CCL2 (C-C Motif Chemokine Ligand 2) Biomarker Responses in Central Versus Peripheral Compartments After Focal Cerebral Ischemia

Background and Purpose: Inflammatory mediators in blood have been proposed as potential biomarkers in stroke. However, a direct relationship between these circulating factors and brain-specific ischemic injury remains to be fully defined. Methods: An unbiased screen in a nonhuman primate model of stroke was used to find out the most responsive circulating biomarker flowing ischemic stroke. Then this phenomenon was checked in human beings and mice. Finally, we observed the temporospatial responsive characteristics of this biomarker after ischemic brain injury in mice to evaluate the direct relationship between this circulating factor and central nervous system–specific ischemic injury. Results: In a nonhuman primate model, an unbiased screen revealed CCL2 (C-C motif chemokine ligand 2) as a major response factor in plasma after stroke. In mouse models of focal cerebral ischemia, plasma levels of CCL2 showed a transient response, that is, rapidly elevated by 2 to 3 hours postischemia but then renormalized back to baseline levels by 24 hours. However, a different CCL2 temporal profile was observed in whole brain homogenate, cerebrospinal fluid, and isolated brain microvessels, with a progressive increase over 24 hours, demonstrating a mismatch between brain versus plasma responses. In contrast to the lack of correlation with central nervous system responses, 2 peripheral compartments showed transient profiles that matched circulating plasma signatures. CCL2 protein in lymph nodes and adipose tissue was significantly increased at 2 hours and renormalized by 24 hours. Conclusions: These findings may provide a cautionary tale for biomarker pursuits in plasma. Besides a direct central nervous system response, peripheral organs may also contribute to blood signatures in complex and indirect ways.

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Tacrolimus, a Potential Neuroprotective Agent, Ameliorates Ischemic Brain Damage and Neurologic Deficits after Focal Cerebral Ischemia in Nonhuman Primates

Journal of Cerebral Blood Flow & Metabolism ◽

10.1097/01.wcb.0000088761.02615.eb ◽

2003 ◽

Vol 23 (10) ◽

pp. 1183-1194 ◽

Cited By ~ 22

Author(s):

Yasuhisa Furuichi ◽

Masashi Maeda ◽

Akira Moriguchi ◽

Taiji Sawamoto ◽

Akio Kawamura ◽

...

Keyword(s):

Cerebral Infarction ◽

Nonhuman Primate ◽

Focal Cerebral Ischemia ◽

Sensory Function ◽

Neuroprotective Activity ◽

Nonhuman Primate Model ◽

Primate Model ◽

Neurologic Deficits ◽

Infarction Volume

Tacrolimus (FK506), an immunosuppressive drug, is known to have potent neuroprotective activity and attenuate cerebral infarction in experimental models of stroke. Here we assess the neuroprotective efficacy of tacrolimus in a nonhuman primate model of stroke, photochemically induced thrombotic occlusion of the middle cerebral artery (MCA) in cynomolgus monkeys. In the first experiment, tacrolimus (0.01, 0.032, or 0.1 mg/kg) was intravenously administered immediately after MCA occlusion, and neurologic deficits and cerebral infarction volumes were assessed 24 hours after the ischemic insult. Tacrolimus dose-dependently reduced neurologic deficits and infarction volume in the cerebral cortex, with statistically significant amelioration of neurologic deficits at 0.032 and 0.1 mg/kg and significant reduction of infarction at 0.1 mg/kg. In the second experiment, the long-term efficacy of tacrolimus on neurologic deficits and cerebral infarction was assessed. Vehicle-treated monkeys exhibited persistent and severe deficits in motor and sensory function for up to 28 days. A single intravenous bolus injection of tacrolimus (0.1 or 0.2 mg/kg) produced long-lasting amelioration of neurologic deficits and significant reduction of infarction volume. In conclusion, we have provided compelling evidence that a single dose of tacrolimus not only reduces brain infarction but also ameliorates long-term neurologic deficits in a nonhuman primate model of stroke, strengthening the view that tacrolimus might be beneficial in treating stroke patients.

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An atypical role for the myeloid receptor Mincle in CNS injury

10.1101/044602 ◽

2016 ◽

Author(s):

Thiruma V. Arumugam ◽

Silvia Manzanero ◽

Milena Furtado ◽

Patrick J. Biggins ◽

Yu-Hsuan Hsieh ◽

...

Keyword(s):

Central Nervous System ◽

Nervous System ◽

Cerebral Ischemia ◽

Functional Outcome ◽

Research Council ◽

Tissue Injury ◽

Focal Cerebral Ischemia ◽

Sterile Inflammation ◽

Peripheral Tissues ◽

The Brain

AbstractMincle is a C-type lectin known to play a role in innate immune responses to sterile inflammation, but its contribution to pathologies following an ischemic or traumatic injury is not well understood. In the current study we demonstrate a key role for Mincle in ischemic (i.e. transient middle cerebral artery occlusion) but not traumatic central nervous system injury; absence of Mincle also did not significantly alter the extent of tissue damage or functional outcome in peripheral models of ischemic tissue injury. In the stroke model mice lacking Mincle displayed significantly improved functional outcome from focal cerebral ischemia. The functional improvements in Mincle KO animals were accompanied by reduced infiltration of neutrophils and lower levels of proinflammatory cytokines in recruited peripheral blood cells. Bone marrow chimera experiments revealed that presence of Mincle in the central nervous system, but not peripheral immune cells, was the critical regulator of a poor outcome following transient focal cerebral ischemia, however we exclude a direct role for Mincle in microglia or neural activation. We demonstrate that Mincle lacks widespread expression in the brain, but is specifically associated with macrophages resident in the perivascular niche. These findings implicate Mincle in the initiation, extent and severity of local responses to ischemic injury in the brain, but not peripheral tissues. Mincle signalling therefore offers a novel therapeutic target in the quest to limit damage after stroke.Sources of support:Australian National Health & Medical Research Council [1057846, 1060538 and Fellowship to NAR], SpinalCure Australia (Career Development Fellowship to MJR), the Australian Research Council, the State Government of Victoria, the Australian Government and The University of Queensland.

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