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

In the paper

“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”

What the sources say

• Supported

  Citation 66 is attached to GDNF, not to VEGF, tPA, or proteoglycan downregulation. The Results (page not supplied) report increased GDNF after ischemia and identify reactive astrocytes as its major source; the Discussion also reports upregulated GDNF gene expression in astrocytes after oxygen-glucose deprivation. (LLM, conf=0.92)

  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
• Partly supported

  The cited paper’s discussion (page unavailable in our copy) says MSC treatment stimulates VEGF expression primarily in brain astrocytes after stroke. That supports the astrocyte–VEGF link, but not the claim that focal ischaemia itself induces de novo expression without MSC treatment. Citation 67 is attached to VEGF, so the separately cited GDNF and tPA claims are not assessed here. (LLM, conf=0.85)

  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 sourceExperimental — accuracy not yet measured
• Supported

  Citation 68 is attached to the tPA clause, not the separately cited claims about GDNF and VEGF. The Discussion states that reactive astrocytes secrete tPA early after stroke, supporting the point attributed to this source. (LLM, conf=0.92)

  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

In the paper

“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”

What the sources say

• Not checked yetcites [64] Carmichael, 2005, Growth-associated gene expression after stroke: evidence for a growth-promoting region in peri-infarct cortex, Exp Neurol source
• Partly supported

  The Introduction reports that bone marrow stromal cell transplantation ameliorates functional deficits in rodent stroke models. But this paper administered cells 24 hours after ischemia and assessed the animals eight days after stroke (Materials and Methods; Discussion), not months later. A one-month treatment appears only in a cited study’s title in the References; the paper does not establish the claimed months-later timing or sequence of brain remodelling. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured
• Partly supported

  The study reports that MSC treatment promoted angiogenesis and vascular stabilization in rats after stroke. But the Methods passage (indexed as Abstract; page unavailable) says MSCs were given 24 hours after stroke, with measurements at 4 and 14 days. It does not support successful treatment initiated months after stroke. (LLM, conf=0.88)

  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 sourceExperimental — accuracy not yet measured

In the paper

“Additionally, brain capillaries sprout, and glial cells are activated to create a favourable cerebral environment for neuronal growth and plasticity.3,4”

What the sources say

• Not checked yetcites [3] Zhang, 2009, Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic, Lancet Neurol source
• Not checked yetcites [4] Hermann, 2009, Implications of vascular endothelial growth factor for postischemic neurovascular remodeling, J Cereb Blood Flow Metab source

In the paper

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

In the paper

“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.”

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [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 yetcites [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 yetcites [14] Bacigaluppi, 2009, Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms, Brain source
• Not checked yetcites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

In the paper

“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”

What the sources say

• Not checked yetcites [1] Carmichael, 2006, Cellular and molecular mechanisms of neural repair after stroke: making waves, Ann Neurol source
• Not checked yetcites [2] Murphy, 2009, Plasticity during stroke recovery: from synapse to behaviour, Nat Rev Neurosci source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [21] Li, 2009, MRI identification of white matter reorganization enhanced by erythropoietin treatment in a rat model of focal ischemia, Stroke source
• Not checked yetcites [22] Liu, 2009, Remodeling of the corticospinal innervation and spontaneous behavioral recovery after ischemic stroke in adult mice, Stroke source

In the paper

“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.”

In the paper

“Neurogenesis is stimulated in response to stroke and is substantially amplified by therapeutic interventions that promote functional recovery.33–36”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [35] Arvidsson, 2002, Neuronal replacement from endogenous precursors in the adult brain after stroke, Nat Med source
• Not checked yetcites [36] Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann Neurol source

In the paper

“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).”

What the sources say

• Not checked yetcites [14] Bacigaluppi, 2009, Delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms, Brain source
• Not checked yetcites [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 yetcites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source
• Not checked yetcites [46] Lee, 2008, Antiinflammatory mechanism of intravascular neural stem cell transplantation in haemorrhagic stroke, Brain source

In the paper

“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”

What the sources say

• Not checked yetcites [35] Arvidsson, 2002, Neuronal replacement from endogenous precursors in the adult brain after stroke, Nat Med source
• Not checked yetcites [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 yetcites [40] Bacigaluppi, 2008, Neural stem/precursor cells for the treatment of ischemic stroke, J Neurol Sci source
• Not checked yetcites [41] Zhang, 2011, Ascl1 lineage cells contribute to ischemia-induced neurogenesis and oligodendrogenesis, J Cereb Blood Flow Metab source
• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [4] Hermann, 2009, Implications of vascular endothelial growth factor for postischemic neurovascular remodeling, J Cereb Blood Flow Metab source
• Not checked yetcites [47] Forsythe, 1996, Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1, Mol Cell Biol source
• Not checked yetcites [48] Marti, 2000, Hypoxia-induced vascular endothelial growth factor expression precedes neovascularization after cerebral ischemia, Am J Pathol source
• Not checked yetcites [49] Wang, 2005, VEGF overexpression induces post-ischaemic neuroprotection, but facilitates haemodynamic steal phenomena, Brain source
• Not checked yetcites [51] Ridgway, 2006, Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis, Nature source
• Not checked yetcites [52] Hellström, 2007, Dll4 signalling through Notch1 regulates formation of tip cells during angiogenesis, Nature source

In the paper

“When a stroke occurs, these cells proliferate and migrate in the direction of the ischaemic lesion, propagating in chains along blood vessels.37,38”

What the sources say

• Not checked yetcites [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 yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source
• Not checked yetcites [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 yetcites [24] Reitmeir, 2012, Vascular endothelial growth factor induces contralesional corticobulbar plasticity and functional neurological recovery in the ischemic brain, Acta Neuropathol source
• Not checked yetcites [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 yetcites [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 yetcites [15] Andres, 2011, Human neural stem cells enhance structural plasticity and axonal transport in the ischaemic brain, Brain source

In the paper

“AMPA receptor antagonists impair neurological outcome, as does blockade of BDNF by TrkB-Fc-impregnated hydrogel.75”

What the sources say

• Not checked yetcites [75] Clarkson, 2011, AMPA receptor-induced local brain-derived neurotrophic factor signaling mediates motor recovery after stroke, J Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [74] Clarkson, 2010, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke, Nature source

In the paper

“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.”

In the paper

“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.”

In the paper

“Astrocytes also remove excitatory neurotransmitters (eg, glutamate) and electrolytes (eg, potassium) from the extracellular space, thus controlling neuronal excitability and enabling synaptic plasticity.62”

What the sources say

• Not checked yetcites [62] Pannasch, 2011, Astroglial networks scale synaptic activity and plasticity, Proc Natl Acad Sci USA source

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [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 yetcites [69] Shen, 2011, Endogenous tissue plasminogen activator mediates bone marrow stromal cell-induced neurite remodeling after stroke in mice, Stroke source
• Not checked yetcites [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

In the paper

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

In the paper

“Neuronal activity induces temporally and spatially tuned responses in the brain (figure 3).”

In the paper

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

In the paper

“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).”

In the paper

“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”

What the sources say

• Not checked yetcites [74] Clarkson, 2010, Reducing excessive GABA-mediated tonic inhibition promotes functional recovery after stroke, Nature source

In the paper

“Aged rats respond to plasticity-promoting therapies, but age might have an effect on some of the processes targeted by neurorestorative interventions.”

What the sources say

• Not checked yetcites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source
• Not checked yetcites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source
• Not checked yetcites [76] Zhang, 2005, Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source
• Not checked yetcites [76] Zhang, 2005, Functional recovery in aged and young rats after embolic stroke: treatment with a phosphodiesterase type 5 inhibitor, Stroke source
• Not checked yetcites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [78] Darsalia, 2005, Stroke-induced neurogenesis in aged brain, Stroke source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [77] Gillani, 2010, Cognitive recovery in the aged rat after stroke and anti-Nogo-A immunotherapy, Behav Brain Res source

In the paper

“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”

What the sources say

• Not checked yetcites [72] Li, 2010, An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke, Nat Neurosci source

In the paper

“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.”

What the sources say

• Not checked yetcites [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 yetcites [61] Thiyagarajan, 2008, Activated protein C promotes neovascularization and neurogenesis in postischemic brain via protease–activated receptor 1, J Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [97] Corsini, 2009, The death receptor CD95 activates adult neural stem cells for working memory formation and brain repair, Cell Stem Cell source

In the paper

“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.”

What the sources say

• Not checked yetcites [85] Chen, 2007, Niaspan increases angiogenesis and improves functional recovery after stroke, Ann Neurol source

In the paper

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

In the paper

“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”

What the sources say

• Not checked yetcites [85] Chen, 2007, Niaspan increases angiogenesis and improves functional recovery after stroke, Ann Neurol source

In the paper

“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”

What the sources say

• Not checked yetcites [88] Cui, 2010, Niacin treatment of stroke increases synaptic plasticity and axon growth in rats, Stroke source

In the paper

“Hypercholesterolaemia reduces angiogenesis83 and promotes blood–brain barrier permeability.84”

What the sources say

• Not checked yetcites [83] Duan, 2000, Hypercholesterolemia inhibits angiogenesis in response to hindlimb ischemia: nitric oxide-dependent mechanism, Circulation
• Not checked yetcites [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

In the paper

“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.”

What the sources say

• Not checked yetcites [17] Markus, 2005, Recovery and brain reorganization after stroke in adult and aged rats, Ann Neurol source
• Not checked yetcites [26] Shen, 2007, One-year follow-up after bone marrow stromal cell treatment in middle-aged female rats with stroke, Stroke source
• Not checked yetcites [72] Li, 2010, An age-related sprouting transcriptome provides molecular control of axonal sprouting after stroke, Nat Neurosci source

In the paper

“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”

What the sources say

• Not checked yetcites [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

In the paper

“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”

What the sources say

• Not checked yetcites [99] Doeppner, 2011, Enhancement of endogenous neurogenesis in ephrin-B3 deficient mice after transient focal cerebral ischemia, Acta Neuropathol source

In the paper

“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”

What the sources say

• Not checked yetcites [90] Ehrenreich, 2009, Recombinant human erythropoietin in the treatment for acute ischemic stroke, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [96] Reich, 2008, Death receptor Fas (CD95) signaling in the central nervous system: tuning neuroplasticity?, Trends Neurosci source
• Not checked yetcites [5] Cramer, 2000, Recovery recapitulates ontogeny, Trends Neurosci source
• Not checked yetcites [100] Lo, 2008, A new penumbra: transitioning from injury into repair after stroke, Nat Med source

In the paper

“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.”

In the paper

“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”

What the sources say

• Not checked yetcites [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 yetcites [92] Jia, 2010, Erythropoietin in combination with tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source

In the paper

“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”

What the sources say

• Not checked yetcites [98] Zuliani, 2006, Control of neuronal branching by the death receptor CD95 (Fas/Apo-1), Cell Death Differ source

In the paper

“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.”

What the sources say

• Not checked yetcites panel 1

In the paper

“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”

What the sources say

• Not checked yetcites [79] Gao, 2009, Attenuation of brain response to vascular endothelial growth factor-mediated angiogenesis and neurogenesis in aged mice, Stroke source

In the paper

“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.”

What the sources say

• Not checked yetcites [90] Ehrenreich, 2009, Recombinant human erythropoietin in the treatment for acute ischemic stroke, Stroke source

In the paper

“Statins also have neurorestorative properties (ie, promotion of neuronal survival, angiogenesis, and neurogenesis).36,89”

What the sources say

• Not checked yetcites [36] Chen, 2003, Statins induce angiogenesis, neurogenesis, and synaptogenesis after stroke, Ann Neurol source
• Not checked yetcites [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

In the paper

“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).”

What the sources say

• Not checked yetcites [80] Chen, 2011, Adverse effects of bone marrow stromal cell treatment of stroke in diabetic rats, Stroke source
• Not checked yetcites [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 yetcites [92] Jia, 2010, Erythropoietin in combination with tissue plasminogen activator exacerbates brain hemorrhage when treatment is initiated 6 hours after stroke, Stroke source

In the paper

“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.”

What the sources say

• Not checked yetcites [101] Cramer, 1997, A functional MRI study of subjects recovered from hemiparetic stroke, Stroke source
• Not checked yetcites [102] Gerloff, 2006, Multimodal imaging of brain reorganization in motor areas of the contralesional hemisphere of well recovered patients after capsular stroke, Brain source

In the paper

“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.”

In the paper

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

In the paper

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

In the paper

“The benefits of restorative therapy are evident.”

In the paper

“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.”