Browsing by Author "Lei, Zhigang"

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    Blood Purification by Non-Selective Hemoadsorption Prevents Death after Traumatic Brain Injury and Hemorrhagic Shock in Rats
    (Wolters Kluwer, 2018-09) McKinley, Todd O.; Lei, Zhigang; Kalbas, Yannik; White, Fletcher A.; Shi, Zhongshang; Wu, Fan; Xu, Zao C.; Rodgers, Richard B.; Anesthesia, School of Medicine
    Background Patients who sustain traumatic brain injury (TBI) and concomitant hemorrhagic shock (HS) are at high risk of high-magnitude inflammation which can lead to poor outcomes and death. Blood purification by hemoadsorption (HA) offers an alternative intervention to reduce inflammation after injury. We tested the hypothesis that HA would reduce mortality in a rat model of TBI and HS. Methods Male Sprague Dawley rats were subjected to a combined injury of a controlled cortical impact (CCI) to their brain and pressure-controlled hemorrhagic shock (HS). Animals were subsequently instrumented with an extracorporeal blood circuit that passed through a cartridge for sham or experimental treatment. In experimental animals, the treatment cartridge was filled with proprietary beads (Cytosorbents; Monmouth Junction, NJ) that removed circulating molecules between 5 KDa and 60 KDa. Sham rats had equivalent circulation but no blood purification. Serial blood samples were analyzed with multiplex technology to quantify changes in a trauma-relevant panel of immunologic mediators. The primary outcome was survival to 96hr post-injury. Results HA improved survival from 47% in sham treated rats to 86% in HA treated rats. There were no treatment-related changes in histologic appearance. HA affected biomarker concentrations both during the treatment and over the ensuing four days after injury. Distinct changes in biomarker concentrations were also measured in survivor and non-survivor rats from the entire cohort of rats indicating biomarker patterns associated with survival and death after injury. Conclusions Blood purification by non-selective HA is an effective intervention to prevent death in a combined TBI/HS rat model. HA changed circulating concentrations of multiple inmmunologically active mediators during the treatment time frame and after treatment. HA has been safely implemented in human patients with sepsis and may be a treatment option after injury.
  • Thumbnail Image
    Item
    Carbon nanotube multilayered nanocomposites as multifunctional substrates for actuating neuronal differentiation and functions of neural stem cells
    (Elsevier, 2018-08) Shao, Han; Li, Tingting; Zhu, Rong; Xu, Xiaoting; Yu, Jiandong; Chen, Shengfeng; Song, Li; Ramakrishna, Seeram; Lei, Zhigang; Ruan, Yiwen; He, Liumin; Anatomy and Cell Biology, School of Medicine
    Carbon nanotubes (CNTs) have shown potential applications in neuroscience as growth substrates owing to their numerous unique properties. However, a key concern in the fabrication of homogeneous composites is the serious aggregation of CNTs during incorporation into the biomaterial matrix. Moreover, the regulation mechanism of CNT-based substrates on neural differentiation remains unclear. Here, a novel strategy was introduced for the construction of CNT nanocomposites via layer-by-layer assembly of negatively charged multi-walled CNTs and positively charged poly(dimethyldiallylammonium chloride). Results demonstrated that the CNT-multilayered nanocomposites provided a potent regulatory signal over neural stem cells (NSCs), including cell adhesion, viability, differentiation, neurite outgrowth, and electrophysiological maturation of NSC-derived neurons. Importantly, the dynamic molecular mechanisms in the NSC differentiation involved the integrin-mediated interactions between NSCs and CNT multilayers, thereby activating focal adhesion kinase, subsequently triggering downstream signaling events to regulate neuronal differentiation and synapse formation. This study provided insights for future applications of CNT-multilayered nanomaterials in neural fields as potent modulators of stem cell behavior.
  • Thumbnail Image
    Item
    Increased Sestrin3 Contributes to Post-ischemic Seizures in the Diabetic Condition
    (Frontiers Media, 2021-01-15) Shi, Zhongshan; Lei, Zhigang; Wu, Fan; Xia, Luoxing; Ruan, Yiwen; Xu, Zao C.; Anatomy and Cell Biology, School of Medicine
    Seizures are among the most common neurological sequelae of stroke, and diabetes notably increases the incidence of post-ischemic seizures. Recent studies have indicated that Sestrin3 (SESN3) is a regulator of a proconvulsant gene network in human epileptic hippocampus. But the association of SESN3 and post-ischemic seizures in diabetes remains unclear. The present study aimed to reveal the involvement of SESN3 in seizures following transient cerebral ischemia in diabetes. Diabetes was induced in adult male mice and rats via intraperitoneal injection of streptozotocin (STZ). Forebrain ischemia (15 min) was induced by bilateral common carotid artery occlusion, the 2-vessel occlusion (2VO) in mice and 4-vessel occlusion (4VO) in rats. Our results showed that 59% of the diabetic wild-type mice developed seizures after ischemia while no seizures were observed in non-diabetic mice. Although no apparent cell death was detected in the hippocampus of seizure mice within 24 h after the ischemic insult, the expression of SESN3 was significantly increased in seizure diabetic mice after ischemia. The post-ischemic seizure incidence significantly decreased in SESN3 knockout mice. Furthermore, all diabetic rats suffered from post-ischemic seizures and non-diabetic rats have no seizures. Electrophysiological recording showed an increased excitatory synaptic transmission and intrinsic membrane excitability in dentate granule cells of the rat hippocampus, together with decreased IA currents and Kv4.2 expression levels. The above results suggest that SESN3 up-regulation may contribute to neuronal hyperexcitability and seizure generation in diabetic animals after ischemia. Further studies are needed to explore the molecular mechanism of SESN3 in seizure generation after ischemia in diabetic conditions.
  • Thumbnail Image
    Item
    Neuroprotective Mechanisms of Lycium barbarum Polysaccharides Against Ischemic Insults by Regulating NR2B and NR2A Containing NMDA Receptor Signaling Pathways
    (Frontiers, 2017-09-27) Shi, Zhongshan; Zhu, Lihui; Li, Tingting; Tang, Xiaoya; Xiang, Yonghui; Han, Xinjia; Xia, Luoxing; Zeng, Ling; Nie, Junhua; Huang, Yongxia; Tsang, Chi Kwan; Wang, Ying; Lei, Zhigang; Xu, Zaocheng; So, Kwok-fai; Ruan, Yiwen; Anatomy and Cell Biology, School of Medicine
    Glutamate excitotoxicity plays an important role in neuronal death after ischemia. However, all clinical trials using glutamate receptor inhibitors have failed. This may be related to the evidence that activation of different subunit of NMDA receptor will induce different effects. Many studies have shown that activation of the intrasynaptic NR2A subunit will stimulate survival signaling pathways, whereas upregulation of extrasynaptic NR2B will trigger apoptotic pathways. A Lycium barbarum polysaccharide (LBP) is a mixed compound extracted from Lycium barbarum fruit. Recent studies have shown that LBP protects neurons against ischemic injury by anti-oxidative effects. Here we first reported that the effect of LBP against ischemic injury can be achieved by regulating NR2B and NR2A signaling pathways. By in vivo study, we found LBP substantially reduced CA1 neurons from death after transient global ischemia and ameliorated memory deficit in ischemic rats. By in vitro study, we further confirmed that LBP increased the viability of primary cultured cortical neurons when exposed to oxygen-glucose deprivation (OGD) for 4 h. Importantly, we found that LBP antagonized increase in expression of major proteins in the NR2B signal pathway including NR2B, nNOS, Bcl-2-associated death promoter (BAD), cytochrome C (cytC) and cleaved caspase-3, and also reduced ROS level, calcium influx and mitochondrial permeability after 4 h OGD. In addition, LBP prevented the downregulation in the expression of NR2A, pAkt and pCREB, which are important cell survival pathway components. Furthermore, LBP attenuated the effects of a NR2B co-agonist and NR2A inhibitor on cell mortality under OGD conditions. Taken together, our results demonstrated that LBP is neuroprotective against ischemic injury by its dual roles in activation of NR2A and inhibition of NR2B signaling pathways, which suggests that LBP may be a superior therapeutic candidate for targeting glutamate excitotoxicity for the treatment of ischemic stroke.
  • Thumbnail Image
    Item
    Reduced expression of IA channels is associated with post-ischemic seizures
    (Elsevier, 2016-08) Lei, Zhigang; Zhang, Hui; Liang, Yanling; Xu, Zao C.; Anatomy and Cell Biology, School of Medicine
    Purpose Post-stroke seizures are considered as a major cause of epilepsy in adults. The pathophysiologic mechanisms resulting in post-stroke seizures are not fully understood. The present study attempted to reveal a new mechanism underlying neuronal hyperexcitability responsible to the seizure development after ischemic stroke. Methods Transient global ischemia was produced in adult Wistar rats using the 4-vessel occlusion (4-VO) method. The spontaneous behavioral seizures were defined by the Racine scale III – V. The neuronal death in the brain was determined by hematoxylineosin staining. The expression levels of A-type potassium channels were analyzed by immunohistochemical staining and western blotting. Results We found that the incidence of spontaneous behavioral seizures increased according to the severity of ischemia with 0% after 15-min ischemia and ~50% after 25- min ischemia. All behavioral seizures occurred with 48 hrs after ischemia. Morphological analysis indicated that brain damage was not correlated with behavioral seizures. Immunohistochemical staining showed that the expression levels of the A-type potassium channel subunit Kv4.2 was significantly reduced in ischemic brains with behavioral seizures, but not in ischemic brains without seizures. In addition, rats failing to develop spontaneous behavioral seizures within 2 days after ischemia were more sensitive to bicuculline-induced seizures at 2 months after ischemia than control rats. Meanwhile, Kv4.2 expression was decreased in brain at 2 months after ischemia. Conclusion Our results demonstrated the reduction of Kv4.2 expression might contribute to the development of post-ischemic seizures and long-term increased seizure susceptibility after ischemia. The mechanisms underlying post-stroke seizures and epilepsy is unknown so far. The down-regulation of IA channels may explained the abnormal neuronal hyperexcitability responsible for the seizure development after ischemic stroke.