Inhibition of Reactive Astrocytes with Fluorocitrate Retards Neurovascular Remodeling and Recovery after Focal Cerebral Ischemia in Mice

Hayakawa, Kazuhide; Nakano, Takafumi; Irie, Keiichi; Higuchi, Shunichi; Fujioka, Masayuki; Orito, Kensuke; Iwasaki, Katsunori; Jin, Guang; Lo, Eng H.; Mishima, Kenichi; Fujiwara, Michihiro

doi:10.1038/jcbfm.2009.257

Cited by 140 publications

(95 citation statements)

References 43 publications

(61 reference statements)

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“…Astrocytes are capable of secreting MMPs that disrupt the BBB, or releasing trophic factors that protect the BBB. During cerebral ischemia, pericapillary astrocyte end feet are the first cellular elements to swell [118], and MMPs and IL-1β released by astrocytes contribute to BBB disruption and vasogenic edema [119,120]. Astrocytes may also encourage angiogenesis [106] and regulate vascular tone [121], both processes crucial in restoring blood flow to infarcted tissues.…”

Section: Astrocytesmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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Ischemic preconditioning (IPC) is a robust neuroprotective phenomenon in which a brief period of cerebral ischemia confers transient tolerance to subsequent ischemic challenge. Research on IPC has implicated cellular, molecular, and systemic elements of the immune response in this phenomenon. Potent molecular mediators of IPC include innate immune signaling pathways such as Toll-like receptors and type 1 interferons. Brain ischemia results in release of proand anti-inflammatory cytokines and chemokines that orchestrate the neuroinflammtory response, resolution of inflammation, and transition to neurological recovery and regeneration. Cellular mediators of IPC include microglia, the resident central nervous system immune cells, astrocytes, and neurons. All of these cell types engage in cross-talk with each other using a multitude of signaling pathways that modulate activation/ suppression of each of the other cell types in response to ischemia. As the postischemic neuroimmune response evolves over time there is a shift in function toward provision of trophic support and neuroprotection. Peripheral immune cells infiltrate the central nervous system en masse after stroke and are largely detrimental, with a few subtypes having beneficial, protective effects, though the role of these immune cells in IPC is largely unknown. The role of neural progenitor cells in IPC-mediated neuroprotection is another active area of investigation as is the role of microglial proliferation in this setting. A mechanistic understanding of these molecular and cellular mediators of IPC may not only facilitate more effective direct application of IPC to specific clinical scenarios, but also, more broadly, reveal novel targets for therapeutic intervention in stroke.

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Section: Astrocytesmentioning

confidence: 99%

Neuroimmune Response in Ischemic Preconditioning

McDonough

Weinstein

2016

Neurotherapeutics

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“…It is well-known that stroke induces the activation of astrocytes to prevent immune cell invasion and to induce neurovascular remodeling. [32][33][34] Reactive astrocytes also are reported to show the progenitor markers Nestin, NG2, and Musashi-1 in the peri-infarct area. 25,35 Therefore, reactive astrocytes could play a key role in the recovery of function after stroke, although the relation between cell transplantation and reactive astrocytes is yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

Intra-arterial Cell Transplantation Provides Timing-Dependent Cell Distribution and Functional Recovery After Stroke

Ishizaka

Horie

Satoh

et al. 2013

Stroke

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Background and Purpose-Intra-arterial cell transplantation offers a novel therapeutic strategy for stroke; however, it remains unclear how the timing of cell administration affects cell distribution, brain repair processes, and functional recovery. Here, we investigate the hypothesis that the timing of cell transplantation changes the behavior of the cell graft and the host environment in a way that affects functional recovery. Methods-Rats received human mesenchymal stem cells via the internal carotid artery at 1, 4, or 7 days (D1, D4, or D7) after middle cerebral artery occlusion and reperfusion. Animals were euthanized at various time points to assess cell distribution, infiltration of activated microglia, expression of brain-derived neurotrophic factor, reactive astrocytes, angiogenesis, and functional recovery. Results-Human mesenchymal stem cells were widely distributed both in the peri-infarct and core in D1, and dominantly in the peri-infarct in D4. Very few cells were observed on D7. At day 7 poststroke, microglia activation was significantly suppressed in both the peri-infarct and core in D1, and predominantly in the peri-infarct in D4. At day 21 poststroke, brain-derived neurotrophic factor was widely distributed throughout the peri-infarct in D1 and D4, along with many reactive astrocytes and considerable angiogenesis. Motor function improved earlier in D1 and later in D4, but no recovery was obtained in D7. Conclusions-Our

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“…However, emerging studies suggest that glia suppress the invasion of immune cells into the peri-infarct region [22], suggesting that they are not only protecting neurons in the acute phase of cerebral ischemia, but also promoting neurogensis and angiogenesis in the chronic phase [23,24]. Reactive astrocytes in peri-ischemic cortex may promote neurovascular remodeling, which becomes useful for the functional recovery after stroke [25]. IA plays an important role in the structural repair of brain tissue after cerebral ischemia.…”

Section: Discussionmentioning

confidence: 99%