytic GS expression may be due to the activation of H1 receptor and PKC pathway. Histamine may be an endogenous protective factor and calls for its further study as a regulator of astrocyte function during ischemic stroke.

Wang XF ，Hu WW ，Yan HJ ，Tan L ，Gao JQ ，Tian YY ，Shi XJ ，Hou WW ，Li J ，Shen Y ，Chen Z ... -  《-》

Carnosine modulates glutamine synthetase expression in senescent astrocytes exposed to oxygen-glucose deprivation/recovery.

Carnosine is believed to be neuroprotective in cerebral ischemia. However, few reports concern its function on senescent astrocytes during cerebral ischemia. The aim of this study was to investigate the effects of carnosine on cell damage and glutamine synthetase (GS) expression in D-galactose-induced senescent astrocytes exposed to oxygen-glucose deprivation/recovery (OGD/R). The results showed that OGD/R caused massive cell damage and a significant decrease in GS expression both in the young and senescent astrocytes. The GS expression level was partly recovered whereas it continued to decline in the recovery stage in the young and senescent astrocytes, respectively. Decreased GS expression significantly inhibited glutamate uptake and glutamine production and release. Carnosine prevented the cell damage, rescued the expression of GS and reversed the glutamate uptake activity and glutamine production in the senescent astrocytes exposed to OGD/R. The modulatory effect of carnosine on GS expression was partly antagonized by pyrilamine, a selective histamine H1 receptors antagonist, but not bestatin. Bisindolylmaleimide II, a broad-spectrum inhibitor of PKC could also reverse the action of carnosine on GS expression. Thus, histamine H1 receptors and PKC pathway may be involved in the modulatory action of carnosine in GS expression in the senescent astrocytes exposed to OGD/R.

Shi X ，Wang B ，Liu Y ，Zhang J ，Huang Y ，Cao P ，Shen Y ，Lyu J ... -  《-》

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.

Fang Q ，Hu WW ，Wang XF ，Yang Y ，Lou GD ，Jin MM ，Yan HJ ，Zeng WZ ，Shen Y ，Zhang SH ，Xu TL ，Chen Z ... -  《-》

Propofol inhibits aquaporin 4 expression through a protein kinase C-dependent pathway in an astrocyte model of cerebral ischemia/reoxygenation.

Zhu SM ，Xiong XX ，Zheng YY ，Pan CF ... -  《-》

High extracellular glutamate modulates expression of glutamate transporters and glutamine synthetase in cultured astrocytes.

Lehmann C ，Bette S ，Engele J 《-》