Brain Repair and Recovery from Stroke

Brain Repair and Recovery from Stroke

Chen Jieli , Chopp Michael, Li Yi , Zhang Rui Lan , Zhang Zheng Gang
Published: US Neurology - Volume 4 - Issue I
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For decades, the overwhelming emphasis on the development of therapeutic interventions for the treatment of stroke has been in the area of neuroprotection, acute intervention to reduce the volume of cerebral infarction, and the sequellae of secondary cell death, whether by necrosis or apoptosis.1,2 Concerted efforts to elucidate mechanisms of cell death were translated into the development of many neuroprotective agents, including antioxidants, n-methyl-D-aspartate (NMDA) antagonists, and antiinflammatory agents.1,2

However, none of these agents has been proved clinically effective and the field of clinical trials in stroke neuroprotection is littered with failed and costly efforts.1,2 The only ‘effective’ therapeutic approach was the development of thrombolytic therapy with recombinant tissue plasminogen activator (rtPa).3 When administered within three hours after stroke, rtPa can improve outcome.3,4 However, fewer than 5% of ischemic stroke patients in the US receive rtPa.1–3,5 This is due to its short therapeutic window and potential adverse effects of hemorrhagic transformation.

For the sake of the stroke patient, we must shift the therapeutic paradigms. The focus of therapy should not necessarily be on the ischemic lesion destined to infarct, but on the remodeling of the intact brain and spinal cord to promote recovery of neurological function. In other words, treat the noninjured brain and not the infarct. The overemphasis on neuroprotection has been based on the erroneous assumption that the brain contains a fixed number of neurons and is difficult to remodel.6,7

However, since the 1960s it has been known that new neurons are generated in the animal brain.8–10 Today, we know that the injured brain is highly malleable and the intact entire brain responds to injury and stroke by producing new brain cells (neurogenesis), new vasculature (angiogenesis and arteriogenesis), and new wiring (synaptogenesis and axonal growth), and these events collectively improve neurological function after stroke.6,11,12 However, the majority of patients fail to regain full function after stroke, and more than 30% are left with severe disabilities.7 To address this compelling clinical problem, it is necessary to amplify the endogenous neurorestorative response of the brain to stroke and injury in order to stimulate intrinsic neurorestorative pathways so that we can further improve neurological function after stroke.

Pre-clinical data demonstrate that after stroke the brain expresses an array of developmental genes and proteins—particularly in the boundary of the ischemic lesion—reminiscent of the developing brain. 13–15 We can capitalize on this attempted return to youth and amplify these restorative processes to rewire and restructure the central nervous system (CNS) in order to minimize loss of function.

In this article, we will focus on two complementary approaches of enhancing neuroplasticity and thereby promoting neurological function: cell-based and pharmacological therapies. Both restorative treatments improve functional outcome after stroke, with no reduction in infarct volume.

Cell-based Remodeling of Brain After Stroke—Concepts and Pre-clinical Studies
Cell-based therapy induces the recovery of function post-stroke by stimulating endogenous restorative mechanisms rather than by replacing infarcted tissue. When injected into the adult, the cells do not repopulate the adult brain tissue, regardless of whether they are bone marrow mesenchymal (MSC),16,17 neurospheres,18–20 umbilical cord blood,21 or fetal and embryonic progenitor or stem cells.22 Conversely, they produce an array of factors, including angiogenic and neurotrophic factors, that initiate the restorative cascade of recovery. 23 More importantly, these administered cells also act as catalysts to stimulate parenchymal cells—e.g. astrocytes, microglia, and endothelial cells—to produce the restorative factors that mediate brain remodeling and recovery of function.24,25

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