Cell type-specific activation of p38 MAPK in the brain regions of hypoxic preconditioned mice. Neurochem Int

Texas A&M University - Galveston, Galveston, Texas, United States
Neurochemistry International (Impact Factor: 3.09). 01/2008; 51(8):459-66. DOI: 10.1016/j.neuint.2007.04.028
Source: PubMed


Activation of p38 mitogen-activated protein kinase (p38 MAPK) has been implicated as a mechanism of ischemia/hypoxia-induced cerebral injury. The current study was designed to explore the involvement of p38 MAPK in the development of cerebral hypoxic preconditioning (HPC) by observing the changes in dual phosphorylation (p-p38 MAPK) at threonine180 and tyrosine182 sites, protein expression, and cellular distribution of p-p38 MAPK in the brain of HPC mice. We found that the p-p38 MAPK levels, not protein expression, increased significantly (p<0.05) in the regions of frontal cortex, hippocampus, and hypothalamus of mice in response to repetitive hypoxic exposure (H1-H6, n=6 for each group) when compared to values of the control normoxic group (H0, n=6) using Western blot analysis. Similar results were also confirmed by an immunostaining study of the p-p38 MAPK location in the frontal cortex, hippocampus, and hypothalamus of mice from HPC groups. To further define the cell type of p-p38 MAPK positive cells, we used a double-labeled immunofluorescent staining method to co-localize p-p38 MAPK with neurofilaments heavy chain (NF-H, neuron-specific marker), S100 (astrocyte-specific marker), and CD11b (microglia-specific maker), respectively. We found that the increased p-p38 MAPK occurred in microglia of cortex and hippocampus, as well as in neurons of hypothalamus of HPC mice. These results suggest that the cell type-specific activation of p38 MAPK in the specific brain regions might contribute to the development of cerebral HPC mechanism in mice.

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    • "All procedures in this study were conducted according to the guidelines set by the University Animal Care and Use Committee of Capital Medical University and they are consistent with the NIH Guide for the care and use of laboratory animals (NIH Publications No. 80– 23). HPC mouse model was prepared as in our previous reports (Niu et al. 2005; Bu et al. 2007; Zhang et al. 2007). Mice were placed individually in a 125-mL airtight jar with fresh air and sealed with a rubber plug to duplicate acute and repetitive exposure to progressive hypoxic environment. "
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    ABSTRACT: J. Neurochem. (2012) 120, 830–841. We previously reported the involvement of conventional protein kinase C (cPKC) βII, γ, novel PKC (nPKC) ε and their interacting proteins in hypoxic pre-conditioning (HPC)-induced neuroprotection. In this study, the large-scale miRNA microarrays and bioinformatics analysis were used to determine the differentially expressed miRNAs and their PKC-isoform specific gene network in mouse brain after HPC and 6 h middle cerebral artery occlusion (MCAO). We found 4 up-regulated and 13 down-regulated miRNAs in the cortex of HPC mice, 26 increased and 39 decreased gene expressions of miRNAs in the peri-infarct region of 6 h MCAO mice, and 11 up-regulated and 22 down-regulated miRNAs in the peri-infarct region of HPC and 6 h MCAO mice. Based on Diff Score, 19 differentially expressed miRNAs were identified in HPC and 6 h MCAO mouse brain. Then the miRNA-gene-network of 19 specified miRNAs target genes of cPKCβII, γ and nPKCε-interacting protein was predicted by using bioinformatics analysis of genome databases. Furthermore, the down-regulated miR-615-3p during HPC had a detrimental effect on the oxygen-glucose deprivation (OGD)-induced N2A cell injury. These results suggested that the identified 19 miRNAs, notably miR-615-3p, might target these genes of cPKCβII, γ and nPKCε-interacting proteins involved in HPC-induced neuroprotection.
    Preview · Article · Dec 2011 · Journal of Neurochemistry
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    • "Previous studies, mainly from cell culture-based assays, indicate that p38 MAPK plays a role in regulating neuronal death on various insults (Harper & LoGrasso, 2001). In neuronal cells or cell lines, a number of stimulations have been reported to activate p38 MAPK (Xia et al., 1995; Heidenreich & Kummer, 1996; Horstmann et al., 1998; Park et al., 2002) and studies have reported activated p38 MAPK in rat and mouse models of neonatal HI brain injury (Hee Han et al., 2002; Bu et al., 2007). However, there are no data regarding the role of p38 MAPK activation in the increased generation of reactive oxygen species associated with the neuronal death in the neonatal brain exposed to HI. "
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    ABSTRACT: The pathological basis of neonatal hypoxia-ischemia (HI) brain damage is characterized by neuronal cell loss. Oxidative stress is thought to be one of the main causes of HI-induced neuronal cell death. The p38 mitogen-activated protein kinase (MAPK) is activated under conditions of cell stress. However, its pathogenic role in regulating the oxidative stress associated with HI injury in the brain is not well understood. Thus, this study was conducted to examine the role of p38 MAPK signaling in neonatal HI brain injury using neonatal rat hippocampal slice cultures exposed to oxygen/glucose deprivation (OGD). Our results indicate that OGD led to a transient increase in p38 MAPK activation that preceded increases in superoxide generation and neuronal death. This increase in neuronal cell death correlated with an increase in the activation of caspase-3 and the appearance of apoptotic neuronal cells. Pre-treatment of slice cultures with the p38 MAPK inhibitor, SB203580, or the expression of an antisense p38 MAPK construct only in neuronal cells, through a Synapsin I-1-driven adeno-associated virus vector, inhibited p38 MAPK activity and exerted a neuroprotective effect as demonstrated by decreases in OGD-mediated oxidative stress, caspase activation and neuronal cell death. Thus, we conclude that the activation of p38 MAPK in neuronal cells plays a key role in the oxidative stress and neuronal cell death associated with OGD.
    Full-text · Article · Sep 2011 · European Journal of Neuroscience
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    • "Furthermore, the result reasonably explains some clinical state that was previously unclear. For example, lidocaine has neuroprotective effect on rat suffering from cerebral ischemia by attenuating the activation of p38 MAPK in cortex, which has been implicated as an important inducer for ischemia/hypoxiainduced cerebral injury [4]. This research increases our current understanding of lidocaine, and provides a new, non-opioid therapeutic avenue for treating chronic pain. "
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    ABSTRACT: Increasing evidences approve the long-term analgesia effects of intrathecal lidocaine in patients with chronic pain and in animal peripheral nerve injury models, but the underlying mechanism remains elusive. Previous evidences suggest that the activation of the p38 MAPK signaling pathway in hyperactive microglia in the dorsal horn of spinal cord involves in nerve injury-induced neuropathic pain. In this study, we demonstrate that attenuating phosphorylation of p38 MAPK in the activated microglia of spinal cord, at least partly, is the mechanism of intrathecal lidocaine reversing established tactile allodynia in chronic constriction injury model of rats. This finding not only provides a new insight into the mechanisms underlying long-term therapeutic effects of lidocaine on neuropathic pain, but also reveals one more specific drug target for analgesia.
    Preview · Article · Feb 2008 · Neuroscience Letters
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