Transient focal ischemia results in persistent and widespread neuroinflammation and loss of glutamate NMDA receptors

Medical Department, Brookhaven National Laboratory, Building 490, Upton, NY 11973, USA.
NeuroImage (Impact Factor: 6.36). 03/2010; 51(2):599-605. DOI: 10.1016/j.neuroimage.2010.02.073
Source: PubMed


Stroke is accompanied by neuroinflammation in humans and animal models. To examine the temporal and anatomical profile of neuroinflammation and NMDA receptors (NMDAR) in a stroke model, rats (N=17) were subjected to a 90 min occlusion of the middle cerebral artery (MCAO) and compared to sham (N=5) and intact (N=4) controls. Striatal and parietal cortical infarction was confirmed by MRI 24h after reperfusion. Animals were killed 14 or 30-40 days later and consecutive coronal cryostat sections were processed for quantitative autoradiography with the neuroinflammation marker [(3)H]PK11195 and the NMDAR antagonist [(3)H]MK801. Significantly increased specific binding of [(3)H]PK11195 relative to non-ischemic controls was observed in the ipsilateral striatum (>3 fold, p<0.0001), substantia innominata (>2 fold) with smaller (20%-80%) but statistically significant (p=0.002-0.04) ipsilateral increases in other regions partially involved in the infarct such as the parietal and piriform cortex, and in the lateral septum, which was not involved in the infarct. Trends for increases in PBR density were also observed in the contralateral hemisphere. In the same animals, NMDAR specific binding was significantly decreased bilaterally in the septum, substantia innominata and ventral pallidum. Significant decreases were also seen in the ipsilateral striatum, accumbens, frontal and parietal cortex. The different anatomical distribution of the two phenomena suggests that neuroinflammation does not cause the observed reduction in NMDAR, though loss of NMDAR may be locally augmented in ipsilateral regions with intense neuroinflammation. Persistent, bilateral loss of NMDAR, probably reflecting receptor down regulation and internalization, may be responsible for some of the effects of stroke on cognitive function which cannot be explained by infarction alone.

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Available from: Jasbeer Dhawan, Nov 25, 2014
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    • "Interestingly, the impaired neurogenesis and the cognitive decline in the aging hippocampus (Freret et al., 2009; Dhawan et al., 2010; Zvejniece et al., 2012) also accompany stroke (Dhawan et al., 2010; Wattanathorn et al., 2011; Zvejniece et al., 2012). Whereas our cognitive test results did not show any difference in learning performance between the transplanted and vehicleinfused stroke animals, the AFS cell-transplanted stroke animals demonstrated a significantly improved reference memory compared to the vehicle-infused stroke animals. "
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    Frontiers in Cellular Neuroscience 08/2014; 8:227. DOI:10.3389/fncel.2014.00227 · 4.29 Impact Factor
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    • "Microglia are resident macrophages within the central nervous system and are responsible for the majority of inflammatory activity in the brain [4]. When microglia detect invading pathogens or tissue injury, they become 'activated', and start proliferating, migrating, phagocytizing, and producing proinflammatory cytokines and oxidants, leading to neuronal damage [2] [3] [5]. Cold-inducible RNA-binding protein (CIRP) is the first identified cold shock protein in mammalian cells. "
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    ABSTRACT: Background Neuroinflammation is a key cascade after cerebral ischemia. Excessive production of proinflammatory mediators in ischemia exacerbates brain injury. Cold-inducible RNA- binding protein (CIRP) is a newly discovered proinflammatory mediator that can be released into the circulation during hemorrhage or septic shock. Here, we examine the involvement of CIRP in brain injury during ischemic stroke. Methods Stroke was induced by middle cerebral artery occlusion (MCAO). In vitro hypoxia was conducted in a hypoxia chamber containing 1% oxygen. CIRP and tumor necrosis factor-α (TNF-α) levels were assessed by RT-PCR and Western blot analysis. Results CIRP is elevated along with an upregulation of TNF-α expression in mouse brain after MCAO. In CIRP-deficient mice, the brain infarct volume, induction of TNF-α, and activation of microglia are markedly reduced after MCAO. Using microglial BV2 cells, we demonstrate that hypoxia induces the expression, translocation, and release of CIRP, which is associated with an increase of TNF-α levels. Addition of recombinant murine (rm) CIRP directly induces TNF-α release from BV2 cells and such induction is inhibited by neutralizing antisera to CIRP. Moreover, rmCIRP activates the NF-κB signaling pathway in BV2 cells. The conditioned medium from BV2 cells exposed to hypoxia triggers the apoptotic cascade by increasing caspase activity and decreasing Bcl-2 expression in neural SH-SY5Y cells, which is inhibited by antisera to CIRP. Conclusion Extracellular CIRP is a detrimental factor in stimulating inflammation to cause neuronal damage in cerebral ischemia. General significance Development of an anti-CIRP therapy may benefit patients with brain ischemia.
    Biochimica et Biophysica Acta (BBA) - General Subjects 07/2014; 1840(7). DOI:10.1016/j.bbagen.2014.02.027 · 4.38 Impact Factor
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    • "[ 3 H] PK11195 binding in the hippocampus after treatment with lipopolysaccharide has been reported to increase to 152% in mice (Liraz-Zaltsman et al., 2011). On the other hand, the maximum increase of [ 3 H]PK11195 binding in and around the infarct area was 320% of the non-ischemic side in rats subjected to occlusion of the middle cerebral artery (Dhawan et al., 2010). These previous findings suggest that the intensity of [ 3 H]PK11195 enhancement in the spinal cord in neuropathic pain rats was comparable to that of neuroinflammation by LPS or stroke. "
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    ABSTRACT: The role of glial activation has been implicated in the development and persistence of neuropathic pain after nerve injury by recent studies. PK11195 binding to the translocator protein 18 kDa (TSPO) has been shown to be enhanced in activated microglia. This study was designed to assess PK11195 imaging in spinal microglia during activation after nerve injury. The development of neuropathic pain was induced by partial sciatic nerve ligation (PSL). PSL rats on day 7 and 14 after nerve injury were subjected to imaging with a small-animal positron emission tomography/computed tomography (PET/CT) scanner using [(11)C]PK11195 to detect spinal microglial activation by means of noninvasive in vivo imaging. Spinal [(3)H]PK11195 autoradiography was performed to confirm the results of [(11)C]PK11195 PET in PSL rats. Quantitative RT-PCR of CD11b and GFAP mRNA, and the immunohistochemistry of Iba1 and GFAP were investigated to detect activated microglia and astrocytes. Mechanical allodynia was observed in the ipsilateral paw of PSL rats from day 3 after nerve injury and stably persisted from day 7 to 14. PET/CT fusion images clearly showed large amounts of accumulation of [(11)C]PK11195 in the lumbar spinal cord on day 7 and 14 after nerve injury. [(11)C]PK11195 enhanced images were restricted to the L3-L6 area of the spinal cord. The standardized uptake value (SUV) of [(11)C]PK11195 was significantly increased in the lumbar spinal cord compared to that of the thoracic region. Increased specific binding of [(11)C]PK11195 to TSPO in the spinal cord of PSL rats was confirmed by competition studies using unlabeled (R, S)-PK11195. Increased [(3)H]PK11195 binding was also observed in the ipsilateral dorsal horn of the L3-L6 spinal cord on day 7 and 14 after nerve injury. CD11b mRNA and Iba1 immunoreactive cells increased significantly on day 7 and 14 after nerve injury by PSL. However, changes in GFAP mRNA and immunoreactivity were slight in the ipsilateral side of PSL rats. In the present study, we showed that glial activation could be quantitatively imaged in the spinal cord of neuropathic pain rats using [(11)C]PK11195 PET, suggesting that high resolution PET using TSPO-specific radioligands might be useful for imaging to assess the role of glial activation, including neuroinflammatory processes, in neuropathic pain patients.
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