HIF-1α Activation Attenuates IL-6 and TNF-α Pathways in Hippocampus of Rats Following Transient Global Ischemia

Abstract

Background/Aims: This study was to examine the role played by hypoxia inducible factor-1 (HIF-1α) in regulating pro-inflammatory cytokines (PICs) pathway in the rat hippocampus after cardiac arrest (CA) induced-transient global ischemia followed by cardiopulmonary resuscitation (CPR). Those PICs include interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α). Methods: A rat model of CA induced by asphyxia was used in the current study. Following CPR, the hippocampus CA1 region was obtained for ELISA to determine the levels of HIF-1α and PICs; and Western Blot analysis to determine the protein levels of PIC receptors. Results: Our data show that IL-1β, IL-6 and TNF-α were significant elevated in the hippocampus after CPR as compared with control group. This was companied with increasing of HIF-1α and the time courses for HIF-1α and PICs were similar. In addition, PIC receptors, namely IL-1R, IL-6R and TNFR1 were upregulated in CA rats. Also, stimulation of HIF-1α by systemic administration of ML228, HIF-1α activator, significantly attenuated the amplified IL-6/IL-6R and TNF-α /TNFR1 pathway in the hippocampus of CA rats, but did not modify IL-1β and its receptor. Moreover, ML228 attenuated upregulated expression of Caspase-3 indicating cell apoptosis evoked by CA. Conclusion: Transient global ischemia induced by CA increases the levels of IL-1β, IL-6 and TNF-α and thereby leads to enhancement in their respective receptor in the rat hippocampus. Stabilization of HIF-1α plays a role in attenuating amplified expression IL-6R, TNFR1 and Caspase-3 in the processing of transient global ischemia. Results of our study suggest that PICs contribute to cerebral injuries evoked by transient global ischemia and in this pathophysiological process activation of HIF-1α improves tissues against ischemic injuries. Our data revealed specific signaling pathways in alleviating CA-evoked global cerebral ischemia by elucidating that HIF-1α plays an important role in regulating PIC signal pathways and Caspase-3. The subsequent induction of HIF-1α and its target signals is likely a part of the intrinsic neuroprotective effects aimed at attenuating damage as a result of global cerebral ischemia. Thus, targeting one or more of these signaling molecules has clinical implications for treatment and improvement of CA-evoked global cerebral ischemia often observed in clinics.

Effects of ulinastatin on global ischemia via brain pro-inflammation signal

“…It should also be noted that we determined the levels of IL-1β, IL-6 and TNF-α as well as their respective receptors in the specific brain regions, cortex and hippocampus CA1 region. Those specific brain regions were selected in our study because expression of PICs and their receptors is upregulated in those regions following CA in rats and in general they are also more related to neurological deficits after cerebral ischemia than other brain regions [18, 20]. Our results showed that CA amplifies the levels of IL-6 and TNF-α in addition to IL-1β, which is consistent with the previous report [11].…”

“…Prior studies have demonstrated that hypoxia inducible factor-1 (HIF-1) subtype HIF-1α is expressed in the brain tissues including the neocortex and hippocampus and engaged in neuronal apoptosis after induction of global ischemia [14-17]. In particular, a recent study using this model has further demonstrated that CA increases IL-1β, IL-6 and TNF-α and upregulates their receptors IL-1R, IL-6R and TNFR1 in the hippocampus [18]. Systemic activation of HIF-1α attenuates these exaggerated PIC signal pathways [18], and as a result neuronal apoptosis and neurological deficits induced by CA are attenuated [19].…”

“…In particular, a recent study using this model has further demonstrated that CA increases IL-1β, IL-6 and TNF-α and upregulates their receptors IL-1R, IL-6R and TNFR1 in the hippocampus [18]. Systemic activation of HIF-1α attenuates these exaggerated PIC signal pathways [18], and as a result neuronal apoptosis and neurological deficits induced by CA are attenuated [19]. In the present study, we administered UTI and then examined its effects on neurological deficits observed in CA rats.…”

Treatment with Enriched Environment Reduces Neuronal Apoptosis in the Periinfarct Cortex after Cerebral Ischemia/Reperfusion Injury

“…Previous studies have shown that both passive and pre-ischemic exercise suppressed the apoptosis and reduced neurons loss in the periinfarct area via upregulating expression of Bcl-2 and maintaining the balance ratio of Bax/Bcl-2 [37-39]. Except for Bcl-2 family, caspase-3 is one of the most important downstream executors in the mitochondrial apoptotic pathway, which is considered as an indicator of neuronal apoptosis [40]. Previous studies have demonstrated that deletion and inhibition of caspase-3 provided neuroprotection through mediating neuronal death and rendering neurons resistant to ischemic injury in vivo and in vitro [41].…”

LPS Pretreatment Attenuates Cerebral Ischaemia/Reperfusion Injury by Inhibiting Inflammation and Apoptosis

“…A large number of inflammatory cytokines (TNF-α, IL-1β, IL-6, IL-10) are involved in brain cell apoptosis and necrosis after I/R [47-50]. Reducing the inflammatory factors could protect the brain from IRI.…”