Browsing by Author "Ma, Cungen"

Now showing 1 - 6 of 6
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    Blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) prevents posttraumatic epileptogenesis in mice
    (Wiley, 2021) Ping, Xingjie; Chai, Zhi; Wang, Weiping; Ma, Cungen; White, Fletcher A.; Jin, Xiaoming; Anatomy, Cell Biology and Physiology, School of Medicine
    Objective: Effective treatment for the prevention of posttraumatic epilepsy is still not available. Here, we sought to determine whether blocking receptor for advanced glycation end products (RAGE) or toll-like receptor 4 (TLR4) signaling pathways would prevent posttraumatic epileptogenesis. Methods: In a mouse undercut model of posttraumatic epilepsy, daily injections of saline, RAGE monoclonal antibody (mAb), or TAK242, a TLR4 inhibitor, were made for 1 week. Their effects on seizure susceptibility and spontaneous epileptic seizures were evaluated with a pentylenetetrazol (PTZ) test in 2 weeks and with continuous video and wireless electroencephalography (EEG) monitoring between 2 and 6 weeks after injury, respectively. Seizure susceptibility after undercut in RAGE knockout mice was also evaluated with the PTZ test. The lesioned cortex was analyzed with immunohistology. Results: Undercut animals treated with RAGE mAb or TAK242 showed significantly higher seizure threshold than saline-treated undercut mice. Consistently, undercut injury in RAGE knockout mice did not cause a reduction in seizure threshold in the PTZ test. EEG and video recordings revealed a significant decrease in the cumulative spontaneous seizure events in the RAGE mAb- or TAK242-treated group (p < 0.001, when the RAGE mAb or TAK242 group is compared with the saline group). The lesioned cortical tissues of RAGE mAb- or TAK242-treated undercut group showed higher neuronal densities of Nissl staining and higher densities of glutamic acid decarboxylase 67-immunoreactive interneurons than the saline-treated undercut group. Immunostaining to GFAP and Iba-1 revealed lower densities of astrocytes and microglia in the cortex of the treatment groups, suggesting reduced glia activation. Significance: RAGE and TLR4 signaling are critically involved in posttraumatic epileptogenesis. Blocking these pathways early after traumatic brain injury is a promising strategy for preventing posttraumatic epilepsy.
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    Cortical stimulation for treatment of neurological disorders of hyperexcitability: a role of homeostatic plasticity
    (Wolters Kluwer, 2019-01) Chai, Zhi; Ma, Cungen; Jin, Xiaoming; Anatomy and Cell Biology, IU School of Medicine
    Hyperexcitability of neural network is a key neurophysiological mechanism in several neurological disorders including epilepsy, neuropathic pain, and tinnitus. Although standard paradigm of pharmacological management of them is to suppress this hyperexcitability, such as having been exemplified by the use of certain antiepileptic drugs, their frequent refractoriness to drug treatment suggests likely different pathophysiological mechanism. Because the pathogenesis in these disorders exhibits a transition from an initial activity loss after injury or sensory deprivation to subsequent hyperexcitability and paroxysmal discharges, this process can be regarded as a process of functional compensation similar to homeostatic plasticity regulation, in which a set level of activity in neural network is maintained after injury-induced activity loss through enhanced network excitability. Enhancing brain activity, such as cortical stimulation that is found to be effective in relieving symptoms of these disorders, may reduce such hyperexcitability through homeostatic plasticity mechanism. Here we review current evidence of homeostatic plasticity in the mechanism of acquired epilepsy, neuropathic pain, and tinnitus and the effects and mechanism of cortical stimulation. Establishing a role of homeostatic plasticity in these disorders may provide a theoretical basis on their pathogenesis as well as guide the development and application of therapeutic approaches through electrically or pharmacologically stimulating brain activity for treating these disorders.
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    Enhancing excitatory activity of somatosensory cortex alleviates neuropathic pain through regulating homeostatic plasticity
    (Nature Publishing group, 2017-10-06) Xiong, Wenhui; Ping, Xingjie; Ripsch, Matthew S.; Chavez, Grace Santa Cruz; Hannon, Heidi Elise; Jiang, Kewen; Bao, Chunhui; Jadhav, Vaishnavi; Chen, Lifang; Chai, Zhi; Ma, Cungen; Wu, Huangan; Feng, Jianqiao; Blesch, Armin; White, Fletcher A.; Jin, Xiaoming; Anatomy and Cell Biology, School of Medicine
    Central sensitization and network hyperexcitability of the nociceptive system is a basic mechanism of neuropathic pain. We hypothesize that development of cortical hyperexcitability underlying neuropathic pain may involve homeostatic plasticity in response to lesion-induced somatosensory deprivation and activity loss, and can be controlled by enhancing cortical activity. In a mouse model of neuropathic pain, in vivo two-photon imaging and patch clamp recording showed initial loss and subsequent recovery and enhancement of spontaneous firings of somatosensory cortical pyramidal neurons. Unilateral optogenetic stimulation of cortical pyramidal neurons both prevented and reduced pain-like behavior as detected by bilateral mechanical hypersensitivity of hindlimbs, but corpus callosotomy eliminated the analgesic effect that was ipsilateral, but not contralateral, to optogenetic stimulation, suggesting involvement of inter-hemispheric excitatory drive in this effect. Enhancing activity by focally blocking cortical GABAergic inhibition had a similar relieving effect on the pain-like behavior. Patch clamp recordings from layer V pyramidal neurons showed that optogenetic stimulation normalized cortical hyperexcitability through changing neuronal membrane properties and reducing frequency of excitatory postsynaptic events. We conclude that development of neuropathic pain involves abnormal homeostatic activity regulation of somatosensory cortex, and that enhancing cortical excitatory activity may be a novel strategy for preventing and controlling neuropathic pain.
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    Homeostatic activity regulation as a mechanism underlying the effect of brain stimulation
    (BMC, 2019-09-25) Chai, Zhi; Ma, Cungen; Jin, Xiaoming; Anatomy and Cell Biology, School of Medicine
    Hyperexcitability of the neural network often occurs after brain injuries or degeneration and is a key pathophysiological feature in certain neurological diseases such as epilepsy, neuropathic pain, and tinnitus. Although the standard approach of pharmacological treatments is to directly suppress the hyperexcitability through reducing excitation or enhancing inhibition, different techniques for stimulating brain activity are often used to treat refractory neurological conditions. However, it is unclear why stimulating brain activity would be effective for controlling hyperexcitability. Recent studies suggest that the pathogenesis in these disorders exhibits a transition from an initial activity loss after acute injury or progressive neurodegeneration to subsequent development of hyperexcitability. This process mimics homeostatic activity regulation and may contribute to developing network hyperexcitability that underlies neurological symptoms. This hypothesis also predicts that stimulating brain activity should be effective in reducing hyperexcitability due to homeostatic activity regulation and in relieving symptoms. Here we review current evidence of homeostatic plasticity in the development of hyperexcitability in some neurological diseases and the effects of brain stimulation. The homeostatic plasticity hypothesis may provide new insights into the pathophysiology of neurological diseases and may guide the use of brain stimulation techniques for treating them.
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    In vivo Two-Photon Imaging Reveals Acute Cerebral Vascular Spasm and Microthrombosis After Mild Traumatic Brain Injury in Mice
    (Frontiers Media, 2020-03) Han, Xinjia; Chai, Zhi; Ping, Xingjie; Song, Li-Juan; Ma, Cungen; Ruan, Yiwen; Jin, Xiaoming; Anatomy and Cell Biology, School of Medicine
    Mild traumatic brain injury (mTBI), or concussion, is reported to interfere with cerebral blood flow and microcirculation in patients, but our current understanding is quite limited and the results are often controversial. Here we used longitudinal in vivo two-photon imaging to investigate dynamic changes in cerebral vessels and velocities of red blood cells (RBC) following mTBI. Closed-head mTBI induced using a controlled cortical impact device resulted in a significant reduction of dwell time in a Rotarod test but no significant change in water maze test. Cerebral blood vessels were repeatedly imaged through a thinned skull window at baseline, 0.5, 1, 6 h, and 1 day following mTBI. In both arterioles and capillaries, their diameters and RBC velocities were significantly decreased at 0.5, 1, and 6 h after injury, and recovered in 1 day post-mTBI. In contrast, decreases in the diameter and RBC velocity of venules occurred only in 0.5–1 h after mTBI. We also observed formation and clearance of transient microthrombi in capillaries within 1 h post-mTBI. We concluded that in vivo two-photon imaging is useful for studying earlier alteration of vascular dynamics after mTBI and that mTBI induced reduction of cerebral blood flow, vasospasm, and formation of microthrombi in the acute stage following injury. These changes may contribute to early brain functional deficits of mTBI.
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    miR-1908 as a novel prognosis marker of glioma via promoting malignant phenotype and modulating SPRY4/RAF1 axis
    (Spandidos Publications, 2017-11) Chai, Zhi; Fan, Huijie; Li, Yanyan; Song, Lijuan; Jin, Xiaoming; Yu, Jiezhong; Li, Yanhua; Ma, Cungen; Zhou, Ran; Medicine, School of Medicine
    MicroRNAs (miRNAs) are reported to be involved in the development of glioma. However, study on miRNAs in glioma is limited. The present study aimed to identify miRNAs which can act as potential novel prognostic markers for glioma and analyze its possible mechanism. We show that miR-1908 correlates with shorter survival time of glioma patients via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRY4/RAF1 axis. Analysis of GEO and TCGA database found that miR-1908 was significantly upregulated in glioma tissues, and strongly associated with shorter survival time of glioma patients. Further Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis revealed that miR-1908 is mainly involved in regulating cell proliferation, invasion and apoptosis. To further confirm the above results, in vitro, glioma U251 cells were transfected with miR-1908 mimics or inhibitor, and upregulated miR-1908 promoted U251 cell proliferation, and enhanced the ability of invasion by transwell assay. In addition, upregulated miR-1908 also enhanced anti-apoptosis ability of U251 cells through decreasing pro-apoptosis protein Bax expression. Since miRNAs regulate numerous biological processes by targeting broad set of messenger RNAs, validated target genes of miR-1908 in glioma were analyzed by Targetscan and miRTarBase databases. Among them SPRY4 was significantly decreased in glioma tissues and associated with short survival time, which was selected as the key target gene of miR-1908. Moreover, protein-protein interaction (PPI) showed that SPRY4 could interacted with pro-oncogene RAF1 and negatively correlated with RAF1 expression. Consistent with above analysis, in vitro, western blot analysis identified that miR-1908 upregulated significantly decreased SPRY4 expression and increased RAF1 expression. Hence, miR-1908 was correlated with poor prognosis of glioma via promoting cell proliferation, invasion, anti-apoptosis and regulating SPRF4/RAF1 axis. Our results elucidated the tumor promoting role of miR-1908 and established miR-1908 as a potential novel prognostic marker for glioma.