Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain

Merino, Paola; Yepes, Manuel

doi:10.17756/jnen.2018-039

Cited by 11 publications

(6 citation statements)

References 43 publications

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“…In brain, the protease/PAR axis appears to play significant roles in development and neurodegeneration (De Luca et al, ; Junge et al, ; Krenzlin, Lorenz, Danckwardt, Kempski, & Alessandri, ; Rohatgi et al, ; Xi, Reiser, & Keep, ). Recently another protease, urokinase, was shown to activate astrocytes, which then provided a neuroprotective effect (Diaz et al, ; Merino & Yepes, ), supporting our conceptual formulation.…”

Section: Discussionsupporting

confidence: 80%

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Rajput

Lamb

Kothari

et al. 2019

Glia

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Astrocytes protect neurons during cerebral injury through several postulated mechanisms. Recent therapeutic attention has focused on enhancing or augmenting the neuroprotective actions of astrocytes but in some instances astrocytes can assume a neurotoxic phenotype. The signaling mechanisms that drive astrocytes toward a protective versus toxic phenotype are not fully known but cell–cell signaling via proteases acting on cell‐specific receptors underlies critical mechanistic steps in neurodevelopment and disease. The protease activated receptor (PAR), resides in multiple brain cell types, and most PARs are found on astrocytes. We asked whether neuron‐generated thrombin constituted an important astrocyte activation signal because our previous studies have shown that neurons contain prothrombin gene and transcribed protein. We used neuron and astrocyte mono‐cell cultures exposed to oxygen‐glucose deprivation and a model of middle cerebral artery occlusion. We found that ischemic neurons secrete thrombin into culture media, which leads to astrocyte activation; such astrocyte activation can be reproduced with low doses of thrombin. Media from prothrombin‐deficient neurons failed to activate astrocytes and adding thrombin to such media restored activation. Astrocytes lacking PAR1 did not respond to neuron‐generated thrombin. Induced astrocyte activation was antagonized dose‐dependently with thrombin inhibitors or PAR1 antagonists. Ischemia‐induced astrocyte activation in vivo was inhibited after neuronal prothrombin knockout, resulting in larger strokes. Restoring prothrombin to neurons with a lentiviral gene vector restored astrocyte activation and reduced stroke damage. We conclude that neuron‐generated thrombin, released during ischemia, acts via PAR1 and may cause astrocyte activation and paracrine neuroprotection.

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Section: Discussionsupporting

confidence: 80%

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Rajput

Lamb

Kothari

et al. 2019

Glia

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“…Neuroprotection: expressed on microglia-phagocytosis of myelin debris [75] IGF-BP2 Neuronal plasticity, learning, and memory as well as information processing [76,77] uPA Neuroprotection and repair [78,79] AgRP Functional activity [80,81] repeated contact with multiple mice. Jugular vein cannulation and blood apheresis procedures were performed as previously published [18,21].…”

Section: Osteoactivinmentioning

confidence: 99%

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Mehdipour

Skinner

et al. 2020

GeroScience

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Our recent study has established that young blood factors are not causal, nor necessary, for the systemic rejuvenation of mammalian tissues. Instead, a procedure referred to as neutral blood exchange (NBE) that resets signaling milieu to a pro-regenerative state through dilution of old plasma, enhanced the health and repair of the muscle and liver, and promoted better hippocampal neurogenesis in 2-year-old mice (Mehdipour et al., Aging 12:8790–8819, 2020). Here we expand the rejuvenative phenotypes of NBE, focusing on the brain. Namely, our results demonstrate that old mice perform much better in novel object and novel texture (whisker discrimination) tests after a single NBE, which is accompanied by reduced neuroinflammation (less-activated CD68+ microglia). Evidence against attenuation/dilution of peripheral senescence-associated secretory phenotype (SASP) as the main mechanism behind NBE was that the senolytic ABT 263 had limited effects on neuroinflammation and did not enhance hippocampal neurogenesis in the old mice. Interestingly, peripherally acting ABT 263 and NBE both diminished SA-βGal signal in the old brain, demonstrating that peripheral senescence propagates to the brain, but NBE was more robustly rejuvenative than ABT 263, suggesting that rejuvenation was not simply by reducing senescence. Explaining the mechanism of the positive effects of NBE on the brain, our comparative proteomics analysis demonstrated that dilution of old blood plasma yields an increase in the determinants of brain maintenance and repair in mice and in people. These findings confirm the paradigm of rejuvenation through dilution of age-elevated systemic factors and extrapolate it to brain health and function.

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“…As increased suPAR levels reflect inflammation and are found to be associated with endothelial dysfunction, one could speculate that there is an association between suPAR levels and neuro-inflammation through endothelial cell dysfunction in the microvasculature of the brain [ 10 , 53 ] as well as impaired neuro repair [ 13 ].…”

Section: Discussionmentioning

confidence: 99%

Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms

et al. 2021

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Background There is evidence of increased low grade inflammation (LGI) in schizophrenia patients. However, the inter-individual variation is large and the association with demographic, somatic and psychiatric factors remains unclear. Our aim was to explore whether levels of the novel LGI marker soluble urokinase plasminogen activator receptor (suPAR) were associated with clinical factors in schizophrenia and if such associations were sex-dependent. Method In this observational study a total of 187 participants with schizophrenia (108 males, 79 females) underwent physical examination and assessment with clinical interviews (Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS), Alcohol Use Disorder Identification Test (AUDIT), and Drug Use Disorder Identification Test (DUDIT)). Blood levels of suPAR, glucose, lipids, and high sensitivity C-reactive protein (hsCRP) were determined and body mass index (BMI) calculated. Multivariable linear regression analyses were used adjusting for confounders, and sex interaction tested in significant variables. Results Adjusting for sex, age, current tobacco smoking and BMI, we found that levels of hsCRP and depressive symptoms (CDSS) were positively associated with levels of suPAR (p < 0.001). The association between suPAR and CDSS score was significant in females (p < 0.001) but not in males. Immune activation measured by hsCRP was not associated with depressive symptoms after adjusting for BMI. Conclusion Our findings indicate that increased suPAR levels are associated with depressive symptoms in females with schizophrenia, suggesting aberrant immune activation in this subgroup. Our results warrant further studies, including longitudinal follow-up of suPAR levels in schizophrenia and experimental studies of mechanisms.

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Urokinase-type Plasminogen Activator Induces Neurorepair in the Ischemic Brain

Cited by 11 publications

References 43 publications

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Neuron‐generated thrombin induces a protective astrocyte response via protease activated receptors

Plasma dilution improves cognition and attenuates neuroinflammation in old mice

Exploring low grade inflammation by soluble urokinase plasminogen activator receptor levels in schizophrenia: a sex-dependent association with depressive symptoms

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