Abstract
BackgroundBoth hydrogen sulphide (H2S) and mild hypothermia have been reported to prevent brain damage caused by reperfusion assault through regulating the N-methyl-D-aspartate receptor (NMDAR). However, the relationship between the two treatments and how they exert neuro-protective effects through NMDARs remain to be elucidated.MethodsTransient cerebral ischemia was induced using the Pulsinelli four-vessel occlusion method. We used sodium hydrosulphide (NaHS) as the H2S donor. We randomly divided 100 Sprague–Dawley rats into five groups of 20: Sham operation group (Sh), normothermic (36-37 °C) ischemia group (NT), mild hypothermic (32-33 °C) ischemia group (mHT), normothermic ischemia combined with NaHS treatment group (NT + NaHS), and mild hypothermic ischemia combined with NaHS treatment group (mHT + NaHS). After 6 hrs of reperfusion, rats were decapitated and hippocampus samples were immediately collected. We measured NR2A (GluN1), NR2B (GluN2) and p-CREB protein levels using western blotting. We further analyzed BDNF mRNA expression by real-time PCR. Hematoxylin and eosin (HE) staining was used to examine pyramidal cell histology at the CA1 region. All statistical analyses were carried out by ANOVA and LSD t-test as implemented by the SPSS 13.0 software.ResultsIn the four test groups with ischemia-reperfusion, hippocampal H2S concentration increased following treatment, and administration of NaHS further increased H2S levels. Moreover, administration of both NaHS and mild hypothermia resulted in up-regulation of NR2A and NR2B protein expressions, as well as p-CREB protein and BDNF mRNA levels. At the cellular level, NaHS and mild hypothermia groups exhibited lower damage caused by ischemia-reperfusion in the CA1 region of the hippocampus. The strongest protective effect was observed in rats treated with combined NaHS and mild hypothermia, suggesting their effects were additive.ConclusionOur results support previous findings that hydrogen sulphide and mild hypothermia can prevent ischemia-reperfusion injury. Both treatments caused an up-regulation of NMDA receptors, as well as an elevation in p-CREB protein and BDNF mRNA levels. Thus, hydrogen sulphide and mild hypothermia may provide neuro-protective effect through activating the pro-survival CREB signaling pathway.
Highlights
Both hydrogen sulphide (H2S) and mild hypothermia have been reported to prevent brain damage caused by reperfusion assault through regulating the N-methyl-D-aspartate receptor (NMDAR)
We showed that H2S and mild hypothermia treatments induced up-regulation of downstream effectors of the cAMPresponse element-binding protein (CREB) pathway, including p-CREB and Brain-derived neurotrophic factor (BDNF), suggesting these treatments may activate the CREB pathway to exert their effects
Both Sodium hydrosulphide (NaHS) and mild hypothermia result in increased hippocampal H2S levels Since H2S is known to have a protective effect on brain function, we first wished to establish what effect administration of the H2S donor compound NaHS and mild hypothermia had on hippocampal H2S content. 100 rats were randomly divided into five groups: (1) Sham operation group (Sh): sham operation group (2) normothermic ischemia-reperfusion group (NT): normothermic group (3) mHT: mild hypothermia group; (4) NT + NaHS: normothermic and NaHS treatment group (5) mHT + NaHS: mild hypothermia and NaHS treatment group
Summary
Both hydrogen sulphide (H2S) and mild hypothermia have been reported to prevent brain damage caused by reperfusion assault through regulating the N-methyl-D-aspartate receptor (NMDAR). N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity has been shown to be a critical factor in neuronal damage following ischemia-reperfusion insults such as stroke or brain trauma [2]. The NMDA receptor is a plasma membrane channel that exists as a heteromeric complex composed of two glycine-binding NR1 subunits in combination with various glutamate binding NR2 subunits (A-D). These NR2 subunits vary according to the brain region and confer distinct electrophysiological and pharmacological properties on the receptors. The activation of NMDA-receptors at synaptic locations likely promotes neuronal survival, whereas activation of NMDARs at extrasynaptic locations may promote neuronal death. The pro-apoptotic pathways associated with extrasynaptic NMDARs appear to function predominantly through inhibition of CREB or activation of nNOS or JUN [5,6,7]
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