Hypoxic-ischemic encephalopathy is a condition caused by reduced oxygen and cerebral blood flow to the brain resulting in neurological impairments. Effective therapeutic treatments to ameliorate these disabilities are still lacking. We sought to investigate the role of sestrin2, a highly conserved stress-inducible protein, in a neonatal rat hypoxic-ischemic encephalopathy model. Ten-day-old rat pups underwent right common carotid artery ligation followed by 2.5 h hypoxia. At 1 h post hypoxic-ischemic encephalopathy, rats were intranasally administered with recombinant human sestrin2 and sacrificed for brain infarct area measurement, Fluoro-Jade C, immunofluorescence staining, Western blot, and neurological function testing. rh-sestrin2 reduced brain infarct area, brain atrophy, apoptosis, ventricular area enlargement, and improved neurological function. Western blot showed that sestrin2 expression levels were increased after treatment with rh-sestrin2, and sestrin2 exerts neuroprotective effects via activation of the adenosine monophosphate-activated protein kinase pathway which in turn inhibits mammalian target of rapamycin signaling resulting in the attenuation of apoptosis. In conclusions: Sestrin2 plays an important neuroprotective role after hypoxic-ischemic encephalopathy via adenosine monophosphate-activated protein kinase signaling pathway and serves as a negative feedback regulator of mammalian target of rapamycin. Administration of rh-sestrin2 not only reduced infarct area and brain atrophy, but also significantly improved neurological function.

Objective Hypoxic ischemic (HI) encephalopathy remains the leading cause of perinatal brain injury resulting in long term disabilities. Stabilization of blood brain barrier (BBB) after HI is an important target, therefore, in this study we aim to determine the role of sestrin2, a stress inducible protein which is elevated after various insults, on BBB stabilization after moderate and severe HI injury. Methods Rat pups underwent common carotid artery ligation followed by either 150 min (severe model) or 100 min (moderate model) of hypoxia. 1h post HI, rats were intranasally administered with recombinant human sestrin2 (rh-sestrin2) and sacrificed for infarct area, brain water content, righting reflex and geotaxis reflex. Sestrin2 was silenced using siRNA and an activator/inhibitor of hypoxia inducible factor1α (HIF1α) were used to examine their roles on BBB permeability. Results Rats subjected to severe HI exhibited larger infarct area and higher sestrin2 expression compared to rats in the moderate HI group. rh-sestrin2 attenuated brain infarct and edema, while silencing sestrin2 reversed these protective effects after severe HI. HIF1α induced sestrin2 activation in severe HI but not in moderate HI groups. A HIF1a agonist was shown to increase permeability of the BBB via vascular endothelial growth factor (VEGF) after moderate HI. However, after severe HI, HIF1α activated both VEGF and sestrin2. But HIF1α dependent sestrin2 activation was the predominant pathway after severe HI which inhibited VEGF and attenuated BBB permeability. Conclusions rh-sestrin2 attenuated BBB permeability via upregulation of endogenous sestrin2 which was induced by HIF1α after severe HI. However, HIF1α’s effects as a prodeath or prosurvival signal were influenced by the severity of HI injury.

These data suggest that in the early phase of postoperative pain, pain-related anxiety and mechanical hypersensitivity are tightly linked and regulated by the ERK activation in the ACC. However, in the late phase of postoperative pain, ERK activation in the ACC is only required for the expression of pain-related anxiety but not mechanical hypersensitivity.

Extracellular signal‑regulated kinase (ERK) 1/2 in the spinal cord has been implicated in the development of neuropathic pain and inflammatory pain. However, a limited number of studies have investigated the role of spinal ERK in incisional pain. The present study aimed to determine the role of ERK in the spinal cord in incisional pain. Incisional pain was established in rats by a unilateral hind paw incision. ERK1/2 expression was analyzed by immunohistochemistry. Hypersensitivity to pain was evaluated by measuring the paw withdrawal threshold using the von Frey test. The mitogen‑activated protein kinase kinase (MEK) inhibitor, U0126, was administered 20 min prior to or 10 min following the incision by intrathecal or intraperitoneal injection. Phosphorylated ERK1/2 in the ipsilateral L4‑5 spinal superficial dorsal horn was activated 1 min following the incision, reached its peak level at 5 min and then returned to the basal level 20 min following the incision. Pretreatment, but not post‑treatment with U0126 markedly attenuated the pain hypersensitivity induced by the incision. Therefore, the present study indicates that the transient activation of spinal ERK1/2 contributes to the initiation of pain hypersensitivity following surgical incision.

Background. The ideal management of SAH patients with negative initial DSA findings remains unresolved. Objective. (i) To present risk factors, clinical courses, and outcomes in different types of SAH patients with negative DSA findings; (ii) to explore the differences of basal vein between aSAH patients and NASAH patients; and (iii) to evaluate the value of repeated DSA for these patients. Methods. All SAH patients with negative initial DSA findings between 2013 and 2015 in our hospital were enrolled and were further categorized as perimesencephalic SAH (PMN-SAH) or nonperimesencephalic SAH (nPMN-SAH). Risk factors, clinical courses, outcomes, and the basal vein drainage patterns were compared. Results. A total of 137 patients were enrolled in the present study. The PMN-SAH group had better GOS and mRS values at 1-year follow-up. Moreover, the nPMN-SAH group had a higher rate of complications. The basal vein drainage pattern showed significant difference when comparing each of the NASAH subtypes with aSAH groups. There was a significant higher rate of a responsible aneurysm in nPMN-SAH group upon repeated DSA. Conclusions. SAH patients with negative initial DSA findings had benign clinical courses and outcomes. Repeated DSA studies are strongly advised for patients with the nPMN-SAH pattern.

Cyclooxygenase (COX)-2 inhibitors are widely used for postoperative pain control in clinical practice. However, it is unknown whether spinal sensitization is involved in the analgesic effects of COX-2 inhibitors on surgical pain. Extracellular signal-regulated kinase (ERK) in the spinal cord is implicated in various types of pain, including surgical pain. The present study investigated the role of spinal ERK signaling in the analgesic effect of the COX-2 inhibitor parecoxib on surgical pain. Surgical pain was produced in rats by surgical incision of the hind paw. Phosphorylated (p)-ERK1/2 expression was determined by immunohistochemistry. Pain hypersensitivity was evaluated by measuring the paw withdrawal threshold using the von Frey test. The selective COX-2 inhibitor parecoxib was delivered 20 min before or 20 min after the incision by intraperitoneal injection. Pretreatment with parecoxib markedly attenuated the pain hypersensitivity induced by incision. However, post-treatment with parecoxib produced minimal analgesic effects. Parecoxib inhibited the increase in spinal p-ERK expression following surgical incision. The present study thus suggests that the COX-2 inhibitor parecoxib exerts its analgesic effect on surgical pain through the inhibition of neuronal ERK activation in the spinal cord. COX-2 inhibitor delivery prior to surgery has more potent analgesic effects, suggesting the advantage of preventive analgesia for post-operative pain control.

Based on the current understanding of sestrins, it is believed that sestrins are one of the potential endogenous protective molecules/mechanisms following cerebral stroke, which are associated with neuronal protection, neuroinflammation suppression, and blood brain barrier preservation.

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