Limb ischemic preconditioning induces brain ischemic tolerance via p38 MAPK

Department of Pathophysiology, Institute of Basic Medicine, Hebei Medical University, 361 Zhongshan East Road, Shijiazhuang 050017, PR China.
Brain Research (Impact Factor: 2.84). 05/2006; 1084(1):165-74. DOI: 10.1016/j.brainres.2006.02.041
Source: PubMed


It has been reported that limb ischemic preconditioning (LIP) could induce brain ischemic tolerance. In the present study, we investigated the role of p38 MAPK in the induction of brain ischemic tolerance by observing expression of phosphorylated p38 (p-p38) MAPK in the hippocampus after LIP and the effect of p38 MAPK inhibitor SB 203580 on the protection of LIP against delayed neuronal death (DND) in the CA1 hippocampus induced normally by brain ischemic insult. The results of Flow cytometry and Western blotting showed that expression of p-p38 MAPK initially increased at 6 h after LIP compared with sham group in the CA1 hippocampus. The increases reached peak at 12 h and lasted to 24 h after LIP. Expression of p-p38 MAPK was also increased in the CA3/dentate gyrus (DG) regions after LIP, but the beginning and peaking times were 1 and 3 days after LIP, which were relatively later than those in the CA1. Histological evaluation showed that LIP protected the CA1 hippocampal pyramidal neurons against DND induced by global brain ischemic insult for 8 min, suggesting the occurrence of brain ischemic tolerance. Pretreatment with SB 203580 at 30 min before LIP effectively blocked the ischemic tolerance induced by LIP. Together, it could be concluded that activation of p38 MAPK played an important role in the brain ischemic tolerance induced by LIP, and that components of the p38 MAPK cascade might be targets to modify neuronal survival in ischemic tolerance.

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    • "It has been shown that p38 MAPK may participate in the mechanism of cell death in response to excitotoxic and ischemic insults in the hippocampus (Molz et al., 2008; Shinozaki et al., 2007; Sugino et al., 2000). However, neuroprotective roles for p38 MAPK pathway in this structure have also been reported in ischemic preconditioning (Sun et al., 2006). Furthermore, adult hippocampal slices submitted to hyperosmotic stress for 3 h showed that the activation of p38 MAPK may be part of a neuroprotective response (Niswander and Dokas, 2006). "
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    ABSTRACT: The developing brain is very sensitive to damage by toxic agents, many of which only manifest in adulthood. Cadmium [Cd(II)] is an environmental pollutant which is widely used in industry and is a constituent of tobacco smoke. Exposure to Cd(II) has been linked to detrimental effects on mammalian cells including neural cells. We have investigated the action of Cd(II) on immature hippocampus by assessing cell viability and modulation of AKT/PKB and mitogen-activated protein kinase (MAPK) family members including extracellular signal-regulated kinase (ERK)-1/2, p38 MAPK and c-Jun N-terminal kinases (JNK). Hippocampal slices from immature rats (postnatal day 14; PN14) were incubated with Cd(II) (5-200 microM) for 3h and the effects on protein phosphorylation were analyzed by western blotting. Phosphorylation of p38(MAPK) was enhanced by Cd(II) at all doses tested. Cd(II) also stimulated the phosphorylation of ERK1/2 in a concentration-dependent manner. However, the phosphorylation of JNK and AKT was not altered by the metal. Moreover, Cd(II) reduced cell viability, as measured by MTT reduction. Inhibition of p38 MAPK by SB203580 aggravated the acute Cd(II)-induced impairment of cell viability, whereas inhibition of MEK by PD98059 did not alter the effects of Cd(II). The present data suggest that in immature hippocampal cells p38 MAPK may be a part of signaling pathway that counteracts acute Cd(II) neurotoxicity. In conclusion, our results showed that Cd(II) impairs cell viability and disturbs MAPKs pathways in an important developmental stage for synaptic organization.
    NeuroToxicology 08/2008; 29(4):727-34. DOI:10.1016/j.neuro.2008.04.017 · 3.38 Impact Factor
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    • "For example, pretreatment with SB203580 could aggravate the infarction size of brain and cerebral vascular leakage induced by focal cerebral ischemia (Lennmyr et al., 2003). Limb ischemic preconditioning induced brain ischemic tolerance via p38 MAPK activation, and SB203580 blocked the protection to CA1 hippocampal pyramidal neurons against delayed neuronal death (Sun et al., 2006). However, these studies were lack of morphological evidences of p-p38MAPK and used different kind of models. "
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    ABSTRACT: 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.
    Neurochemistry International 01/2008; 51(8):459-66. DOI:10.1016/j.neuint.2007.04.028 · 3.09 Impact Factor
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    ABSTRACT: Exposure of one tissue to ischemia–reperfusion confers a systemic protective effect, referred to as remote ischemic preconditioning (RIPC). Confirmation that the desired effect of ischemia is occurring in tissues used to induce RIPC requires an objective demonstration before this technique can be used consistently in the clinical practice. Enrolled patients underwent three to four RIPC sessions on non-consecutive days. Sessions consisted of 4 cycles of 5 min of leg cuff inflation to 30 mmHg above the systolic blood pressure followed by reperfusion. Absence of leg pulse was confirmed by Doppler evaluation. To evaluate limb transient ischemia, patients were monitored with muscle microdialysis. Glucose, lactate, lactate/pyruvate ratio, and glycerol levels were measured. Fourteen microdialysis sessions were performed in seven patients undergoing RIPC (42.8 % male; mean age, 51.8; Fisher grade 4 in all seven patients, Hunt and Hess grade 5 in five patients, four in one patient and one in one patient). An average follow-up of 29 days demonstrated no complications associated with the procedure. Muscle microdialysis during RIPC sessions showed a significant increase in lactate/pyruvate ratio (21.2 to 26.8, p = 0.001) and lactate (3.0 to 3.9 mmol/L, p = 0.002), indicating muscle ischemia. There was no significant variation in glycerol (234 to 204 μg/L, p = 0.43), indicating no permanent cell damage. The RIPC protocol used in this study is safe, well tolerated, and induces transient metabolic changes consistent with sublethal ischemia. Muscle microdialysis can be used safely as a confirmatory tool in the induction of RIPC.
    06/2012; 3(2). DOI:10.1007/s12975-012-0153-1
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