Chopp_US_edit.qxp 30/7/08 12:31 pm Page 60
Stroke
Brain Repair and Recovery from Stroke
a report by
Michael Chopp, PhD, Yi Li, MD, Jieli Chen, MD, Rui Lan Zhang, MD and Zheng Gang Zhang, MD
Neuroscience Institute, Henry Ford Hospital
For decades, the overwhelming emphasis on the development of highly malleable and the intact entire brain responds to injury and stroke
therapeutic interventions for the treatment of stroke has been in the area of by producing new brain cells (neurogenesis), new vasculature
neuroprotection, acute intervention to reduce the volume of cerebral (angiogenesis and arteriogenesis), and new wiring (synaptogenesis and
infarction, and the sequellae of secondary cell death, whether by necrosis or axonal growth), and these events collectively improve neurological function
apoptosis.
1,2
Concerted efforts to elucidate mechanisms of cell death were after stroke.
6,11,12
However, the majority of patients fail to regain full
translated into the development of many neuroprotective agents, including function after stroke, and more than 30% are left with severe disabilities.
7
antioxidants, n-methyl-D-aspartate (NMDA) antagonists, and anti- To address this compelling clinical problem, it is necessary to amplify the
inflammatory agents.
1,2
endogenous neurorestorative response of the brain to stroke and injury in
order to stimulate intrinsic neurorestorative pathways so that we can
However, none of these agents has been proved clinically effective and the further improve neurological function after stroke.
field of clinical trials in stroke neuroprotection is littered with failed and
costly efforts.
1,2
The only ‘effective’ therapeutic approach was the Pre-clinical data demonstrate that after stroke the brain expresses an array
development of thrombolytic therapy with recombinant tissue plasminogen of developmental genes and proteins—particularly in the boundary of the
activator (rtPa).
3
When administered within three hours after stroke, rtPa ischemic lesion—reminiscent of the developing brain.
13–15
We can capitalize
can improve outcome.
3,4
However, fewer than 5% of ischemic stroke on this attempted return to youth and amplify these restorative processes to
patients in the US receive rtPa.
1–3,5
This is due to its short therapeutic window rewire and restructure the central nervous system (CNS) in order to minimize
and potential adverse effects of hemorrhagic transformation. loss of function.
For the sake of the stroke patient, we must shift the therapeutic paradigms. In this article, we will focus on two complementary approaches of enhancing
The focus of therapy should not necessarily be on the ischemic lesion neuroplasticity and thereby promoting neurological function: cell-based and
destined to infarct, but on the remodeling of the intact brain and spinal cord pharmacological therapies. Both restorative treatments improve functional
to promote recovery of neurological function. In other words, treat the non- outcome after stroke, with no reduction in infarct volume.
injured brain and not the infarct. The overemphasis on neuroprotection has
been based on the erroneous assumption that the brain contains a fixed Cell-based Remodeling of Brain After Stroke—
number of neurons and is difficult to remodel.
6,7
Concepts and Pre-clinical Studies
Cell-based therapy induces the recovery of function post-stroke by
However, since the 1960s it has been known that new neurons are stimulating endogenous restorative mechanisms rather than by replacing
generated in the animal brain.
8–10
Today, we know that the injured brain is 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
Michael Chopp, PhD, is Vice Chairman for Research in the
and embryonic progenitor or stem cells.
22
Conversely, they produce an array
Department of Neurology, Scientific Director of the Neuroscience
of factors, including angiogenic and neurotrophic factors, that initiate the
Institute, and Zoltan J Kovacs Chair in Neuroscience Research at
restorative cascade of recovery.
23
More importantly, these administered cells
Henry Ford Hospital, Detroit. He is also a Distinguished Professor
of Physics at Oakland University, Rochester. Dr Chopp is a
also act as catalysts to stimulate parenchymal cells—e.g. astrocytes,
Fellow of the American Heart Association (AHA), is on the
microglia, and endothelial cells—to produce the restorative factors that
Editorial Boards of Stroke and the Journal of Cerebral Blood Flow
mediate brain remodeling and recovery of function.
24,25
and Metabolism, and has chaired and been a member of
National Institutes of Health (NIH) study sections. His research
has focused primarily on the cellular and molecular biology of ischemic cell injury, the
The vast majority of the many pre-clinical studies performed to date have
pathophysiology of stroke and traumatic brain injury, combination neuro- and vascular protective
employed cells injected directly into the brain
26,27
or administered via a
therapies for stroke, cell-based and pharmacological neuro-restorative therapies for stroke,
traumatic brain injury, and neurodegenerative disease, treatment of glioma, and magnetic
vascular route that localizes to the region of cerebral injury.
16,28
Few of these
resonance imaging. Dr Chopp received his training in mathematical and solid state physics at
injected cells express the parenchymal cell phenotype.
16
Functional
New York University.
improvement tends to be rapid and is often obvious within one week, which
E: chopp@neuro.hfh.edu
is clearly insufficient time for these alien cells to become neurons and
successfully integrate into the brain circuitry.
16
At least for the adult, the
60 © TOUCH BRIEFINGS 2008
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