Article

Promoting axonal rewiring to improve outcome after stroke

Laboratories for Neuroscience Research in Neurosurgery and F.M. Kirby Neurobiology Program, Children's Hospital, USA.
Neurobiology of Disease (Impact Factor: 5.08). 11/2009; 37(2):259-66. DOI: 10.1016/j.nbd.2009.11.009
Source: PubMed

ABSTRACT

A limited amount of functional recovery commonly occurs in the weeks and months after stroke, and a number of studies show that such recovery is associated with changes in the brain's functional organization. Measures that augment this reorganization in a safe and effective way may therefore help improve outcome in stroke patients. Here we review some of the evidence for functional and anatomical reorganization under normal physiological conditions, along with strategies that augment these processes and improve outcome after brain injury in animal models. These strategies include counteracting inhibitors of axon growth associated with myelin, activating neurons' intrinsic growth state, enhancing physiological activity, and having behavioral therapy. These approaches represent a marked departure from the recent focus on neuroprotection and may provide a more effective way to improve outcome after stroke.

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Available from: S. Thomas Carmichael, Mar 11, 2014
    • "It is currently acknowledged that an ideal therapeutic intervention to decrease stroke-associated disability should comprise both neuroprotective and neurorestorative approaches implementing local spontaneous postinjury repair mechanisms. However, spontaneous repair is very limited and constrained with poor improvement of neurological outcome (Benowitz and Carmichael, 2010). Data accumulated so far provide evidence that not only neurons but also oligodendrocytes are vulnerable to ischemia (Dewar et al., 2003). "
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    ABSTRACT: Oligodendrocytes are the myelin-forming cells in the CNS. They enwrap axons, thus permitting fast impulse transmission and exerting trophic actions on neurons. Demyelination accompanied by neurological deficit is a rather frequent condition that is not only associated with multiple sclerosis but has been also recognized in several other neurodegenerative diseases, including brain trauma and stroke, Alzheimer's disease and amyotrophic lateral sclerosis. Recently, alterations of myelin function have been also reported in neuropsychiatric diseases, like depression and autism. Highly relevant for therapeutic purposes, oligodendrocyte precursor cells (OPCs) still persist in the adult brain and spinal cord. These cells are normally rather quiescent, but under specific circumstances, they can be stimulated to undergo differentiation and generate mature myelinating oligodendrocytes. Thus, approaches aimed at restoring myelin integrity and at fostering a correct oligodendrocyte function are now viewed as novel therapeutic opportunities for both neurodegenerative and neuropsychiatric diseases. Both OPCs and mature oligodendrocytes express purinergic receptors. For some of these receptors, expression is restricted at specific differentiation stages, suggesting key roles in OPCs maturation and myelination. Some of these receptors are altered under demyelinating conditions, suggesting that their disregulation may contribute to disease development and could represent adequate new targets for remyelinating therapies. Here, we shall describe the current literature available on all these receptors, with special emphasis on the P2Y-like GPR17 receptor, that represents one of the most studied receptor subtypes in these cells.
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    • "Compared to rodents, primates possess an evolutionally expanded volume of white matter, and white matter damage is a clinically important aspect of several CNS diseases, such as stroke or vascular dementia [39] [40] [41] [42] [43]. This may explain the reasons why many neuroprotectants (e.g. "
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    ABSTRACT: Oligodendrocytes, which are the main cell type in cerebral white matter, are generated from their precursor cells (oligodendrocyte precursor cells: OPCs). However, the differentiation from OPCs to oligodendrocytes is disturbed under stressed conditions. Therefore, drugs that can improve oligodendrocyte regeneration may be effective for white matter-related diseases. Here we show that a vasoactive peptide adrenomedullin (AM) promotes the in vitro differentiation of OPCs under pathological conditions. Primary OPCs were prepared from neonatal rat brains, and differentiated into myelin-basic-protein expressing oligodendrocytes over time. This in vitro OPC differentiation was inhibited by prolonged chemical hypoxic stress induced by non-lethal CoCl2 treatment. However, AM promoted the OPC differentiation under the hypoxic stress conditions, and the AM receptor antagonist AM22-52 canceled the AM-induced OPC differentiation. In addition, AM treatment increased the phosphorylation level of Akt in OPC cultures, and correspondingly, the PI3K/Akt inhibitor LY294002 blocked the AM-induced OPC differentiation. Taken together, AM treatment rescued OPC maturation under pathological conditions via an AM-receptor-PI3K/Akt pathway. Oligodendrocytes play critical roles in white matter by forming myelin sheath. Therefore, AM signaling may be a promising therapeutic target to boost oligodendrocyte regeneration in CNS disorders. Copyright © 2015. Published by Elsevier B.V.
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    • "However, recent studies demonstrate that inosine has neuroprotective, cardioprotective and immunomodulatory effects. Inosine increases neuronal survival and neurite outgrowth in vitro, enhances axon regeneration and axonal sprouting after damage of the central nervous system, and promotes recovery in rodent models of stroke and focal brain trauma123. Administration of inosine improves myocardial function during acute left ventricular failure and protects myocardial and endothelial function after heart transplantation45. Inosine also augments mast-cell degradation, suppresses macrophage, lymphocyte and neutrophil activation, and attenuates inflammatory diseases67. "
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    ABSTRACT: Inosine, a breakdown product of adenosine, has recently been shown to exert immunomodulatory and neuroprotective effects. We show here that the oral administration of inosine has antidepressant-like effects in two animal models. Inosine significantly enhanced neurite outgrowth and viability of primary cultured neocortical neurons, which was suppressed by adenosine A1 and A2A receptor agonists. Oral administration of inosine to mice transiently increased its concentration in the brain and enhanced neuronal proliferation in the dentate gyrus, accompanied by phosphorylation of mitogen-activated protein kinase and increase in transcript level of brain-derived neurotrophic factor. In stress models, oral inosine prevented an increase in immobility time in forced swim test after chronically unexpected stress and mitigated a reduction in sucrose preference after chronic social defeat stress. These results indicate that oral administration of inosine has the potential to prevent depressive disorder via adenosine receptors.
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