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Dennis Bourdette, MDDennis Bourdette, MDVA MS Center of Excellence-West VA MS Center of Excellence-West
and and Department of NeurologyDepartment of Neurology
Oregon Health & Science UniversityOregon Health & Science University
Neuroprotection: The Future Neuroprotection: The Future for the Treatment of for the Treatment of
Progressive Multiple Sclerosis?Progressive Multiple Sclerosis?
CMSC, June 2004
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MS is an Inflammatory DiseaseMS is an Inflammatory Disease
CMSC, June 2004
Cartoon of cells in spinal cord (plasma, regulatory T cells, pathogenic T cells, antibodies)
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Neuroprotection in MSNeuroprotection in MS Current DMT are primarily anti-inflammatory Current DMT are primarily anti-inflammatory DMT are ineffective in treating progressive DMT are ineffective in treating progressive
forms of MSforms of MS Progressive neurodegenerative axonopathy Progressive neurodegenerative axonopathy
may underlie progressive diseasemay underlie progressive disease ““Neuroprotective” therapies may be Neuroprotective” therapies may be
necessary to arrest progressive diseasenecessary to arrest progressive disease
CMSC, June 2004
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The Pathogenesis of MS May Involve The Pathogenesis of MS May Involve Both Inflammation and Both Inflammation and
NeurodegenerationNeurodegenerationInflammationInflammation
NeurodegenerationNeurodegenerationRRMSRRMS SPMSSPMS
+ Relapses - Relapses+ Relapses - RelapsesPPMSPPMS
CMSC, June 2004
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MS and Axonal LossMS and Axonal Loss
Adams, A Colour Atlas of Multiple Sclerosis, 1989
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Cerebral Atrophy Occurs in MSCerebral Atrophy Occurs in MS
Courtesy of Richard Rudick, MD
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MS and Acute Axonal InjuryMS and Acute Axonal Injury
Trapp et al, N Engl J Med, 338:278, 1998
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How Can We Prevent Brain Atrophy?How Can We Prevent Brain Atrophy?
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StrategiesStrategies Early highly effective anti-Early highly effective anti-
inflammatory therapyinflammatory therapy Neuroprotective therapies to Neuroprotective therapies to
prevent oligodendrocyte and prevent oligodendrocyte and axonal injuryaxonal injury
Promote remyelinationPromote remyelination Provide missing “trophic factors”Provide missing “trophic factors”
CMSC, June 2004
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Glutamate Receptor Blockade Glutamate Receptor Blockade is Neuroprotective in EAEis Neuroprotective in EAE
Pitt et al, Nature Medicine 6:67, 2000
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Glutamate Receptor Blockade is Glutamate Receptor Blockade is Neuroprotective in EAENeuroprotective in EAE
Pitt et al, Nature Medicine 6:67, 2000
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Phenytoin protects Axons in EAE: Phenytoin protects Axons in EAE: Na+ Channel BlockadeNa+ Channel Blockade
Lo et al, NeuroReport 13:1909, 2002
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FK506 Decreases Spinal Cord FK506 Decreases Spinal Cord White Matter DamageWhite Matter Damage
Gold et al, J Neurosci Res, 2004
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FK506 Decreases Axonal Loss FK506 Decreases Axonal Loss and Demyelinationand Demyelination
Saline
FK506
Gold et al, J Neurosci Res, 2004
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Without FK506Without FK506 With FK506With FK506
NeuronsNeurons NeuronsNeurons
NeuriteNeurite NeuriteNeurite
Courtesy of Dr. Bruce Gold
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MS and RemyelinationMS and Remyelination
Adams, A Colour Atlas of Multiple Sclerosis, 1989
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MS and RemyelinationMS and Remyelination
Adams, A Colour Atlas of Multiple Sclerosis, 1989
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ObstaclesObstacles It is uncertain how we should be studying It is uncertain how we should be studying
neuroprotective therapiesneuroprotective therapies MRI measurementsMRI measurements Slowing of clinical disabilitySlowing of clinical disability
Experience in other neurologic diseases with Experience in other neurologic diseases with neuroprotective therapies is discouragingneuroprotective therapies is discouraging StrokeStroke ALSALS PDPD
CMSC, June 2004
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ConclusionsConclusions We should continue to treat early and We should continue to treat early and
develop highly effective anti-develop highly effective anti-inflammatory regimensinflammatory regimens
Neuroprotective and neuroregenerative Neuroprotective and neuroregenerative therapies need to be tested in MStherapies need to be tested in MS
CMSC, June 2004