Dennis Bourdette, MDDennis Bourdette, MD

VA 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

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)

Neuroprotection in MSNeuroprotection in MS

Current DMT are primarily anti-Current DMT are primarily anti-inflammatory 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

The Pathogenesis of MS May Involve The Pathogenesis of MS May Involve Both Inflammation and Both Inflammation and

NeurodegenerationNeurodegeneration

InflammationInflammation

NeurodegenerationNeurodegenerationRRMSRRMS SPMSSPMS

+ Relapses - Relapses+ Relapses - Relapses

PPMSPPMS

CMSC, June 2004

MS and Axonal LossMS and Axonal Loss

Adams, A Colour Atlas of Multiple Sclerosis, 1989

Cerebral Atrophy Occurs in MSCerebral Atrophy Occurs in MS

Courtesy of Richard Rudick, MD

MS and Acute Axonal InjuryMS and Acute Axonal Injury

Trapp et al, N Engl J Med, 338:278, 1998

How Can We Prevent Brain Atrophy?How Can We Prevent Brain Atrophy?

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

Glutamate Receptor Blockade Glutamate Receptor Blockade is Neuroprotective in EAEis Neuroprotective in EAE

Pitt et al, Nature Medicine 6:67, 2000

Glutamate Receptor Blockade is Glutamate Receptor Blockade is Neuroprotective in EAENeuroprotective in EAE

Pitt et al, Nature Medicine 6:67, 2000

Phenytoin protects Axons in EAE: Phenytoin protects Axons in EAE: Na+ Channel BlockadeNa+ Channel Blockade

Lo et al, NeuroReport 13:1909, 2002

FK506 Decreases Spinal Cord FK506 Decreases Spinal Cord White Matter DamageWhite Matter Damage

Gold et al, J Neurosci Res, 2004

FK506 Decreases Axonal Loss FK506 Decreases Axonal Loss and Demyelinationand Demyelination

Saline

FK506

Gold et al, J Neurosci Res, 2004

Without FK506Without FK506 With FK506With FK506

NeuronsNeurons NeuronsNeurons

NeuriteNeurite NeuriteNeurite

Courtesy of Dr. Bruce Gold

MS and RemyelinationMS and Remyelination

Adams, A Colour Atlas of Multiple Sclerosis, 1989

MS and RemyelinationMS and Remyelination

Adams, A Colour Atlas of Multiple Sclerosis, 1989

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

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