The penumbra is an area of brain tissue that is damaged but not yet dead after focal ischemia. The existence of a penumbra implies that therapeutic salvage is theoretically possible after stroke. The ...first decade of penumbral science investigated the ischemic regulation of electrophysiology, cerebral blood flow and metabolism. The second decade advanced our understanding of molecular mechanisms that mediate penumbral cell death. And the third decade saw the rapid development of clinical neuroimaging tools that are now increasingly applied in stroke patients. But how can we look ahead as we move into the fourth decade of penumbra research? This author speculates that a paradigm shift is needed. Most molecular targets for therapy have biphasic roles in stroke pathophysiology. During the acute phase, these targets mediate injury. During the recovery phase, the same mediators contribute to neurovascular remodeling. It is this boundary zone that comprises the new penumbra, and future investigations should dissect where, when and how damaged brain makes the transition from injury into repair.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Neurons can release damaged mitochondria and transfer them to astrocytes for disposal and recycling. This ability to exchange mitochondria may represent a potential mode of cell-to-cell signalling in ...the central nervous system. Here we show that astrocytes in mice can also release functional mitochondria that enter neurons. Astrocytic release of extracellular mitochondrial particles was mediated by a calcium-dependent mechanism involving CD38 and cyclic ADP ribose signalling. Transient focal cerebral ischaemia in mice induced entry of astrocytic mitochondria into adjacent neurons, and this entry amplified cell survival signals. Suppression of CD38 signalling by short interfering RNA reduced extracellular mitochondria transfer and worsened neurological outcomes. These findings suggest a new mitochondrial mechanism of neuroglial crosstalk that may contribute to endogenous neuroprotective and neurorecovery mechanisms after stroke.
This review focuses on mechanisms and emerging concepts that drive the science of stroke in a therapeutic direction. Once considered exclusively a disorder of blood vessels, growing evidence has led ...to the realization that the biological processes underlying stroke are driven by the interaction of neurons, glia, vascular cells, and matrix components, which actively participate in mechanisms of tissue injury and repair. As new targets are identified, new opportunities emerge that build on an appreciation of acute cellular events acting in a broader context of ongoing destructive, protective, and reparative processes. The burden of disease is great, and its magnitude widens as a role for blood vessels and stroke in vascular and nonvascular dementias becomes more clearly established. This review then poses a number of fundamental questions, the answers to which may generate new directions for research and possibly new treatments that could reduce the impact of this enormous economic and societal burden.
BACKGROUND AND PURPOSE:There is an urgent need to develop adjunct therapies that can be added onto reperfusion for acute ischemic stroke. Recently, mitochondrial transplantation has emerged as a ...promising therapeutic approach for boosting brain tissue protection. In this proof-of-concept study, we investigate the feasibility of using placenta as a source for mitochondrial transplantation in a mouse model of transient focal cerebral ischemia-reperfusion.
METHODS:Mitochondria-enriched fractions were isolated from cryopreserved mouse placenta. Mitochondrial purity and JC1 membrane potentials were assessed by flow cytometry. Adenosine triphosphate and mitochondrial proteins were measured by luminescence intensity and western blot, respectively. Therapeutic efficacy of mitochondrial fractions was assessed in a mouse model of transient focal cerebral ischemia-reperfusion.
RESULTS:Flow cytometry analysis demonstrated that about 87% of placental mitochondria were viable and maintained JC1 membrane potentials after isolation. Placental mitochondrial fractions contained adenosine triphosphate equivalent to mitochondrial fractions isolated from skeletal muscle and brown fat tissue. Normalized mitochondrial antioxidant enzymes (glutathione reductase, MnSOD manganese superoxide dismutase) and HSP70 (heat shock protein 70) were highly preserved in placental mitochondrial fractions. Treatment with placental mitochondrial fractions immediately after reperfusion significantly decreased infarction after focal cerebral ischemia in mice.
CONCLUSIONS:Cryopreserved placenta can be a feasible source for viable mitochondrial isolation. Transplantation with placental mitochondria may amplify beneficial effects of reperfusion in stroke.
Divergent disease triggers in neurodegeneration may induce convergent endogenous pathways in neuronal, glial and vascular elements as the central nervous system (CNS) attempts to compensate, remodel ...and recover. Dissecting these multicellular mechanisms and the integrative responses in cerebral blood flow and metabolism may allow us to understand the balance between injury and repair, validate new targets and define therapeutic time windows for neurodegeneration.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Self-preservation is required for life. At the cellular level, this fundamental principle is expressed in the form of molecular mechanisms for preconditioning and tolerance. When the cell is ...threatened, internal cascades of survival signaling become triggered to protect against cell death and defend against future insults. Recently, however, emerging findings suggest that this principle of self-preservation may involve not only intracellular signals; the release of extracellular signals may provide a way to recruit adjacent cells into an amplified protective program. In the central nervous system where multiple cell types co-exist, this mechanism would allow threatened neurons to "ask for help" from glial and vascular compartments. In this review, we describe this new concept of help-me signaling, wherein damaged or diseased neurons release signals that may shift glial and vascular cells into potentially beneficial phenotypes, and help remodel the neurovascular unit. Understanding and dissecting these non-cell autonomous mechanisms of self-preservation in the CNS may lead to novel opportunities for neuroprotection and neurorecovery.
We show that cerebral endothelial cells secrete trophic factors that support the survival and proliferation of rat oligodendrocyte precursor cells (OPCs). This OPC-supportive phenomenon was mediated ...by Akt and Src signaling pathways. Noncytotoxic levels of oxidative stress downregulate trophic factor production and disrupt the ability of cerebral endothelial cells to support OPCs. These data suggest that a novel oligovascular niche may be important for sustaining oligodendrocyte renewal and homeostasis in mammalian brain.
For efficient stroke recovery, the entire neurovascular unit must be repaired. A recent study underscores this concept by highlighting the importance of cellular crosstalk for white mater remodeling. ...In developing brains and in brains injured by hypoxia, interactions between oligodendrocyte precursors and endothelium play an essential role for physiological and compensatory angiogenesis. Further studies are warranted to build on these emerging findings in the oligovascular niche in order to identify novel therapeutic targets for stroke and other CNS diseases.
Astrocytes comprise the major non-neuronal cell population in the mammalian neurovascular unit. Traditionally, astrocytes are known to play broad roles in central nervous system (CNS) homeostasis, ...including the management of extracellular ion balance and pH, regulation of neurotransmission, and control of cerebral blood flow and metabolism. After CNS injury, cell⁻cell signaling between neuronal, glial, and vascular cells contribute to repair and recovery in the neurovascular unit. In this mini-review, we propose the idea that astrocytes play a central role in organizing these signals. During CNS recovery, reactive astrocytes communicate with almost all CNS cells and peripheral progenitors, resulting in the promotion of neurogenesis and angiogenesis, regulation of inflammatory response, and modulation of stem/progenitor response. Reciprocally, changes in neurons and vascular components of the remodeling brain should also influence astrocyte signaling. Therefore, understanding the complex and interdependent signaling pathways of reactive astrocytes after CNS injury may reveal fundamental mechanisms and targets for re-integrating the neurovascular unit and augmenting brain recovery.
BACKGROUND AND PURPOSE—Recent studies suggest that extracellular mitochondria may be involved in the pathophysiology of stroke. In this study, we assessed the functional relevance of endogenous ...extracellular mitochondria in cerebrospinal fluid (CSF) in rats and humans after subarachnoid hemorrhage (SAH).
METHODS—A standard rat model of SAH was used, where an intraluminal suture was used to perforate a cerebral artery, thus leading to blood extravasation into subarachnoid space. At 24 and 72 hours after SAH, neurological outcomes were measured, and the standard JC1 (5,5’,6,6’-tetrachloro-1,1’,3,3’-tetraethyl-benzimidazolylcarbocyanineiodide) assay was used to quantify mitochondrial membrane potentials in the CSF. To further support the rat model experiments, CSF samples were obtained from 41 patients with SAH and 27 control subjects. Mitochondrial membrane potentials were measured with the JC1 assay, and correlations with clinical outcomes were assessed at 3 months.
RESULTS—In the standard rat model of SAH, extracellular mitochondria was detected in CSF at 24 and 72 hours after injury. JC1 assays demonstrated that mitochondrial membrane potentials in CSF were decreased after SAH compared with sham-operated controls. In human CSF samples, extracellular mitochondria were also detected, and JC1 levels were also reduced after SAH. Furthermore, higher mitochondrial membrane potentials in the CSF were correlated with good clinical recovery at 3 months after SAH onset.
CONCLUSIONS—This proof-of-concept study suggests that extracellular mitochondria may provide a biomarker-like glimpse into brain integrity and recovery after injury.
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