Migration activity of microglia and macrophages into rat brain

Imai, Fumihiro; Sawada, Makoto; Suzuki, Hiromi; Kiya, Nobuo; Hayakawa, Motoharu; Nagatsu, Toshiharu; Marunouchi, Tohru; Kanno, Tetsuo

doi:10.1016/s0304-3940(97)00808-2

Cited by 37 publications

(23 citation statements)

References 18 publications

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“…After transient ischemia in Mongolian gerbils, exogenous microglia accumulated in ischemic lesion sites (hippocampal CA1) and expressed glial cell line-derived neurotrophic factor and brainderived neurotrophic factor (12,14). In the present study, although endogenous microglia accumulated in the ischemic core, massive neurodegeneration occurred, suggesting that the activation of only endogenous microglia may not be enough to protect against neurodegeneration.…”

contrasting

confidence: 55%

“…Recent studies have suggested that when microglia (1 -2´10 6 cells), macrophages (1 -2´10 6 cells) or bone marrow cells (1´10 7 cells) were peripherally injected, microglia (but not macrophages) migrated specifically to the brain parenchyma (12), and some populations of immature hematopoietic cells also reached the brain (13). After transient ischemia in Mongolian gerbils, exogenous microglia accumulated in ischemic lesion sites (hippocampal CA1) and expressed glial cell line-derived neurotrophic factor and brainderived neurotrophic factor (12,14).…”

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confidence: 99%

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Intracerebroventricular Injection of Microglia Protects Against Focal Brain Ischemia

et al. 2004

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Abstract. Microglia are macrophage-like phagocytic cells in the brain parenchyma. However, microglial function after neurodegeneration is not fully understood. In this study, occlusion of the middle cerebral artery (MCA) and reperfusion caused massive neuronal loss in the rat cerebral cortex and striatum after 3 days. When exogenous microglia were microinjected into the intracerebroventricle during MCA occlusion, neurodegenerative areas significantly decreased. At that time, migrated microglia were detected in the ischemic lesion. These results suggest that exogenous microglia can migrate into brain parenchyma and then protect against neurodegeneration induced by MCA occlusion and reperfusion.

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confidence: 55%

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confidence: 99%

Intracerebroventricular Injection of Microglia Protects Against Focal Brain Ischemia

et al. 2004

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“…Blood-borne macrophages and microglia may be among the best candidates, because they have the potential to cross the BBB and populate widely in the CNS and PNS (39). Development of such methods for enzyme delivery will benefit GLD and, potentially, other lysosomal storage diseases with severe CNS pathologies, such as Tay-Sachs and Sandhoff disease.…”

Section: Discussionmentioning

confidence: 99%

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

Kondo

Wenger

Gallo

et al. 2005

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

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Globoid cell leukodystrophy (GLD) is a lysosomal storage disease caused by genetic deficiency of galactocerebrosidase (GALC) activity. Failure in catalyzing the degradation of its major substrate, galactocerebroside, in oligodendrocytes (OLs) and Schwann cells leads to death of these myelinating cells, progressive demyelination, and early demise of GLD patients. Transplantation of bone marrow cells and umbilical cord blood have been attempted as a means of enzyme replacement and have shown limited success. It remains unknown whether or how these therapies support survival of GALC-deficient OLs and myelin maintenance. We report that, upon transplantation, GALC-deficient OLs from the twitcher mouse, a model of GLD, achieved widespread myelination in the brain and spinal cord of the myelin-deficient shiverer mouse, which was preserved for the life of the host. GALC immunohistochemistry showed direct evidence for GALC transfer from the shiverer environment to the engrafted mutant OLs in vivo. These findings suggest that the mutant OLs can internalize exogenous GALC and maintain stable myelin, demonstrating that exogenous enzyme replacement will be a key strategy in the therapy of GLD.enzyme replacement ͉ globoid cell leukodystrophy ͉ myelination ͉ transplantation ͉ lysosomal storage disease G loboid cell leukodystrophy (GLD, also called Krabbe's disease) (1) is a lysosomal storage disease caused by genetic deficiency of activity of a lysosomal enzyme galactocerebrosidase (GALC) that catalyzes the digestion of its major substrate galactocerebroside in myelinating oligodendrocytes (OLs) and Schwann cells (2). GLD is characterized pathologically by rapidly progressive demyelination of the CNS and peripheral nervous system (PNS) and accumulation of macrophages in the demyelinating lesions. The majority of GLD patients (infantile form) succumb to severe neurological symptoms in the first two years of life.Homozygous twitcher (GALC twi/twi ; twi) mice (3) have a genetic defect in GALC activity (4, 5), show progressive demyelination and accumulation of macrophages in the CNS and PNS, and rarely survive Ͼ45 days. These similarities to GLD have enabled the mouse to serve as a bona fide model to explore the pathophysiology and therapy of GLD (6). It has recently been shown that twi OLs can internalize exogenous GALC in vitro, resulting in their phenotypic correction (7), raising the possibility that in vivo enzyme replacement could be used to treat GLD. However, it is essential to evaluate the effect of enzyme replacement on OL function in vivo, because in vitro correction cannot unequivocally determine the myelinating capacity of the cell or the longevity. Therefore, the aim of this study was to determine whether twi OLs form and maintain normal myelin when GALC is provided exogenously in the CNS. In search of a method of enzyme replacement in vivo, we transplanted twi mutant oligodendrocyte progenitor cells (OPCs) into the brain and spinal cord of homozygous shiverer (shi) mice in which OLs do not form compact myelin sheath...

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“…Our previous studies showed that microglia isolated from rodent mixed-brain cultures retain the ability to enter the normal brain from the circulation (Imai et al, 1997(Imai et al, , 1999Sawada et al, 1998). Hence, microglia can be introduced into the central nervous system by injection into the bloodstream in animal models of neuronal injury.…”

Section: Introductionmentioning

confidence: 99%

Neuroprotective Effect of Exogenous Microglia in Global Brain Ischemia

Imai

Suzuki

Oda

et al. 2006

J Cereb Blood Flow Metab

189

125

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Exogenous microglia pass through the blood-brain barrier and migrate to ischemic hippocampal lesions when injected into the circulation. We investigated the effect of exogenous microglia on ischemic CA1 pyramidal neurons. Microglia were isolated from neonatal mixed brain cultures, labeled with the fluorescent dye PKH26, and injected into the subclavian artery of Mongolian gerbils subjected to ischemia reperfusion neuronal injury. PKH26-labeled microglia migrated to the ischemic hippocampal lesion, resulting in increased numbers of surviving neurons compared with control animals, even when injected 24 h after ischemia. Interferon-c stimulation of isolated microglia enhanced the neuroprotective effect. Administration of exogenous microglia resulted in normal performance in a passive avoidance-learning task. Additionally, administration of exogenous microglia increased the expression of brain-derived neurotrophic factor and glial cell line-derived neurotrophic factor in the ischemic hippocampus, and thus might have induced neurotrophin-dependent protective activity in damaged neurons. Peripherally injected microglia exhibited a specific affinity for ischemic brain lesions, and protected against ischemic neuronal injury in vivo. It is possible that administration of exogenous microglia can be developed as a potential candidate therapy for central nervous system repair after transitory global ischemia.

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Migration activity of microglia and macrophages into rat brain

Cited by 37 publications

References 18 publications

Intracerebroventricular Injection of Microglia Protects Against Focal Brain Ischemia

Intracerebroventricular Injection of Microglia Protects Against Focal Brain Ischemia

Galactocerebrosidase-deficient oligodendrocytes maintain stable central myelin by exogenous replacement of the missing enzyme in mice

Neuroprotective Effect of Exogenous Microglia in Global Brain Ischemia

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