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Cited by 333Stroke Rehabilitation and RecoveryAcute Ischemic Stroke ManagementNeuroinflammation and Neurodegeneration Mechanisms

Promoting brain remodelling and plasticity for stroke recovery: therapeutic promise and potential pitfalls of clinical translation

Open access
Hermann, Dirk M, Chopp, Michael·2012·The Lancet Neurology
DOI 10.1016/s1474-4422(12)70039-xPMC PMC3964179
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Abstract

Recent laboratory findings suggest that it might be possible to promote cerebral plasticity and neurological recovery after stroke by use of exogenous pharmacological or cell-based treatments. Brain microvasculature and glial cells respond in concert to ischaemic stressors and treatment, creating an environment in which successful recovery can ensue. Neurons remote from and adjacent to the ischaemic lesion are enabled to sprout, and neural precursor cells that accumulate with cerebral microvessels in the perilesional tissue further stimulate brain plasticity and neurological recovery. These factors interact in a highly dynamic way, facilitating temporally and spatially orchestrated responses of brain networks. In view of the complexity of the systems involved, stroke treatments that stimulate and amplify these endogenous restorative mechanisms might also provoke unwanted side-effects. In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows. Balancing the opportunities and possible risks, we provide suggestions for the translation of restorative therapies from the laboratory to the clinic.

Integrity signals

Registry

Crossref · 10.1016/s1474-4422(12)70039-x

Cites

102 of 102 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 233 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Axonal fibre tracts reorganise along the infarct rim after stroke.

    “Subsequently, axonal fibre tracts reorganise along the infarct rim.21,23”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [21] Li, 2009, MRI identification of white matter reorganization enhanced by erythropoietin treatment in a rat model of focal ischemia, Stroke source

      Not checked in the free run.

    • cites [23] Jiang, 2010, MRI evaluation of white matter recovery after brain injury, Stroke source

      Not checked in the free run.

  • Interpretationreasoning

    Because of the long therapeutic time window and lack of reperfusion requirement, neurorestorative therapies can potentially benefit all stroke patients.

    “In view of the long therapeutic time window and the fact that tissue reperfusion is not a requirement, neuro restorative therapies can potentially benefit all stroke patients.”
    Quote in the paperSubstantial claim
  • Premisenone given

    Brain microvasculature and glial cells respond together to ischaemic stressors and treatment, creating an environment that can support recovery.

    “Brain microvasculature and glial cells respond in concert to ischaemic stressors and treatment, creating an environment in which successful recovery can ensue.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Homologous fibres from the contralesional motor cortex grow across the midline to reach denervated neurons in target structures of the lesioned pyramidal tract.

    “Instead, homologous fibres originating from the contralesional motor cortex grow out across the midline to reach denervated neurons in target structures of the lesioned pyramidal tract (figure 1).10–12,15,17,19,24”
    Quote in the paperSubstantial claim0 of 7 sources checked
    • cites [10] Papadopoulos, 2002, Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat, Ann Neurol source

      Not checked in the free run.

    • cites [11] Wiessner, 2003, Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [12] Liu, 2008, Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment, Stroke source

      Not checked in the free run.

    • cites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

      Not checked in the free run.

    • cites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source

      Not checked in the free run.

    • cites [19] Reitmeir, 2011, Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity, Brain source

      Not checked in the free run.

    • cites [24] Reitmeir, 2012, Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain, Acta Neuropathol source

      Not checked in the free run.

  • Premisecitation

    Remodelling of transcallosal projections connecting the two motor cortices occurs after stroke.

    “In addition to the sprouting of pyramidal tract fibres, remodelling of transcallosal projections connecting the two motor cortices occurs.14,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Bacigaluppi, 2009, Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms, Brain source

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    • cites [25] Liu, 2010, Bone marrow stromal cells enhance inter- and intracortical axonal connections after ischemic stroke in adult rats, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • May combine two claims. 54
  • Classified as probably not a substantial claim. 9

  • May combine two claims.

    Premisecitation

    Brain capillaries sprout and glial cells are activated to create a favourable cerebral environment for neuronal growth and plasticity.

    “Additionally, brain capillaries sprout, and glial cells are activated to create a favourable cerebral environment for neuronal growth and plasticity.3,4”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [3] Zhang, 2009, Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic, Lancet Neurol source

      Not checked in the free run.

    • cites [4] Hermann, 2009, Implications of vascular endothelial growth factor for postischemic neurovascular remodeling, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Interpretationreasoning

    These factors interact dynamically to facilitate temporally and spatially orchestrated responses of brain networks.

    “These factors interact in a highly dynamic way, facilitating temporally and spatially orchestrated responses of brain networks.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Neurorestorative therapies target viable tissue with adequate and intact perfusion, whereas neuroprotective agents must be delivered to underperfused ischaemic injury sites.

    “Neuroprotective agents must be delivered to the site of ischaemic injury, which by definition includes tissue that is highly underperfused. Neurorestorative therapies target viable tissue with adequate and intact perfusion.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Many endogenous restorative responses, including neuronal plasticity, neurogenesis, and angiogenesis, can be targeted with pharmacological or cell-based treatments to stimulate neurological recovery after stroke.

    “Many endogenous restorative responses, including neuronal plasticity, neurogenesis, and angiogenesis, can be targeted with pharmacological or cell-based treatments to stimulate neurological recovery after stroke.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Treatments promoting neurological recovery by remodelling brain tissue can be instituted during the stroke recovery phase, unlike neuroprotection which requires acute intervention.

    “By contrast with neuroprotection, which requires an acute intervention, treatments promoting neurological recovery by remodelling of brain tissue can be instituted during the stroke recovery phase.10–15”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [10] Papadopoulos, 2002, Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat, Ann Neurol source

      Not checked in the free run.

    • cites [11] Wiessner, 2003, Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [12] Liu, 2008, Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment, Stroke source

      Not checked in the free run.

    • cites [13] Kilic, 2008, Delayed melatonin administration promotes neuronal survival, neurogenesis and motor recovery, and attenuates hyperactivity and anxiety after mild focal cerebral ischemia in mice, J Pineal Res source

      Not checked in the free run.

    • cites [14] Bacigaluppi, 2009, Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms, Brain source

      Not checked in the free run.

    • cites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A crucial time window opens in the post-acute ischaemic phase, characterised by intense neuronal sprouting, despite active inhibition of neuronal plasticity in adulthood.

    “While neuronal plasticity is actively inhibited during adulthood, a crucial time window opens in the post-acute ischaemic phase that is characterised by intense neuronal sprouting.1,2”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Carmichael, 2006, Cellular and molecular mechanisms of neural repair after stroke: making waves, Ann Neurol source

      Not checked in the free run.

    • cites [2] Murphy, 2009, Plasticity during stroke recovery: from synapse to behaviour, Nat Rev Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    In experimental studies, adverse effects occurred when neurorestorative treatments were given to animals with severe associated illnesses, after alteplase thrombolysis, or outside appropriate time windows.

    “In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Stroke induces anterograde Wallerian degeneration of pyramidal tract axons, with degree depending on severity of ischaemic insult.

    “Stroke induces anterograde Wallerian degeneration of pyramidal tract axons, the degree of which depends on the severity of the ischaemic insult (figure 1).19,21,22”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [19] Reitmeir, 2011, Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity, Brain source

      Not checked in the free run.

    • cites [21] Li, 2009, MRI identification of white matter reorganization enhanced by erythropoietin treatment in a rat model of focal ischemia, Stroke source

      Not checked in the free run.

    • cites [22] Liu, 2009, Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Neural precursor cells accumulate with cerebral microvessels in perilesional tissue and further stimulate brain plasticity and neurological recovery.

    “Neurons remote from and adjacent to the ischaemic lesion are enabled to sprout, and neural precursor cells that accumulate with cerebral microvessels in the perilesional tissue further stimulate brain plasticity and neurological recovery.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Neurogenesis is stimulated in response to stroke and is substantially amplified by therapeutic interventions that promote functional recovery.

    “Neurogenesis is stimulated in response to stroke and is substantially amplified by therapeutic interventions that promote functional recovery.33–36”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [33] Zhang, 2006, Delayed treatment with sildenafil enhances neurogenesis and improves functional recovery in aged rats after focal cerebral ischemia, J Neurosci Res source

      Not checked in the free run.

    • cites [34] Zhang, 2001, Proliferation and differentiation of progenitor cells in the cortex and the subventricular zone in the adult rat after focal cerebral ischemia, Neuroscience source

      Not checked in the free run.

    • cites [35] Arvidsson, 2002, Neuronal replacement from endogenous precursors in the adult brain after stroke, Nat Med source

      Not checked in the free run.

    • cites [36] Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Microvessels and neuroblasts mutually support each other via release of trophic factors, resulting in a tight interplay that stimulates brain remodelling, reduces delayed neuronal degeneration, promotes neuronal plasticity, modulates glial responses, and attenuates brain inflammation.

    “Microvessels and neuroblasts mutually support each other via release of trophic factors, resulting in a tight interplay that stimulates brain remodelling processes, reducing delayed neuronal degeneration,14,45 promoting neuronal plasticity,15 modulating glial responses,14,46 and attenuating brain inflammation14,46 (figure 2).”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [14] Bacigaluppi, 2009, Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms, Brain source

      Not checked in the free run.

    • cites [45] Teng, 2008, Coupling of angiogenesis and neurogenesis in cultured endothelial cells and neural progenitor cells after stroke, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

      Not checked in the free run.

    • cites [46] Lee, 2008, Antiinflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The survival rate of adult neural precursor cells in brain parenchyma is poor, and only a small percentage differentiate into neurons.

    “The survival rate of adult neural precursor cells in the brain parenchyma is poor and only a small percentage of the cells differentiate into neurons.35,39–42”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [35] Arvidsson, 2002, Neuronal replacement from endogenous precursors in the adult brain after stroke, Nat Med source

      Not checked in the free run.

    • cites [39] Zhang, 2004, Stroke transiently increases subventricular zone cell division from asymmetric to symmetric and increases neuronal differentiation in the adult rat, J Neurosci source

      Not checked in the free run.

    • cites [40] Bacigaluppi, 2008, Neural stem/precursor cells for the treatment of ischemic stroke, J Neurol Sci source

      Not checked in the free run.

    • cites [41] Zhang, 2011, Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [42] Doeppner, 2011, Acute hepatocyte growth factor treatment induces long-term neuroprotection and stroke recovery via mechanisms involving neural precursor cell proliferation and differentiation, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    VEGF acting through VEGFR2 induces endothelial proliferation and concurrently upregulates delta-like ligand 4, which signals to microvascular cells in the capillary stalk to downregulate VEGFR2 via Notch 1, preventing uncontrolled capillary sprouting.

    “Acting through VEGF receptor 2 (VEGFR2), which is localised at high concentrations at the tip of newly formed capillaries, VEGF induces endothelial proliferation,4,47–49 and concur rently upregulates the transmembrane ligand delta-like ligand 4, which signals to microvascular cells in the capillary stalk, to downregulate VEGFR2 via interaction with its receptor Notch 1, thus pre venting uncontroll”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [4] Hermann, 2009, Implications of vascular endothelial growth factor for postischemic neurovascular remodeling, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [47] Forsythe, 1996, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Mol Cell Biol source

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    • cites [48] Marti, 2000, Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia, Am J Pathol source

      Not checked in the free run.

    • cites [49] Wang, 2005, VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena, Brain source

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    • cites [51] Ridgway, 2006, Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis, Nature source

      Not checked in the free run.

    • cites [52] Hellström, 2007, Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After stroke, neural precursor cells proliferate and migrate toward the ischaemic lesion, propagating in chains along blood vessels.

    “When a stroke occurs, these cells proliferate and migrate in the direction of the ischaemic lesion, propagating in chains along blood vessels.37,38”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [37] Thored, 2007, Long-term neuroblast migration along blood vessels in an area with transient angiogenesis and increased vascularization after stroke, Stroke source

      Not checked in the free run.

    • cites [38] Zhang, 2009, Patterns and dynamics of subventricular zone neuroblast migration in the ischemic striatum of the adult mouse, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This lesion-remote plasticity involves midline crossing of fibres from contralesional to ipsilesional hemisphere at the red nucleus and re-entry into contralesional hemicord at cervical spinal cord.

    “This lesion-remote plasticity involves the midline crossing of fibres from the contralesional to the ipsilesional hemisphere at the level of the red nucleus10,17,19,24 and the re-entry of fibres into the contralesional hemicord at the level of the cervical spinal cord (figure 1).11,12,15”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [10] Papadopoulos, 2002, Functional recovery and neuroanatomical plasticity following middle cerebral artery occlusion and IN-1 antibody treatment in the adult rat, Ann Neurol source

      Not checked in the free run.

    • cites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source

      Not checked in the free run.

    • cites [19] Reitmeir, 2011, Post-acute delivery of erythropoietin induces stroke recovery by promoting perilesional tissue remodelling and contralesional pyramidal tract plasticity, Brain source

      Not checked in the free run.

    • cites [24] Reitmeir, 2012, Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain, Acta Neuropathol source

      Not checked in the free run.

    • cites [11] Wiessner, 2003, Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats, J Cereb Blood Flow Metab source

      Not checked in the free run.

    • cites [12] Liu, 2008, Contralesional axonal remodeling of the corticospinal system in adult rats after stroke and bone marrow stromal cell treatment, Stroke source

      Not checked in the free run.

    • cites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    AMPA receptor antagonists impair neurological outcome, as does blockade of BDNF by TrkB-Fc-impregnated hydrogel.

    “AMPA receptor antagonists impair neurological outcome, as does blockade of BDNF by TrkB-Fc-impregnated hydrogel.75”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [75] Clarkson, 2011, AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In peri-infarct cortex of the lesioned hemisphere, tonic inhibition of layer 2/3 pyramidal neurons is present from 3-14 days after stroke and is mediated by extrasynaptic GABA_A receptors.

    “In the peri-infarct cortex of the lesioned hemisphere, tonic inhibition of layer 2/3 pyramidal neurons was present from 3–14 days after stroke and was mediated by extrasynaptic GABAA receptors.74”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Clarkson, 2010, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After focal cerebral ischaemia, astrocytes de novo express neurotrophic factors such as GDNF and VEGF, and serine proteases such as tPA, in parallel with downregulation of growth-repulsive proteoglycans.

    “Subsequent to focal cerebral ischaemia, and in parallel to the downregulation of growth-repulsive proteoglycans, astrocytes de novo express neurotrophic factors, such as glial-cell-line-derived neurotrophic factor (GDNF)66 and VEGF,67 and serine proteases, namely tissue plasminogen activator (tPA).68”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Shen, 2010, Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats, Glia source

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    • cites [67] Zacharek, 2007, Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke, J Cereb Blood Flow Metab source

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    • cites [68] Xin, 2010, Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse, PLoS One source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    From a systems biological perspective, an intervention that modulates endogenous restorative responses such as axonal growth, neurogenesis, and angiogenesis will probably alter tissue homoeostasis and could lead to adverse side-effects.

    “From a systems biological perspective, an intervention that modulates endogenous restorative responses, such as axonal growth, neurogenesis, and angiogenesis, will probably alter tissue homoeostasis and could lead to adverse side-effects.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S2 (checkable).

    Interpretationreasoning

    Understanding of this could allow development of rehabilitation strategies to reinforce effects of neurorestorative therapies.

    “The continuous rehearsal of activation patterns provides the basis for temporally and spatially organised axonal growth (figure 3), an understanding of which could allow the development of rehabilitation strategies to reinforce the effects of neurorestorative therapies.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Astrocytes remove excitatory neurotransmitters and electrolytes from extracellular space, controlling neuronal excitability and enabling synaptic plasticity.

    “Astrocytes also remove excitatory neurotransmitters (eg, glutamate) and electrolytes (eg, potassium) from the extracellular space, thus controlling neuronal excitability and enabling synaptic plasticity.62”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [62] Pannasch, 2011, Astroglial networks scale synaptic activity and plasticity, Proc Natl Acad Sci USA source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells further increases levels of GDNF and tPA and reduces levels of tPA inhibitor PAI-1.

    “Delivery of bone-marrow-derived stromal cells or mesenchymal stromal cells was shown to further increase levels of GDNF66 and tPA68,69 and reduce levels of the tPA inhibitor plasminogen activator inhibitor 1.70”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [66] Shen, 2010, Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats, Glia source

      Not checked in the free run.

    • cites [68] Xin, 2010, Increasing tPA activity in astrocytes induced by multipotent mesenchymal stromal cells facilitate neurite outgrowth after stroke in the mouse, PLoS One source

      Not checked in the free run.

    • cites [69] Shen, 2011, Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice, Stroke source

      Not checked in the free run.

    • cites [70] Xin, 2011, Multipotent mesenchymal stromal cells increase tPA expression and concomitantly decrease PAI-1 expression in astrocytes through the sonic hedgehog signaling pathway after stroke (in vitro study), J Cereb Blood Flow Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Glial cells, especially astrocytes, control brain homoeostasis and create a microenvironment for successful brain remodelling.

    “Glial cells, especially astrocytes, control brain homoeostasis and create a microenvironment for successful brain remodelling.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Premisenone given

    Neuronal activity induces temporally and spatially tuned responses in the brain.

    “Neuronal activity induces temporally and spatially tuned responses in the brain (figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationcitation

    Age affects not only neuronal sprouting but also neurogenesis and angiogenesis.

    “An effect of age was not only seen for neuronal sprouting, but also for neurogenesis and angiogenesis.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    Astrocytes and oligodendrocytes provide basic trophic support independent of brain region or surrounding neuronal populations, setting the stage for brain plasticity.

    “Astrocytes and oligodendrocytes provide basic trophic support that is independent of brain region or surrounding neuronal populations, thus setting the stage for brain plasticity processes (figure 3).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    A pharmacological antagonist of GABA_A receptor α5 subunit prevented excessive inhibition, as did genetic deletion of GABA_A receptor α5 or δ subunits, and improved stroke recovery.

    “A pharmacological antagonist of the GABAA receptor α5 subunit prevented the excessive inhibition, as did genetic deletion of the GABAA receptor α5 or δ subunits, and improved stroke recovery.74”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [74] Clarkson, 2010, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke, Nature source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Aged rats can respond to plasticity-promoting treatments, though age may influence some processes that neurorestorative interventions target.

    “Aged rats respond to plasticity-promoting therapies, but age might have an effect on some of the processes targeted by neurorestorative interventions.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source

      Not checked in the free run.

    • cites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source

      Not checked in the free run.

    • cites [76] Zhang, 2005, Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor, Stroke source

      Not checked in the free run.

    • Rests on an assumption: Stroke occurs mainly in later life.

  • May combine two claims.

    Premisecitation

    In aged rats with ischaemia, treatment with anti-NogoA antibodies, pharmacological compounds, or bone-marrow-derived stromal cells improved neurological recovery and was linked to preservation of ipsilateral pyramidal tract axons and enhanced contralateral pyramidal tract sprouting.

    “Improved neurological recovery associated with preservation of pyramidal tract axons ipsilateral to the stroke and enhanced pyramidal tract sprouting contralateral to the stroke was identified in 25-month-old or 12-month-old rats with ischaemia treated with neutralising anti-NogoA antibodies,17 pharmacological compounds, 76 or bone-marrow-derived stromal cells.26”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source

      Not checked in the free run.

    • cites [76] Zhang, 2005, Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor, Stroke source

      Not checked in the free run.

    • cites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After focal cerebral ischaemia, de novo neuron generation in ischaemic striatum was similar in 15-month-old and 3-month-old rats, but neurogenesis was decreased in dentate gyrus of 15-month-old rats.

    “Although the de novo generation of neurons in the ischaemic striatum was very similar in both groups, neurogenesis was decreased in the dentate gyrus of 15-month-old rats when exposed to focal cerebral ischemia.78”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [78] Darsalia, 2005, Stroke-induced neurogenesis in aged brain, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    New vessel formation has roles in ischaemic brain remodelling after stroke independent of blood flow, and angiogenesis contributes substantively to stroke recovery.

    “Studies on angiogenesis suggest that new vessel formation has roles in ischaemic brain remodelling after stroke that are independent of blood flow, and that angiogenesis contributes to stroke recovery in a substantive way.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In old rats (24 months), anti-NogoA antibodies did not affect dendritic and synaptic plasticity of hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells, yet spatial memory improved.

    “Although neurological recovery was successful, dendritic and synaptic plasticity of hippocampal CA3 and CA1 pyramidal and dentate gyrus granule cells was not influenced by anti-NogoA antibodies in old rats (24 months of age), yet improvements in spatial memory were reported.77”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Gillani, 2010, Cognitive recovery in the aged rat after stroke and anti-Nogo-A immunotherapy, Behav Brain Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the rat somatosensory whisker barrel field, ATRX protein contributes to formation of axonal growth cones, which are stabilised by IGF1.

    “In the rat somatosensory whisker barrel field, the ATP-dependent DNA-modifying enzyme α-thalassaemia/mental retardation syndrome X-linked (ATRX) protein, which controls neuronal survival and migration during brain development, contributes to the formation of axonal growth cones, which are stabilised by insulin-like growth factor 1.72”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Li, 2010, An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke, Nat Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated protein C enhances neurovascular interplay by stimulating endothelial proliferation and tube formation and inducing proliferation and migration of neural precursor cells via PAR1.

    “The serine protease activated protein C enhances this neurovascular interplay, stimulating endothelial proliferation and tube formation60 and inducing proliferation and migration of neural precursor cells61 via protease-activated receptor 1.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Uchiba, 2004, Activated protein C induces endothelial cell proliferation by mitogen-activated protein kinase activation in vitro and angiogenesis in vivo, Circ Res source

      Not checked in the free run.

    • cites [61] Thiyagarajan, 2008, Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease–activated receptor 1, J Neurosci source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In histochemical studies, bone-marrow-derived stromal cells exacerbated neointima formation and arteriole narrowing and increased macrophage accumulation in blood vessels of rats with diabetes.

    “In histo chemical studies, neointima formation and arteriole narrowing were exacerbated by bone-marrow-derived stromal cells in rats with diabetes, as was macrophage accumulation in blood vessels.80”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CD95 activation promotes survival and differentiation of neural precursor cells, resulting in enhanced recovery of working memory in mice with global cerebral ischaemia.

    “Instead, CD95 activation was shown to promote survival and differentiation of neural precursor cells, resulting in enhanced recovery of working memory in mice with global cerebral ischaemia.97”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [97] Corsini, 2009, The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair, Cell Stem Cell source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In cerebral endothelial cell culture, eNOS inhibition or Tie2 knockdown reduced the effects of vitamin B3 on capillary tube formation, showing a role for eNOS and angiopoietin 1 in the beneficial effects of HDL elevation.

    “In cerebral endothelial cell culture, the effects of vitamin B3 on capillary tube formation were reduced after eNOS inhibition or Tie2 knockdown,85 showing a role for eNOS and angiopoietin 1 in the beneficial effects of the high-density lipoprotein elevation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Chen, 2007, Niaspan increases angiogenesis and improves functional recovery after stroke, Ann Neurol source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    Neurons, cerebral microvascular cells, and glial cells respond synergistically to therapeutic interventions, creating an environment in which successful recovery can take place.

    “Neurons, cerebral microvascular cells, and glial cells respond synergistically to therapeutic interventions, creating an environment in which successful recovery can take place.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    In rats with cerebral ischaemia, vitamin B3 administration, which raises HDL and lowers serum cholesterol, increased angiogenesis, VEGF and angiopoietin 1 expression, and phosphorylation of eNOS and Tie2, improving neurological recovery.

    “In rats with cerebral ischaemia, vitamin B3 administration, which elevates high-density lipoprotein and thereby reduces serum cholesterol, increased angiogenesis, the expression of VEGF and angiopoietin 1, and enhanced the phosphorylation (ie, activation) of eNOS and the angiopoietin-1 receptor Tie2, thus improving neurological recovery.85”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [85] Chen, 2007, Niaspan increases angiogenesis and improves functional recovery after stroke, Ann Neurol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After focal cerebral ischaemia in rats, vitamin B3 increased HDL concentrations, enhanced white matter remodelling in peri-infarct tissue, increased BDNF and TrkB levels, and downregulated Nogo-receptor levels.

    “After focal cerebral ischaemia in rats, vitamin B3 was used to increase high-density lipoprotein concentrations, which enhanced white matter remodelling in the peri-infarct tissue, increased BDNF and TrkB levels, and down regulated Nogo-receptor levels.88”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [88] Cui, 2010, Niacin treatment of stroke increases synaptic plasticity and axon growth in rats, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Hypercholesterolaemia reduces angiogenesis and promotes blood-brain barrier permeability.

    “Hypercholesterolaemia reduces angiogenesis83 and promotes blood–brain barrier permeability.84”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [83] Duan, 2000, Hypercholesterolemia inhibits angiogenesis in response to hindlimb ischemia: nitric oxide-dependent mechanism, Circulation

      Not checked in the free run.

    • cites [84] ElAli, 2011, Increased blood–brain barrier permeability and brain edema after focal cerebral ischemia induced by hyperlipidemia: role of lipid peroxidation and calpain–1/2, matrix metalloproteinase–2/9, and rhoA overactivation, Stroke source

      Not checked in the free run.

    • Rests on an assumption: The effects of hypertension and hypercholesterolaemia on brain remodelling are not fully known.

  • May combine two claims.

    Interpretationcitation

    Although restorative treatments can promote neurological recovery in old animals, specific findings in ageing animals and in animals with vascular risk factors suggest that efficacy of new therapeutics might be compromised in elderly patients with risk factors.

    “Although restorative treat ments can promote neurological recovery in old ani mals,17,26,72,76–79 specific findings in ageing animals72,77–79 and in animals with vascular risk factors80,82,86,87 suggest that the efficacy of new therapeutics might be compromised in elderly patients with risk factors.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source

      Not checked in the free run.

    • cites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source

      Not checked in the free run.

    • cites [72] Li, 2010, An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke, Nat Neurosci source

      Not checked in the free run.

    • Rests on an assumption: Experiments in animals that are otherwise healthy poorly represent comorbidities.

  • May combine two claims.

    Premisecitation

    In focal cerebral ischaemia, spontaneously hypertensive rats showed preserved contralesional pyramidal tract sprouting in response to anti-NogoA antibodies, with functional improvements similar to non-hypertensive rats.

    “In focal cerebral ischaemia, spontaneously hypertensive rats had preserved contralesional pyramidal tract sprouting in response to treatment with neutralising antibodies directed against NogoA, which was consistent with functional neurological improvements that were very similar to those in non-hypertensive rats.11”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [11] Wiessner, 2003, Anti-Nogo-A antibody infusion 24 hours after experimental stroke improved behavioral outcome and corticospinal plasticity in normotensive and spontaneously hypertensive rats, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Enhanced neurogenesis is associated with enhanced neuronal survival in most but not all conditions; in a study of ephrin-B3 deficiency, proliferation and survival of endogenous neural precursor cells were enhanced but ischaemic injury was exacerbated.

    “Enhanced neurogenesis is associated with enhanced neuronal survival in most but not all conditions: in a recent study examining effects of ephrin-B3 deficiency, enhanced proliferation and survival of endogenous neural precursor cells but exacerbation of ischaemic injury were reported.99”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [99] Doeppner, 2011, Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia, Acta Neuropathol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In that trial, erythropoietin did not improve clinical outcome but increased risk of serious complications (death, bleeding, oedema, thromboembolic events) in patients who received alteplase.

    “Unexpectedly, erythropoietin did not improve clinical outcome in stroke patients but increased the risk of serious complications, namely death, bleeding, oedema, and thromboembolic events in patients who received alteplase.90”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Ehrenreich, 2009, Recombinant human erythropoietin in the treatment for acute ischemic stroke, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Neural surface receptors integrate signals with diverse functions, such as neuronal injury and repair, and depending on pathophysiological context could have Janus-like roles in the ischaemic brain.

    “Neural surface receptors integrate signals with diverse functions, such as neuronal injury and repair,96 which depending on the pathophysiological context could have Janus-like roles in the ischaemic brain.5,100”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [96] Reich, 2008, Death receptor Fas (CD95) signaling in the central nervous system: tuning neuroplasticity?, Trends Neurosci source

      Not checked in the free run.

    • cites [5] Cramer, 2000, Recovery recapitulates ontogeny, Trends Neurosci source

      Not checked in the free run.

    • cites [100] Lo, 2008, A new penumbra: transitioning from injury into repair after stroke, Nat Med source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    With respect to clinical translation, studies in laboratory animals have two important limitations: predominance of studies in young, otherwise healthy animals and scarcity of studies in non-human primates.

    “With respect to clinical translation, these studies have two important limitations: the predominance of studies in young, otherwise healthy animals and the scarcity of studies in non-human primates.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Experiments in animals that are otherwise healthy poorly represent comorbidities.
    • Rests on an assumption: Most current knowledge comes from laboratory animals, chiefly rodents.

  • May combine two claims.

    Premisecitation

    Subsequent experimental studies showed that erythropoietin activated MMP2 and 9 after focal cerebral ischaemia, an effect potentiated by alteplase, causing blood-brain barrier leakage, brain oedema, and haemorrhagic transformation.

    “Subsequent experimental studies have shown that erythropoietin activated matrix metalloproteinases 2 and 9 after focal cerebral ischaemia, an effect that was potentiated by alteplase, thus provoking blood–brain barrier leakage, brain oedema, and haemorrhagic transformation of brain infarcts.91,92”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [91] Zechariah, 2010, Combination of tissue-plasminogen activator with erythropoietin induces blood–brain barrier permeability, extracellular matrix disaggregation and DNA fragmentation after focal cerebral ischemia in mice, Stroke source

      Not checked in the free run.

    • cites [92] Jia, 2010, Erythropoietin in combination with tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In rats with diabetes, bone-marrow-derived stromal cell treatment did not improve neurological recovery and increased mortality, blood-brain barrier leakage, and brain haemorrhage.

    “Para doxically, treatment with bone-marrow-derived stromal cells did not improve neurological recovery in rats with diabetes, but increased mortality, blood–brain barrier leakage, and brain haemorrhage.80”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In embryonic hippocampal and cortical neurons, CD95 activation stimulated neurite branching in a caspase-independent and death-domain-dependent manner, paralleled by an increase in non-phosphorylated Tau.

    “In embryonic hippocampal and cortical neurons, activation of CD95 stimulated neurite branching, which occurred in a caspase-independent and death-domain-dependent manner and was paralleled by an increase in non-phosphorylated Tau.98”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [98] Zuliani, 2006, Control of neuronal branching by the death receptor CD95 (Fas/Apo-1), Cell Death Differ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fibre bundles are frequently affected by strokes in human beings because white matter contributes largely to whole brain volume and strokes commonly manifest in deep brain structures.

    “Fibre bundles are frequently affected by strokes, in human beings, because of the large contribution of white matter to the whole brain volume (panel 1) and the common manifestation of strokes in deep brain structures.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites panel 1

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After AAV VEGF vector delivery, proliferation of neural precursor cells and brain capillary formation were compromised in old mice (24 months).

    “After delivery of an adeno-associated viral VEGF vector, both proliferation of neural precursor cells and formation of brain capillaries were compromised in old mice (24 months).79”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [79] Gao, 2009, Attenuation of brain response to vascular endothelial growth factor-mediated angiogenesis and neurogenesis in aged mice, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In the German multicentre erythropoietin trial, 522 patients were randomly assigned to placebo or erythropoietin within 6 h after ischaemic stroke, and 331 (63%) received alteplase.

    “in which 522 patients were randomly assigned to receive placebo or erythropoietin within 6 h after ischaemic stroke. 331 (63%) patients in this study received alteplase treatment.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [90] Ehrenreich, 2009, Recombinant human erythropoietin in the treatment for acute ischemic stroke, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Statins have neurorestorative properties, including promotion of neuronal survival, angiogenesis, and neurogenesis.

    “Statins also have neurorestorative properties (ie, promotion of neuronal survival, angiogenesis, and neurogenesis).36,89”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [36] Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann Neurol source

      Not checked in the free run.

    • cites [89] Kilic, 2005, Post-ischemic delivery of the 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor rosuvastatin protects against focal cerebral ischemia in mice via inhibition of extracellular-regulated kinase-1/-2, Neuroscience source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Such findings have been reported for severe associated systemic diseases (diabetic vasculopathy), after systemic thrombolysis, and when restorative treatments were initiated at inappropriate timepoints (before stroke).

    “Such findings have been reported for severe associated systemic diseases (ie, diabetic vasculopathy),80 subsequent to systemic thrombolysis,91,92 and when restorative treat ments were initiated at inappropriate timepoints (ie, before stroke;93 table).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source

      Not checked in the free run.

    • cites [91] Zechariah, 2010, Combination of tissue-plasminogen activator with erythropoietin induces blood–brain barrier permeability, extracellular matrix disaggregation and DNA fragmentation after focal cerebral ischemia in mice, Stroke source

      Not checked in the free run.

    • cites [92] Jia, 2010, Erythropoietin in combination with tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke, Stroke source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    This evidence comes from indirect outcome measures, such as MRI and electroencephalography, which provide information about the macroscopic but not microscopic level.

    “However, this evidence results from indirect outcome measures, such as MRI101 and electroencephalography,102 which provide infor mation about the macroscopic (ie, tissue), but not microscopic (ie, cellular or even subcellular) level.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [101] Cramer, 1997, A functional MRI study of subjects recovered from hemiparetic stroke, Stroke source

      Not checked in the free run.

    • cites [102] Gerloff, 2006, Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke, Brain source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Interpretationnone given

    With restorative therapies, we can essentially treat all patients, and we are not hampered by reduced tissue perfusion, which restricts delivery of neuroprotective agents, nor by the requirement of rapid intervention within hours after stroke.

    “With these therapies, we can essentially treat all patients, and we are not hampered by reduced tissue perfusion, which restricts delivery of neuroprotective agents, nor by the requirement of rapid intervention, within hours after stroke.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    A robust biological substrate to drive functional improvements is present in many stroke patients, even in elderly people.

    “A robust biological substrate to drive functional improvements is present in many stroke patients, even in elderly people.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    Although neurorestoration after stroke in animals seems relevant to human beings, testing restorative therapy in people is far more complex than in laboratory animals.

    “Although neurorestoration after stroke in animals seems relevant to human beings, testing restorative therapy in people is far more complex than in laboratory animals.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most current knowledge comes from laboratory animals, chiefly rodents.

  • May combine two claims.

    Premisecitation

    Despite robust evidence for specific time windows in which neuronal plasticity and angiogenesis are most active, neurorestorative treatments were still successful in animals once brain remodelling was induced months after stroke.

    “Despite the robust evidence for specific time windows in which neuronal plasticity and angiogenesis are most active,64,66,67 neurorestorative treatments were still successful in animals once brain remodelling was induced months after the stroke.18,20”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [64] Carmichael, 2005, Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex, Exp Neurol source

      Not checked in the free run.

    • cites [66] Shen, 2010, Astrocytic endogenous glial cell derived neurotrophic factor production is enhanced by bone marrow stromal cell transplantation in the ischemic boundary zone after stroke in adult rats, Glia source

      Not checked in the free run.

    • cites [67] Zacharek, 2007, Angiopoietin1/Tie2 and VEGF/Flk1 induced by MSC treatment amplifies angiogenesis and vascular stabilization after stroke, J Cereb Blood Flow Metab source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    The benefits of restorative therapy are evident.

    “The benefits of restorative therapy are evident.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    Experimental studies use defined pathophysiological states to assess comparably uniform stroke lesions with defined topography in homogeneous, often genetically inbred animals, whereas the clinical setting is much more diverse and complex.

    “Although experimental studies make use of defined pathophysiological states, to assess comparably uniform stroke lesions with defined topography in homogeneous, often genetically inbred, animals, the clinical setting is much more diverse and complex than are laboratory conditions.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Most current knowledge comes from laboratory animals, chiefly rodents.
62 of 62

  • The paper relies on this without support.

    The restorative mechanisms observed in animal models are sufficiently similar to those in humans that therapies targeting them could promote human recovery.

    “Promising results from experimental studies have subsequently led to clinical trials,3,7–9 the results of which are eagerly awaited.”

  • The paper relies on this without support.

    Adverse effects seen in experimental animals under specific conditions predict potential adverse effects in human patients.

    “In experimental studies, adverse effects have been identified when neurorestorative treatments were administered to animals with severe associated illnesses, after thrombolysis with alteplase, and when therapies were initiated outside appropriate time windows.”

  • The paper relies on this without support.

    Stroke occurs mainly in later life.

    “Stroke affects human beings mainly in the later stages of life.”

  • The paper relies on this without support.

    Experiments in animals that are otherwise healthy poorly represent comorbidities.

    “Experimental studies poorly mimic comorbidities, because experiments are done mainly in animals that are otherwise healthy.”

  • The paper relies on this without support.

    The effects of hypertension and hypercholesterolaemia on brain remodelling are not fully known.

    “The consequences of both risk factors for brain remodelling are not completely understood.”

  • The paper relies on this without support.

    Most current knowledge comes from laboratory animals, chiefly rodents.

    “Our current knowledge derives largely from laboratory animals, mainly rodents.”
6 of 6

Claims other papers make about this one

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Cites

Flagged first, then by citations

Research works printed but not linked: 1

  1. Cui, 2010, Niacin treatment of stroke increases synaptic plasticity and axon growth in rats, Stroke, 41, 2044, 10.1161/strokeaha.110.589333 · DOI · Paper page

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Authors
Hermann, D. M., & Chopp, M.
Affiliations
  • Essen University Hospital (DE)
  • Oakland University (US)
Corresponding author
Hermann, Dirk M
ORCID
Venue
The Lancet Neurology
Publisher
Elsevier BV
Published
2012-04
Volume
11
Issue
4
Pages
369-380
ISSN
1474-4422 (ISSN-L)
DOI
10.1016/s1474-4422(12)70039-x
PMC
PMC3964179
OpenAlex
W2112095855
Cited by
333
References
102
Citations by year
2026: 15 · 2025: 10 · 2024: 15 · 2023: 14 · 2022: 15 · 2021: 21 · 2020: 35 · 2019: 28 · 2018: 24 · 2017: 25 · 2016: 35 · 2015: 33 · 2014: 20 · 2013: 36 · 2012: 7
FWCI
3.90
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • The Lancet Neurology (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • German Research Foundation ((HE3173/2-1 and HE3173/3-1))
  • National Institutes of Health ((AG037506))
Topics
  • Health Sciences › Medicine › Rehabilitation › Stroke Rehabilitation and Recovery
  • Health Sciences › Medicine › Epidemiology › Acute Ischemic Stroke Management
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
stroke recovery, neuroplasticity, neurorestoration, cell therapy, pharmacotherapy, cerebral microvasculature, glial cells, neural progenitor cells, perilesional tissue, ischemic stroke, alteplase thrombolysis, adverse effects, clinical translation, time window for treatment
MeSH terms
Animals, Neuronal Plasticity, Neovascularization, Physiologic, Stroke, Rats, Neurogenesis, Translational Research, Biomedical

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

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