Restorative therapies for motor function after stroke (cerebral ischemia)

1
Restorative therapies for motor function after
stroke (cerebral ischemia)
Dr Lawrence Moon
Please take two minutes to fill in the quick
questionnaire During the lecture, do interrupt
with questions if you have any
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After this lecture and appropriate reading you
should be able to

• Describe the anatomy of cortical efferents.
• Describe a focal animal model of stroke. You
  should be able to highlight the patterns of
  midbrain and spinal denervation that occur after
  stroke and identify spared cortical efferents
  that could be exploited by pro-plasticity
  therapies.
• 3. Describe possible mechanisms contributing to
  loss of function.
• 4. Define compensation, collateral sprouting and
  plasticity.
• 5. Explain mechanisms preventing spared axons
  growing in the adult CNS.
• 6. Describe experiments enhancing growth of
  spared axons after stroke.

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Overview / structure

• Anatomy of human cortical efferents
• How do rats reach for food (?!)
• Anatomy of rat cortical efferents
• What is lost after unilateral stroke?
• What is spared after unilateral stroke?
• Why is there little spontaneous recovery?
• How have scientists attempted to restore lost
  function?

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Anatomy of human corticospinal tract
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Anatomy of human corticospinal tract
decussation lateralised CST
n.b. species differ radically n.b. other cortical
efferents
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Anatomy of human corticospinal tract
Thus the right hemisphere largely supplies the
left spinal cord (decussation to contralateral
side) and vice versa. Some minor projections to
the same (ipsilateral) side. In the spinal
cord, the cortical efferents run in the lateral
columns.
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Unilateral cerebral ischemia causes...

• Loss of oxygen and nutrients to neurons and
  glia on one side of brain
• Cell death (primary, secondary)
• Loss of cortical axons (projections /
  efferents) to regions including
• ipsilateral (same side) striatum
• ipsilateral red nucleus
• ipsilateral pons
• contralateral spinal cord
• hence hemiplegia on opposite side of body to
  stroke
• Damage to the human CST is devastating to fine
  and gross motor control.
• Animal models allow us to model this and test
  therapies...

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How do rats reach for food?
Video
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How do rats reach for food?
Excellent precision in their motor control.
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How do rats control their forelimbs?

• Two tracts are vital in rats
• The corticospinal tract
• Piecharka et al., 2005 Brain Research Bulletin
  66203-211.
• The cortico-rubro-spinal tract
• Whishaw et al,. 1998 Behavioural Brain Research
  93167-183.

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Anatomy of rat corticospinal tract
Injection of anterograde tracer (here in the
right cortex) show that the rat CST anatomy is
similar to the human but the cortical efferents
run in the dorsal columns. There is also a minor
dorsolateral component. The ipsilateral
component runs ventrally. Brosamle Schwab
(1997).
Interruption of the rat CST leads only to minor
deficits in motor function.
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Anatomy of rat and human cortico-rubro-spinal
tract
n.b. Rubro- red Cortico-rubral tract runs
ipsilaterally. Rubro-spinal tract decussates and
runs contralaterally. Hence the cortex
influences the contralateral side of the body
directly via the corticospinal tract and
indirectly via the rubrospinal relay.
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Unilateral cerebral ischemia in rat

• Stroke kills cortical neurons.

• Descending axons (efferents) degenerate.

• Loss of input to contralateral spinal cord.

• Loss of input to ipsilateral red nucleus,
  striatum and pons.

• Hence denervated zones.

• But there is a spared cortex.

• with spared efferents

• to one side of the spinal cord

• and to one red nucleus pons

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What if intact axons could be induced to sprout
to denervated zones?
Would the spared circuitries learn to restore the
lost function?
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Novel area of research new therapies?

• There are spared axons.
• These do not, however, spontaneously grow into
  zones of denervation
• e.g. contralateral red nucleus
• e.g. ipsilateral spinal cord
• If we can understand why not, it may be
  possible to exploit spared axons to cause repair.
• Possible new therapies!

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Why little spontaneous recovery?

• Very few new neurons are born (neurogenesis)
• Limited endogenous repair (adult vs neonate)
• Insufficient compensatory plasticity
• Poor intrinsic axon growth
• Pro-growth molecules down-regulated
• Anti-growth pathways switched on
• Inhospitable extrinsic environment
• Growth-inhibitory molecules (intact injured)
• Lack of growth factors, permissive substrates

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Growth inhibitory molecules

• Many growth inhibitory molecules have been
  discovered in the nervous system (read reviews
  Sandvig et al., 2004 Schwab, 2004).
• White matter is particularly growth inhibitory
  (Caroni Schwab, 1989).
• Biochemical fractions of myelin contain
  molecules including Nogo-A, MAG, OMgp.
• These are all inhibitory to axon growth.
• Nogo-A is a component of myelin synthesised by
  oligodendrocytes.

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Neuronal receptors for inhibitors

• Neuronal growth is inhibited because neurons
  express a receptor complex for Nogo-A comprised
  of
• Nogo receptor (NgR)
• p75 / NGF receptor
• LINGO
• This receptor complex cause axon growth failure
  by signalling to the cytoskeleton via
• RhoA
• Rho kinase (ROCK)

Schwab 2004
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Do antibodies against Nogo-A provide a an
effective therapy for stroke?
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• MCAO
• mouse IN-1 antibodies from cells
• no delay to treat
• forepaw reaching test

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Papadopolous et al., 2002 (continued). --
TRACER Spared cortico-rubral axons sprouted
across the midline
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• Improved antibody
• Extra animal model and different reaching test
• Assessment of corticospinal sprouting (c.f.
  rubrospinal in previous)
• Data presented poorly. Is it persuasive? (e.g.
  Fig 6E).
• Is axon sprouting effect big enough to explain
  behaviour?

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Issues to critically evaluate while reading
Do the animal models of stroke adequately model
human strokes? Am I persuaded that antibodies to
Nogo-A restore function after stroke? Critically
evaluate Wiessner et al., 2003 in particular. If
I had a stroke, would I be prepared to be the
first recipient of these antibodies? What extra
data might I want? What would need to be done
to prove that the sprouting axons actually
restore the lost function? If not persuaded, why
not? What remains to be shown?
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Future targets?
Read more and critically question what you
read. What other inhibitors are there in the
midbrain and spinal cord? What are their
receptors? Would interfering with these promote
recovery of function after stroke? How might we
interfere with these interactions? Sandvig et
al,. 2004 Critically evaluate the mechanism of
action of other experimental therapies inosine a
mphetamine rehabilitation Do we know if they
work? Do we know how they work?
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Tips on answering exam questions!
Answer the question, not just the part you
revised! Show evidence of additional reading
and critical thought. e.g. use references to
support EACH claim you make (Bob et al., 2008)
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Any questions?
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Reading list

• Anatomy of cortical efferents
• Kandel, Schwartz Jessell, Principles of Neural
  Science
• Fig.1 Brosamle Schwab, 1997 J Comparative
  Neurology 386293-303.
• Why dont spared axons grow spontaneously after
  stroke?
• Schwab, 2004. Nogo and axon regeneration. Curr
  Opin Neurobiol. 14118-24
• Sandvig et al,. 2004. Myelin-, reactive glia-,
  and scar-derived CNS axon growth inhibitors
  expression, receptor signaling, and correlation
  with axon regeneration. Glia 46225-51
• How might we exploit spared circuits after
  stroke?
• a) Nogo-A antibodies
• Seymour et al., 2005 Delayed treatment with
  monoclonal antibody IN-1 1 week after stroke
  results in recovery of function and corticorubral
  plasticity in adult rats. J Cerebral Blood Flow
  Metabolism 25, 13661375
• Papadopolous et al., 2005 Functional recovery and
  neuroanatomical plasticity following middle
  cerebral artery occlusion and IN-1 antibody
  treatment in the adult rat. Ann Neurol.
  51433-41.
• Markus et al., 2005 Recovery and brain
  reorganization after stroke in adult and aged
  rats.Ann Neurol. 2005 58(6)950-3.
• Wiessner et al., 2003 Anti-Nogo-A antibody
  infusion 24 hours after experimental stroke
  improved behavioral outcome and corticospinal
  plasticity in ... rats J Cerebral Blood Flow
  Metabolism. 23154-165.

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Reading list

• How might we exploit spared circuits after
  stroke?
• b) D-amphetamine
• Ramic et al., 2006. Axonal plasticity is
  associated with motor recovery following
  amphetamine treatment combined with
  rehabilitation after brain injury in the adult
  rat. Brain Res. 1111176-186.
• Platz et al,. 2007. Amphetamine fails to
  facilitate motor performance and to enhance motor
  recovery among stroke patients with mild arm
  paresis interim analysis and termination of a
  double blind, randomised, placebo-controlled
  trial. Restor Neurol Neurosci. 23271-80
• c) inosine
• 1. Chen et al., 2002 Inosine induces axonal
  rewiring and improves behavioral outcome after
  stroke. Proc Natl Acad Sci U S A. 999031-6.
• d) locomotor rehabilitation / cognitive / social
  enrichment
• Boake et al., 2007 Constraint-Induced Movement
  Therapy During Early Stroke Rehabilitation.
  Neurorehabil Neural Repair 2114-24
• Biernaskie Corbett, 2001. Enriched
  rehabilitative training promotes improved
  forelimb motor function and enhanced dendritic
  growth after focal ischemic injury. J Neurosci.
  215272-80.
• Johansson, 2004. Functional and cellular effects
  of environmental enrichment after experimental
  brain infarcts. Restor Neurol Neurosci. 22163-74
  

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Reading list
Plasticity Nudo, 2006 Plasticity. NeuroRx 3420-7
Which neurons have receptors for growth
inhibitors? Barrette et al., 2007. Expression
profile of receptors for myelin-associated
inhibitors of axonal regeneration in the intact
and injured mouse central nervous system.
Molecular and Cellular Neuroscience (Epub ahead
of print).
Powerpoint and pdfs can be downloaded from
http//www.lawrencemoon.co.uk/resources/stroke.asp