Neural Injury and Repair Noam Y. Harel, MD, PhD 12 November
2013 Brain and Behavior
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Disclosures I do not have any financial or other conflicts of
interest to disclose for this learning session. I do not affirm
that all discussions of drug use will be consistent with either FDA
or compendia-approved indications. Off-label and experimental drugs
may be discussed.
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Learning Objectives 1.Recognize differences between axonal
injury and repair in the PNS versus CNS. 2.Understand levels of
neural plasticity from subcellular to network plasticity.
3.Recognize approaches and targets for improving neural repair.
4.Understand principles of neurorehabilitation essential in
conjunction with any other drug, cellular, or engineering-based
treatments.
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Injury: soma or nerve? Scenery: PNS or CNS? Machinery:
intrinsic, extrinsic Strategery: Targets for repair and
recovery
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Injury: Soma Excitotoxicity (may be acute or chronic) Ischemia,
trauma, etc Decreased ATP Inc intracellular Na +, Ca ++ Membrane
Depolarization Increased action potentials Glutamate release
Decreased glutamate reuptake Increased extracellular glutamate Cell
death SPREADING EXCITOTOXICITY Doble 1999 NECROSIS
INFLAMMATIONAPOPTOSIS NO INFLAMMATION
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Injury: Soma DP Agamanolis Chromatolysis
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Injury: Nerve Ray Jurewicz Deumens et al. Focal demyelination
Axon disrupted Endo. disrupted Peri. disrupted Epi. disrupted
Prognosis Good (weeks) Fair (mos) Poor (surgery may help).... NERVE
CONDUCTION STUDIES/ELECTROMYOGRAPHY: Demyelination: Decreased
conduction velocity Axonal loss: Decreased action potential
amplitude
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Intra-axonal organelle and microtubule breakdown
(minutes-hours) Schwann cells begin axon breakdown and recruit more
cells (hrs-days) Macrophages enter, accelerate process (1-2 weeks)
Path cleared for axons to regrow proximal-->distal
(weeks-months) Injury: Nerve Wallerian Degeneration
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Scenery: Peripheral vs Central PNSCNS Ramon y Cajal
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Scenery: Peripheral vs Central Wallerian Degeneration Wallerian
Degeneration PNS yes CNS fail
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Scenery: Peripheral vs Central PNS yes CNS fail Schwanns help
Oligodendrocyte debris, astrocytes, scarring hurt
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Machinery: Intrinsic vs Extrinsic Akbik et al., 2012 CNS
EXTRINSIC Inhibitors CNS Cell Type Inhibitory Product Oligo-
dendrocytes Myelin- associated inhibitors AstrocytesChrondoitin
sulfates Astrocytes+Fibr oblasts Glial/fibrous scar tissue
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Scenery: Peripheral vs Central Intrinsic growth potential (1-3
mm/d) Sluggish growth potential (0.1 mm/d) PNS yes CNS fail
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Machinery: Intrinsic vs Extrinsic Seo & Kiyama, 2011 PNS
INTRINSIC Advantages Regeneration-Associated Genes PNS neurons
possess receptors and signal transduction machinery allowing them
to grow in response to neurotrophins, retrograde injury signals
cAMP
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Machinery: Intrinsic vs Extrinsic Letourneau What does
regeneration look like? Growth Cones
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Machinery: Intrinsic vs Extrinsic What does regeneration look
like? Ramesh 2004Dickson 2002 Growth Cones Dynamic growth through
regulation of actin and microtubule polymerization/depolymerization
Hammarlund et al., 2009
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Machinery: Intrinsic vs Extrinsic What does FAILED regeneration
look like? Ramon y Cajal Retraction Bulbs (of Cajal)
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Synapse regulation Receptor regulation Transmitter regulation
Network adaptation Sprouting CNS PLASTICITY: A more realistic term
than CNS regeneration Short-term, Long-term Long-term
Sprouting: Use What You Got Uninjured 1.Direct regeneration 1 2
3 5 4 7 6 7.Retargeting 2.Itinerant regeneration 4.Direct proximal
sprouting 3.Sprouting from neighbor 5.Sprouting to neighbor
6.Indirect rerouting
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Complexity Redundancy VJ Wedeen Redundancy PlasticityRecovery
through Rerouting, not Regeneration
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Recovery through Rerouting, not Regeneration
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Strategery: Repair and Recovery Targets anyone? *class to
fill-in*
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Improve cleanup macrophages instead of oligos? Reduce inflamm
& scarring steroids; chondroitinases; etc Add guidance scaffold
Schwanns; olfactory ensheathing glia; etc Replace growth factors
but can CNS neurons respond? gradients? Trigger RAGs cAMP
modulators (rolipram); direct gene therapy Activate growth cones
calcium; microtubule stabilizers (eg taxol) Block extrinsic
inhibitors Mabs; receptor decoys; RhoA inhibitors Excite circuits
transmitter agonists; K + blockers; electrical stim; etc Replace
neurons Stem cells Remyelinate axons Stem cells Rehabilitate!!
Strategery: Repair and Recovery Targets anyone? ESSENTIAL IN
CONJUNCTION WITH ALL THE ABOVE
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ANY kind of activity/nerve stimulation: exercise, electrical
stim, magnetic stim, etc Leads to increases in: growth factors,
especially BDNF neurogenesis glial cell support angiogenesis
synaptogenesis Activity Plasticity Wu et al., 2008
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Circuits need Pruning Shore, 1997 14 yo6
yobirthconsolidationregrowthinjury Plasticity isnt just Growth
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Education > Exertion Specificity > Sweaty Learning (or
re-learning) a variety of skilled, task-specific, repetitive tasks
is more beneficial than general exercise alone. Skilled: Better
stimulates cortical networks Task-specific: Real-life skills more
motivating; prune unneeded circuits Repetitive: to maintain
gains/consolidate circuits, need to overlearn
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Education > Exertion Specificity > Sweaty Learning (or
re-learning) a variety of skilled, task-specific, repetitive tasks
is more beneficial than general exercise alone. Rigorous,
CONTROLLED clinical rehabilitation studies are woefully lacking,
sorely needed
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In both animals and humans, repetitive training in a specific
task leads to improved performance in that task, without benefit in
other tasks From the spinal cord injury field Cats trained to stand
can stand but not walk better Cats trained to walk can walk but not
stand better Rats trained to swim can swim but not walk better Rats
trained to reach can reach but not climb better Humans trained on
treadmill can walk better on treadmill but not over ground De Leon
et al, 1998; Smith et al, 2006; Dobkin et al, 2006; Garcia-Alias et
al, 2009 Practice Makes Pigeonholed?
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The Dilemma: How to broaden the benefits of task-specific
training? Practice variety of tasks within same broad category eg
writing in print vs cursive letters, etc - Winstein and Wolf 2009
Random practice order rather than ordered blocks
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Learning Objectives 1.Recognize differences between axonal
injury and repair in the PNS versus CNS. 2.Understand levels of
neural plasticity from subcellular to network plasticity.
3.Recognize approaches and targets for improving neural repair.
4.Understand principles of neurorehabilitation essential in
conjunction with any other drug, cellular, or engineering-based
treatments.
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BAPTISTE, D. C. & FEHLINGS, M. G. (2006) Pharmacological
approaches to repair the injured spinal cord. J Neurotrauma, 23,
318-34. BRADKE, F., FAWCETT, J. W. & SPIRA, M. E. (2012)
Assembly of a new growth cone after axotomy: the precursor to axon
regeneration. Nat Rev Neurosci, 13, 183-93. CAFFERTY, W. B., MCGEE,
A. W. & STRITTMATTER, S. M. (2008) Axonal growth therapeutics:
regeneration or sprouting or plasticity? Trends Neurosci, 31,
215-20. HAREL, N. Y. & STRITTMATTER, S. M. (2006) Can
regenerating axons recapitulate developmental guidance during
recovery from spinal cord injury? Nat Rev Neurosci, 7, 603-16.
KERSCHENSTEINER, M., SCHWAB, M. E., LICHTMAN, J. W. & MISGELD,
T. (2005) In vivo imaging of axonal degeneration and regeneration
in the injured spinal cord. Nat Med, 11, 572- 7. KRAKAUER, J. W.
(2006) Motor learning: its relevance to stroke recovery and
neurorehabilitation. Curr Opin Neurol 1:84-90. PASCUAL-LEONE, A.,
AMEDI, A., FREGNI, F. & MERABET, L. B. (2005) The plastic human
brain cortex. Annu Rev Neurosci, 28, 377-401. RAMON Y CAJAL, S.,
DEFELIPE, J. & JONES, E. G. (1991) Cajal's degeneration and
regeneration of the nervous system, New York, Oxford University
Press. Further Reading