Elsevier

The Lancet Neurology

Volume 8, Issue 5, May 2009, Pages 491-500
The Lancet Neurology

Review
Neurorestorative therapies for stroke: underlying mechanisms and translation to the clinic

https://doi.org/10.1016/S1474-4422(09)70061-4Get rights and content

Summary

Restorative cell-based and pharmacological therapies for experimental stroke substantially improve functional outcome. These therapies target several types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in the ischaemic brain. Interaction between these restorative events probably underpins the improvement in functional outcome. This Review provides examples of cell-based and pharmacological restorative treatments for stroke that stimulate brain plasticity and functional recovery. The molecular pathways activated by these therapies, which induce remodelling of the injured brain via angiogenesis, neurogenesis, and axonal and dendritic plasticity, are discussed. The ease of treating intact brain tissue to stimulate functional benefit in restorative therapy compared with treating injured brain tissue in neuroprotective therapy might more readily help with translation of restorative therapy from the laboratory to the clinic.

Introduction

Stroke is a major cause of morbidity and mortality worldwide. Thrombolytic therapy with alteplase is effective when given within 4·5 h after stroke.1, 2 However, fewer than 5% of patients with ischaemic stroke in the USA receive this treatment. Even with effective thrombolysis, most patients will have neurological deficits.3, 4 Therefore, development of therapies for ischaemic stroke designed specifically to reduce neurological deficits is crucial.

Preclinical data indicate that cell-based and pharmacological therapies that enhance brain-repair processes substantially improve functional recovery when given 24 h or later after stroke or brain injury.5, 6, 7, 8, 9, 10, 11, 12, 13 Cell-based therapies under investigation include use of bone-marrow mesenchymal cells, cord blood cells, fetal cells, and embryonic cells.12, 14, 15, 16, 17, 18, 19, 20 Pharmacological treatments include drugs that increase cGMP (eg, phosphodiesterase 5 inhibitors, such as sildenafil and tadalafil), statins, erythropoietin, granulocyte-colony stimulating factor, nicotinic acid, and minocycline.6, 7, 10, 21, 22, 23, 24, 25 The common restorative characteristic of these therapies is that they target many types of parenchymal cells (including neural stem cells, cerebral endothelial cells, astrocytes, oligodendrocytes, and neurons), leading to enhancement of endogenous neurogenesis, angiogenesis, axonal sprouting, and synaptogenesis in ischaemic brain tissue. These events collectively improve neurological function after stroke. Furthermore, in addition to providing enhanced cerebral tissue perfusion, angiogenic vessels produce neurotrophic compounds, which create a suitable microenvironment within the injured brain that attracts endogenous stem cells and promotes integration of these cells within the parenchyma. Together with parenchymal astrocytes, angiogenic vessels contribute to enhancement of synaptogenesis and axonal sprouting.

In this Review, we describe the mechanisms by which cell-based and pharmacological treatments stimulate endogenous brain remodelling after stroke, particularly neurogenesis, angiogenesis, axonal plasticity, and white-matter change. We also briefly outline the potential of MRI to view these restorative events. Finally, we discuss the challenges of translating these therapies into the clinic and ongoing clinical trials.

Section snippets

Enhancement of neurogenesis

The subventricular zone (SVZ) of the lateral ventricle and the dentate gyrus of the hippocampus of adult rodent brains contain neural stem cells that produce neuroblasts.26, 27 Under physiological conditions, neuroblasts in the SVZ travel via the rostral migratory stream to the olfactory bulb where they differentiate into granule and periglomerular neurons throughout adult life.27, 28 In the SVZ of adult human brains, neural stem cells are present in a band of astrocytes separated from the

Enhancement of cerebral angiogenesis

The cerebral vascular system mainly develops through angiogenesis.70 Although proliferation of cerebral endothelial cells ceases in the adult brain, angiogenesis in adult human and rodent brains can take place under pathophysiological conditions.71, 72 In the rodent brain, capillary sprouting is initiated at the border of the infarct and new vessels develop in the ischaemic boundary between 2 and 28 days after the onset of stroke,73, 74 whereas angiogenesis takes place in the penumbra of human

Coupling of neurogenesis and angiogenesis

Stroke induces angiogenesis and neurogenesis, two processes that are linked together.71, 74, 81, 84, 85, 98, 99, 100, 101, 102 Cerebral blood vessels mainly provide nutritive blood flow. However, cerebral endothelial cells secrete factors that regulate the biological activity of neural progenitor cells. Under physiological conditions, neurogenesis in the subgranular zone of the dentate gyrus takes place within an angiogenic microenvironment.103 The laminin receptor α6β1 integrin expressed by

Effects on astrocytes, oligodendrocytes, and axons

Axons in ischaemic brains have little capability to sprout.118 Astrocytes form glial scars along ischaemic lesions and produce proteoglycans that inhibit axonal growth and that act as physical and biochemical barriers to axonal regeneration.119 In experimental stroke, treatment with bone-marrow mesenchymal cells substantially increases axonal density around the ischaemic lesion, extends axonal fibres, and orients these fibres parallel to the boundary of a coronal section of an ischaemic lesion.

Translation to the clinic

Apart from treatment with alteplase, translation of therapies for stroke to the clinic from those in the laboratory has not been successful.134 These attempts all aimed to develop neuroprotective treatments of stroke with early intervention to reduce the volume of cerebral infarction. Reasons for failure include the short time window required to intervene to salvage cerebral tissue. Many of the drugs tested in the laboratory were given immediately after or within the first hours after onset of

Clinical trials

Approaches to enhance recovery of function after stroke in the laboratory and in clinical trials extend beyond the use of drugs and cell-based treatments and include electromagnetic stimulation, device-based strategies, repetitive training, and task-oriented strategies.136 The recent Extremity Constraint Induced Therapy Evaluation (EXCITE) trial reported significantly positive results for distal and proximal arm motor function in response to constraint-induced therapy.139, 140 Here, we focus on

Conclusions

The cell-based and pharmacological therapies described in this Review target multiple types of parenchymal cells in ischaemic brain tissue to increase neurogenesis, angiogenesis, and axonal outgrowth during recovery. Potential mechanisms underlying these beneficial therapies are emerging. Future studies must investigate mechanisms that temporally and spatially coordinate these events.

Brain remodelling after stroke and subsequent improvement of functional outcome probably result from several

Search strategy and selection criteria

References for this Review were identified through searches of PubMed with the search terms “cell-based and pharmacological therapies”, “experimental stroke”, “restorative therapies”, “neurogenesis”, “angiogenesis”, “MRI”, from January, 1975, to January, 2009. Papers for cell-based and pharmacological therapies were only included if treatments were initiated 24 h or longer after stroke. Only papers published in English were reviewed.

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