Nasal Administration of Osteopontin Peptide Mimetics Confers Neuroprotection in Stroke

Doyle, Kristian P.; Yang, Tao; Lessov, Nikola; Ciesielski, Thomas; Stevens, Susan L.; Simon, Roger P.; King, Jeffrey S.; Stenzel-Poore, Mary P.

doi:10.1038/jcbfm.2008.17

Cited by 93 publications

(101 citation statements)

References 41 publications

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“…S1), indicating that the deficiency of Cryab affected both the early and delayed phases of ischemic damage. Functional outcome was assessed by a 28-point neurobehavioral scoring test (14,15). The Cryab −/− mice had significantly worse scores at both 2-d and 7-d time points compared with wild-type controls (Fig.…”

Section: Resultsmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

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Tissue plasminogen activator is the only treatment option for stroke victims; however, it has to be administered within 4.5 h after symptom onset, making its use very limited. This report describes a unique target for effective treatment of stroke, even 12 h after onset, by the administration of αB-crystallin (Cryab), an endogenous immunomodulatory neuroprotectant. In Cryab −/− mice, there was increased lesion size and diminished neurologic function after stroke compared with wild-type mice. Increased plasma Cryab was detected after experimental stroke in mice and after stroke in human patients. Administration of Cryab even 12 h after experimental stroke reduced both stroke volume and inflammatory cytokines associated with stroke pathology. Cryab is an endogenous anti-inflammatory and neuroprotectant molecule produced after stroke, whose beneficial properties can be augmented when administered therapeutically after stroke.

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Section: Resultsmentioning

confidence: 99%

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Arac

Brownell

Rothbard

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

128

View full text Add to dashboard Cite

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“…For intranasal administration, mice were administered CpG or vehicle in a total volume of 20 mL as described previously. 17 Temperature, weight, and general appearance were assessed in a subset of animals at 2, 7, 24, 48, and 72 hours after drug treatment via both routes of administration. There was no effect on temperature, weight, or sickness behavior in CpG treated animals compared with vehicle treated.…”

Section: Drug Treatmentsmentioning

confidence: 99%

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

Packard

Leung

Vartanian

et al. 2012

J Cereb Blood Flow Metab

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Systemic preconditioning with the TLR9 ligand CpG induces neuroprotection against brain ischemic injury through a tumor necrosis factor (TNF)-dependent mechanism. It is unclear how systemic administration of CpG engages the brain to induce the protective phenotype. To address this, we created TLR9-deficient reciprocal bone marrow chimeric mice lacking TLR9 on either hematopoietic cells or radiation-resistant cells of nonhematopoietic origin. We report that wild-type mice reconstituted with TLR9-deficient hematopoietic cells failed to show neuroprotection after systemic CpG preconditioning. Further, while hematopoietic expression of TLR9 is required for CpG-induced neuroprotection it is not sufficient to restore protection to TLR9-deficient mice that are reconstituted with hematopoietic cells bearing TLR9. To determine whether the absence of protection was associated with TNF, we examined TNF levels in the systemic circulation and the brain. We found that although TNF is required for CpG preconditioning, systemic TNF levels did not correlate with the protective phenotype. However, induction of cerebral TNF mRNA required expression of TLR9 on both hematopoietic and nonhematopoietic cells and correlated with neuroprotection. In accordance with these results, we show the therapeutic potential of intranasal CpG preconditioning, which induces brain TNF mRNA and robust neuroprotection with no concomitant increase in systemic levels of TNF.

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“…8,17 The role of OPN in CNS diseases remains controversial. OPN has been shown to be protective in models of stroke 17,20,21 and spinal cord contusion. 18 However, OPN inhibited axonal regeneration after injury in the optic nerve, 22 and the absence of the protein led to a better outcome in models of multiple sclerosis 19 and Parkinson's disease.…”

mentioning

confidence: 99%

Progressive Secondary Neurodegeneration and Microcalcification Co-Occur in Osteopontin-Deficient Mice

Maetzler

Berg

Funke

et al. 2010

The American Journal of Pathology

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In the brain, osteopontin (OPN) may function in a variety of pathological conditions, including neurodegeneration, microcalcification, and inflammation. In this study, we addressed the role of OPN in primary and secondary neurodegeneration, microcalcification, and inflammation after an excitotoxic lesion by examining OPN knock-out (KO) mice. Two, four, and ten weeks after injection of the glutamate analogue ibotenate into the corticostriatal boundary, the brains of 12 mice per survival time and strain were evaluated. OPN was detectable in neuron-shaped cells, in microglia, and at the surface of dense calcium deposits. At this primary lesion site, although the glial reaction was attenuated in OPN-KO mice, lesion size and presence of microcalcification were comparable between OPN-KO and wild-type mice. In contrast, secondary neurodegeneration at the thalamus was more prominent in OPN-KO mice, and this difference increased over time. This was paralleled by a dramatic rise in the regional extent of dense microcalcification. Despite these differences, the numbers of glial cells did not significantly differ between the two strains. This study demonstrates for the first time a genetic model with co-occurrence of neurodegeneration and microcalcification, mediated by the lack of OPN, and suggests a basic involvement of OPN action in these conditions. In the case of secondary retrograde or transneuronal degeneration, OPN may have a protective role as intracellular actor.

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Nasal Administration of Osteopontin Peptide Mimetics Confers Neuroprotection in Stroke

Cited by 93 publications

References 41 publications

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

Systemic augmentation of αB-crystallin provides therapeutic benefit twelve hours post-stroke onset via immune modulation

TLR9 Bone Marrow Chimeric Mice Define a Role for Cerebral TNF in Neuroprotection Induced by CpG Preconditioning

Progressive Secondary Neurodegeneration and Microcalcification Co-Occur in Osteopontin-Deficient Mice

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