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A growing number of studies in humans have linked chronic stress, particularly during early life, to telomere shortening and increased oxidative stress. The effect of stress on telomerase activity, however, is understudied. Given the importance of telomere attrition in a wide range of diseases and immunosenescence, further research to elucidate the mechanisms by which stress alters telomere dynamics is required. However, animal studies are lacking, and it is not clear whether widely used stress models reliably mimic the accelerated telomere shortening observed humans. To this end, we evaluated the effect of maternal separation with early weaning (MSEW) on telomere length, telomerase activity, and oxidative load in rats. A total of 45 animals were used, (17 control: 3 males and 11 females and 28 MSEW: 11 males, 17 females), which were then sacrificed one year after birth. Importantly, we determined that telomerase activity measured in plasma was significantly decreased in the MSEW group, along with a non-significant reduction in telomere length from whole blood cells. We also examined the levels of three oxidative markers: plasma malondialdehyde, glutathione in erythrocytes, and plasma catalase activity. Malondialdehyde was found to be elevated in the plasma, indicating increased lipid peroxidation. Interestingly, while the antioxidant glutathione was upregulated, catalase activity remained unchanged. Our findings indicate that the rat MSEW model induces chronic changes to telomere dynamics and oxidative load and can capitulate long term aspects of human childhood stress. [ABSTRACT FROM AUTHOR]

Ameliorating blood–brain barrier disruption and altering scar formation dynamics are potential strategies that may improve post-stroke recovery. CD36 is a class B scavenger receptor that plays a role in innate immunity, inflammation and vascular dysfunction and regulates post-stroke injury, neovascularization, reactive astrogliosis and scar formation. By subjecting WT and CD36KO mice to different MCAo occlusion durations to generate comparable acute lesion sizes, we addressed the role of CD36 in BBB dysfunction, scar formation and recovery. The majority of stroke recovery studies primarily focus on motor function. Here, we employed an extensive behavioral test arsenal to evaluate psychological and cognitive endpoints. While not evident during the acute phase, CD36 deficient mice displayed significantly attenuated BBB leakage and scar formation at three months after stroke compared to wild-type littermates. Assessment of motor (open field, rotarod), anxiety (plus maze, light-dark box), depression (forced swim, sucrose preference) and memory tests (water maze) revealed that CD36 deficiency ameliorated stroke-induced behavioral impairments in activity, hedonic responses and spatial learning and strategy switching. Our findings indicate that CD36 contributes to stroke-induced BBB dysfunction and scar formation in an injury-independent manner, as well as to the chronic motor and neurophysiological deficits in chronic stroke. [ABSTRACT FROM AUTHOR]

Brain injury from stroke is typically considered an event exclusive to the CNS, but injury progression and repair processes are profoundly influenced by peripheral immunity. Stroke stimulates an acute inflammatory response that results in a massive infiltration of peripheral immune cells into the ischemic area. While these cells contribute to the development of brain injury, their recruitment has been considered as a key step for tissue repair. The paradoxical role of inflammatory monocytes in stroke raises the possibility that the manipulation of peripheral immune cells before infiltration into the brain could influence stroke outcome. One such manipulation is remote ischemic limb conditioning (RLC), which triggers an endogenous tolerance mechanism. We observed that mice subjected to poststroke RLC shifted circulating monocytes to a CCR2 + proinflammatory monocyte subset and had reduced acute brain injury, swelling, and improved motor/gait function in chronic stroke. The RLC benefits were observed regardless of injury severity, with a greater shift to a CCR2 1 subset in severe stroke. Adoptive transfer of CCR2-deficient monocytes abolished RLC-mediated protection. The study demonstrates the importance of RLC-induced shift of monocytes to a CCR2 + proinflammatory subset in attenuating acute injury and promoting functional recovery in chronic stroke. The defined immune-mediated mechanism underlying RLC benefits allows for an evidence-based framework for the development of immune-based therapeutic strategies for stroke patients. [ABSTRACT FROM AUTHOR]

The aim of this study was to explore the signaling and neuroprotective effect of transactivator of transcription (TAT) protein transduction of the apoptosis repressor with CARD (ARC) in in vitro and in vivo models of cerebral ischemia in mice. In mice, transient focal cerebral ischemia reduced endogenous ARC protein in neurons in the ischemic striatum at early reperfusion time points, and in primary neuronal cultures, RNA interference resulted in greater neuronal susceptibility to oxygen glucose deprivation (OGD). TAT.ARC protein delivery led to a dose-dependent better survival after OGD. Infarct sizes 72 h after 60 min middle cerebral artery occlusion (MCAo) were on average 30 ± 8% (mean ± SD; p = 0.005; T2-weighted MRI) smaller in TAT.ARC-treated mice (1 µg intraventricularly during MCAo) compared with controls. TAT.ARC-treated mice showed better performance in the pole test compared with TAT.β-Gal-treated controls. Importantly, post-stroke treatment (3 h after MCAo) was still effective in affording reduced lesion volume by 20 ± 7% (mean ± SD; p < 0.05) and better functional outcome compared with controls. Delayed treatment in mice subjected to 30 min MCAo led to sustained neuroprotection and functional behavior benefits for at least 28 d. Functionally, TAT.ARC treatment inhibited DAXX-ASK1-JNK signaling in the ischemic brain. ARC interacts with DAXX in a CARD-dependent manner to block DAXX trafficking and ASK1-JNK activation. Our work identifies for the first time ARC-DAXX binding to block ASK1-JNK activation as an ARC-specific endogenous mechanism that interferes with neuronal cell death and ischemic brain injury. Delayed delivery of TAT.ARC may present a promising target for stroke therapy. [ABSTRACT FROM AUTHOR]

A growing number of studies in humans have linked chronic stress, particularly during early life, to telomere shortening and increased oxidative stress. The effect of stress on telomerase activity, however, is understudied. Given the importance of telomere attrition in a wide range of diseases and immunosenescence, further research to elucidate the mechanisms by which stress alters telomere dynamics is required. However, animal studies are lacking, and it is not clear whether widely used stress models reliably mimic the accelerated telomere shortening observed humans. To this end, we evaluated the effect of maternal separation with early weaning (MSEW) on telomere length, telomerase activity, and oxidative load in rats. A total of 45 animals were used, (17 control: 3 males and 11 females and 28 MSEW: 11 males, 17 females), which were then sacrificed one year after birth. Importantly, we determined that telomerase activity measured in plasma was significantly decreased in the MSEW group, along with a non-significant reduction in telomere length from whole blood cells. We also examined the levels of three oxidative markers: plasma malondialdehyde, glutathione in erythrocytes, and plasma catalase activity. Malondialdehyde was found to be elevated in the plasma, indicating increased lipid peroxidation. Interestingly, while the antioxidant glutathione was upregulated, catalase activity remained unchanged. Our findings indicate that the rat MSEW model induces chronic changes to telomere dynamics and oxidative load and can capitulate long term aspects of human childhood stress.

Brain injury from stroke is typically considered an event exclusive to the CNS, but injury progression and repair processes are profoundly influenced by peripheral immunity. Stroke stimulates an acute inflammatory response that results in a massive infiltration of peripheral immune cells into the ischemic area. While these cells contribute to the development of brain injury, their recruitment has been considered as a key step for tissue repair. The paradoxical role of inflammatory monocytes in stroke raises the possibility that the manipulation of peripheral immune cells before infiltration into the brain could influence stroke outcome. One such manipulation is remote ischemic limb conditioning (RLC), which triggers an endogenous tolerance mechanism. We observed that mice subjected to poststroke RLC shifted circulating monocytes to a CCR2 + proinflammatory monocyte subset and had reduced acute brain injury, swelling, and improved motor/gait function in chronic stroke. The RLC benefits were observed regardless of injury severity, with a greater shift to a CCR2 + subset in severe stroke. Adoptive transfer of CCR2-deficient monocytes abolished RLC-mediated protection. The study demonstrates the importance of RLC-induced shift of monocytes to a CCR2 + proinflammatory subset in attenuating acute injury and promoting functional recovery in chronic stroke. The defined immune-mediated mechanism underlying RLC benefits allows for an evidence-based framework for the development of immune-based therapeutic strategies for stroke patients. SIGNIFICANCE STATEMENT Stroke is the leading cause of physical disability worldwide but has few treatment options for patients. Because remote ischemic limb conditioning (RLC) elicits endogenous tolerance in neither an organ- nor a tissue-specific manner, the immune system has been considered a mediator for an RLC-related benefit. Application of RLC after stroke increased a proinflammatory CCR2 + monocyte subset in the blood and the brain. RLC reduced acute stroke injury and promoted motor/gait function during the recovery phase. The RLC benefits were absent in mice that received CCR2-deficient monocytes. This preclinical study shows the importance of CCR2 + proinflammatory monocytes in RLC benefits in stroke and provides a therapeutic RLC platform as a novel immune strategy to improve outcomes in stroke patients., (Copyright © 2019 the authors.)