Neonatal hypoxic-ischemic encephalopathy (HIE) is a disease caused by insufficient blood supply in the brain in newborns during the perinatal period. Severe HIE leads to patient death, and patients with mild HIE are at increased risk of cognitive deficits and behavioral abnormalities. The NMDA receptor is an important excitatory receptor in the central nervous system, and in adult hypoxic-ischemic injury both subtypes of the NMDA receptor play important but distinct roles. The GluN2A-containing NMDA receptor (GluN2A-NMDAR) could activate neuronal protective signaling pathway, while the GluN2B-NMDAR subtype is coupled to the apoptosis-inducing signaling pathway and leads to neuronal death. However, the expression level of GluN2B is higher in newborns than in adults, while the expression of GluN2A is lower. Therefore, it is not clear whether the roles of different NMDA receptor subtypes in HIE are consistent with those in adults. We investigated this issue in this study and found that in HIE, GluN2B plays a protective role by mediating the protective pathway through binding with PSD95, which is quite different to that in adults. The results of this study provided new theoretical support for the clinical treatment of neonatal hypoxic ischemia.

• MeSH
• Apoptosis MeSH
• Phosphatidylinositol 3-Kinases metabolism   MeSH
• Ischemia MeSH
• Humans MeSH
• Hypoxia-Ischemia, Brain * metabolism   MeSH
• Infant, Newborn MeSH
• Proto-Oncogene Proteins c-akt metabolism   MeSH
• Receptors, N-Methyl-D-Aspartate metabolism   MeSH
• Signal Transduction MeSH
• Pregnancy MeSH
• Check Tag
• Humans MeSH
• Infant, Newborn MeSH
• Pregnancy MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Phosphatidylinositol 3-Kinases MeSH
• NR2B NMDA receptor MeSH Browser
• Proto-Oncogene Proteins c-akt MeSH
• Receptors, N-Methyl-D-Aspartate MeSH

100 rats were randomly divided into a sham-operated group and middle cerebral artery occlusion (MCAO) modeling groups. The sham group after surgery was observed for 14 days. After MCAO, some rats received isometric contraction training (ICT) which was as follows: an atraumatic tourniquet was placed around left or right hind limb to achieve hind limb ischemia for 5 min, followed by 5 min of reperfusion, 4 cycles for one time, once a day, and five days per week. The MCAO modeling groups included the following four groups: i) a group only received MCAO, and was observed for seven days (MCAO-7d), ii) a group only received MCAO, and was observed for 14 days (MCAO-14d), iii) a group, after MCAO, received ICT for seven days (ICT-7d), and iv) a group, after MCAO, received ICT for 14 days (ICT-14d). Brain infarct area, behavioral outcomes, the number of neurons, apoptosis, cerebral edema and cerebral water content were assessed, respectively. The mRNA expression of vascular endothelial growth factor (VEGF) was assayed with RT-PCR, and protein expression of VEGF was quantified with western blot. compared with MCAO controls, cerebral infarction, neurological deficits and neuronal apoptosis were reduced significantly in the ICT groups, while the number of neurons was increased. Moreover, the mRNA expression of VEGF and protein expression of VEGF were enhanced after 1 and 2 weeks of ICT. ICT may promote angiogenesis and neuroprotection after ischemic stroke and this new remodeling method provide a novel strategy for rehabilitation of stroke patients.

• MeSH
• Stroke * therapy   MeSH
• Infarction, Middle Cerebral Artery MeSH
• Brain Ischemia * metabolism   MeSH
• Isometric Contraction * MeSH
• Physical Conditioning, Animal * MeSH
• Rats MeSH
• RNA, Messenger MeSH
• Disease Models, Animal MeSH
• Neuroprotection MeSH
• Rats, Sprague-Dawley MeSH
• Vascular Endothelial Growth Factor A metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• RNA, Messenger MeSH
• Vascular Endothelial Growth Factor A MeSH

Cerebral ischemia-reperfusion injury (CIRI) is the predominant cause of neurological disability after cardiac arrest/cardiopulmonary resuscitation (CA/CPR). The endoplasmic reticulum stress (ERs)-induced apoptosis plays an important role in neuronal survival/death in CIRI. Our previous studies reported that the extracellular signal-regulated kinase (ERK) inhibitor, PD98059, alleviates CIRI after CA/CPR. Whether ERs-induced apoptosis is involved in the neuroprotection of PD98059 remains unknown. This study aims to investigate the effects of ERK inhibition by PD98059 on ERs-induced apoptosis after CIRI in the CA/CPR rat model. The baseline characteristics of male adult Sprague-Dawley (SD) rats in all groups were evaluated before CA/CPR. The SD rats that survived from CA/CPR were randomly divided into 3 groups (n=12/group): normal saline group (1 ml/kg), dimethylsulfoxide (DMSO, the solvent of PD98059, 1 ml/kg) group, PD98059 group (0.3 mg/kg). Another 12 SD rats were randomly selected as the Sham group. Twenty-four hours after resuscitation, neural injury was assessed by survival rate, neurological deficit scores (NDS) and Nissl staining; apoptosis of brain cells was detected using terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining; mRNA expression and protein levels of ERs-related protein BIP, PERK, ATF4 and CHOP were checked with RT-PCR and Western Blot. The results showed that there were no significant differences in baseline characteristics before CA/CPR among all groups. PD98059 significantly improved survival rate and NDS, increased the Nissl bodies in neurons, reduced apoptosis, downregulated the mRNA transcription and expression levels of BIP, PERK, ATF4 and CHOP at 24 h after CA/CPR. Our results demonstrate that inhibition of ERK by PD98059 alleviates ERs-induced apoptosis via BIP-PERK-ATF4-CHOP signaling pathway and mitigates CIRI in the CA/CPR rat model.

• MeSH
• Apoptosis MeSH
• Extracellular Signal-Regulated MAP Kinases MeSH
• Rats MeSH
• RNA, Messenger MeSH
• Brain Injuries * MeSH
• Rats, Sprague-Dawley MeSH
• Reperfusion Injury * metabolism   MeSH
• Heart Arrest * complications   MeSH
• Endoplasmic Reticulum Stress MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Extracellular Signal-Regulated MAP Kinases MeSH
• RNA, Messenger MeSH

Autologous stem cell therapy is the most promising alternative treatment in patients with chronic ischemic diseases, including ischemic heart disease and critical limb ischemia, which are characterized by poor prognosis related to serious impair of quality of life, high risk of cardiovascular events and mortality rates. However, one of the most serious shortcomings of stem cell transplantation are low survival after transplantation to the site of injury, as large number of stem cells are lost within 24 hours after delivery. Multiple studies suggest that combination of lipid-lowering drugs, statins, and stem cell transplantation might improve therapeutic efficacy in regenerative medicine. Statins are inhibitors of HMG-CoA reductase and belong to recommended therapy in all patients suffering from critical limb ischemia. Statins possess non-lipid effects which involve improvement of endothelial function, decrease of vascular inflammation and oxidative stress, anti-cancer and stem cell modulation capacities. These non-lipid effects are explained by inhibition of mevalonate synthesis via blocking isoprenoid intermediates synthesis, such as farnesylpyrophospate and geranylgeranylpyrophospate and result in modulation of the PI3K/Akt pathway. Moreover, statin-mediated microRNA regulation may contribute to the pleiotropic functions. MicroRNA interplay in gene regulatory network of IGF/Akt pathway may be of special significance for the treatment of critical limb ischemia. We assume further studies are needed for detailed analysis of statin interactions with microRNA at the molecular level and their link to PI3K/Akt and IGF/Akt pathway in stem cells, which are currently the most promising treatment strategy used in chronic ischemic diseases.

• MeSH
• Atorvastatin * pharmacology   therapeutic use   MeSH
• Chronic Limb-Threatening Ischemia * drug therapy   therapy   MeSH
• Phosphatidylinositol 3-Kinases * metabolism   MeSH
• Ischemia * drug therapy   therapy   MeSH
• Extremities * blood supply   MeSH
• Quality of Life MeSH
• Humans MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * pharmacology   therapeutic use   MeSH
• Stem Cell Transplantation * MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Atorvastatin * MeSH
• Hydroxymethylglutaryl-CoA Reductase Inhibitors * MeSH