Hypoxia-Ischemia Upregulates TRAIL and TRAIL Receptors in the Immature Rat Brain

Abstract

The immature brain is susceptible to inflammatory injury induced by hypoxia-ischemia (HI) or infection, which causes serious neurodevelopmental disabilities in the survivors of preterm births. Recently, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptors (death receptor DR4/5 and decoy receptor DcR1/2) were reported to mediate various neuroinflammatory responses. However, little information is available regarding the role of TRAIL and its receptors in the immature brain after HI. The purpose of this study was to evaluate the expression of TRAIL and its receptors in the immature brain after HI and relate this expression to neurological function. We performed right common carotid artery ligation followed by hypoxia (6% O₂, 37°C) for 2.5 h to induce HI in postnatal day 3 rats. The distribution of TRAIL and its receptors, caspase-3 and CD68-labeled microglia/macrophages was evaluated 24 h after HI by immunostaining. The protein and mRNA expression of TRAIL and DR5 was measured by Western blot and real-time PCR, respectively. Delayed neuronal loss was evaluated by NeuN and Nissl staining 7 days after HI. Furthermore, neurological deficits were evaluated by a righting reflex test, time of eye opening and T-maze test. The expression of TRAIL, DR5 and DcR1/2 receptors and caspase-3 was more pronounced in the ipsilateral hemisphere compared with the contralateral part and the control group 24 h after HI. DR5/active caspase-3 double-positive cells were observed at 24 h after HI in the ipsilateral hemisphere but not in the contralateral hemisphere. The TRAIL and CD68 double-labeled cells were more pronounced in the ipsilateral cortical regions compared with the corresponding regions of the contralateral part. HI also resulted in a significant increase in TRAIL and DR5 protein and mRNA expression at 24 h, which corresponded to neuronal cell loss 7 days after HI. Furthermore, the HI group displayed impaired neurobehavioral development compared with the control group (p < 0.05). Altogether our results show that the TNF-α superfamily ligand TRAIL is induced on CD68+ microglia/macrophages after perinatal HI and that one of its receptors, DR5, is induced on neocortical neurons and glial cells. That many DR5+ cells were also caspase-3+ strongly supports the conclusion that these signaling molecules are involved in the delayed loss of neurons in the neocortex and in the neurobehavioral deficits that are often seen after perinatal HI.

Ischemic tolerance modulates TRAIL expression and its receptors and generates a neuroprotected phenotype

“…18, 28 Indeed, TRAIL and DR5 are upregulated in the immature rat brain after perinatal hypoxia–ischemia 18 as well as after transient global ischemia. 17 In addition, it has been shown that blocking TRAIL by soluble DR5 mitigate selective neuronal death after transient global ischemia–reperfusion in mice.…”

“…This represents an important finding, as, so far, few studies have investigated the role of TRAIL in cell death induced by ischemia, 17, 18, 19, 28 and no one investigated about the possible involvement of TRAIL in the neuroprotective phenomenon known as ischemic PC.…”

“…Although recent work attempted to establish a relationship between TRAIL pathway and brain ischemia, 17, 18 only scant data are available on the role of TRAIL and its receptors in focal ischemia, 19 and no data are known on the role of TRAIL in brain PC-induced neuroprotection.…”

Tumor Necrosis Factor-related Apoptosis-inducing Ligand (TRAIL) Signaling and Cell Death in the Immature Central Nervous System after Hypoxia-Ischemia and Inflammation

“…This pathway is important in the pathogenesis of adult stroke (22), trauma (23), infection (24), and multiple sclerosis (25), but there is limited information available with respect to the involvement of TRAIL and its receptors in the demise of immature neurons such as in neonatal HI (26). …”

Pathophysiology and Neuroprotection of Global and Focal Perinatal Brain Injury: Lessons From Animal Models

“…Furthermore, in preterm infants, the structural immaturity of blood vessels, which appear thin walled, may predispose to bleeding 60 . Previously some studies have shown that the immature brain has a large potential to compensate for perinatal injury to the motor system 61, 62 , but recently this concept has questioned by several authors 63,64 …”