Neuroprotection: The Future for the Treatment of Progressive Multiple Sclerosis? Dennis Bourdette, MD VA MS Center of Excellence-West and Department of Neurology Oregon Health & Science University CMSC, June 2004

MS is an Inflammatory Disease Cartoon of cells in spinal cord (plasma, regulatory T cells, pathogenic T cells, antibodies) Slide shows a Cartoon of cells in spinal cord (plasma, regulatory T cells, pathogenic T cells, antibodies) CMSC, June 2004

Neuroprotection in MS Current DMT are primarily anti-inflammatory DMT are ineffective in treating progressive forms of MS Progressive neurodegenerative axonopathy may underlie progressive disease “Neuroprotective” therapies may be necessary to arrest progressive disease CMSC, June 2004

The Pathogenesis of MS May Involve Both Inflammation and Neurodegeneration RRMS SPMS + Relapses - Relapses PPMS A chart showing a split pathogenesis between inflammation and neurodegeneration for the varying types of MS. CMSC, June 2004

MS and Axonal Loss Adams, A Colour Atlas of Multiple Sclerosis, 1989 Detailed magnified picture of MS and axonal loss Adams, A Colour Atlas of Multiple Sclerosis, 1989

Cerebral Atrophy Occurs in MS Pictures of x-rays showing the changing state of the brain (cerbral atrophy) as it occurs with MS Courtesy of Richard Rudick, MD

MS and Acute Axonal Injury 2 magnified pictures of MS and Acute axonal injury Trapp et al, N Engl J Med, 338:278, 1998

This slide shows 2 pictures: one showing a drawing of myelination of the peripheral nervous system, the other myelination of the central nervous system

How Can We Prevent Brain Atrophy? A funny picture showing an x-ray of Homer Simpson and his tiny brain

Strategies Early highly effective anti-inflammatory therapy Neuroprotective therapies to prevent oligodendrocyte and axonal injury Promote remyelination Provide missing “trophic factors” CMSC, June 2004

A cartoon of the axon and how the myelin sheath is being deteriorated

Glutamate Receptor Blockade is Neuroprotective in EAE Slide shows 2 charts. One shows the average clinical score and the days after injection, the other shows the % loss of oligodendrocytes per dorsal column section for normal, EAE vehicle treated, and EAE NBQX treatment Pitt et al, Nature Medicine 6:67, 2000

Glutamate Receptor Blockade is Neuroprotective in EAE 2 pictures of brain fluids, one treated by Vehicle - treated EAE, the other NBQX – treated EAE Pitt et al, Nature Medicine 6:67, 2000

Phenytoin protects Axons in EAE: Na+ Channel Blockade This slide shows 2 charts. One shows the clinical score opposed to the days, the other shows the total optic nerve axons for CONT + Phen, EAE, and EAE + Phen Lo et al, NeuroReport 13:1909, 2002

FK506 Decreases Spinal Cord White Matter Damage A chart showing decreases in white matter damage for both dorsal and lateral/ventral matter Gold et al, J Neurosci Res, 2004

FK506 Decreases Axonal Loss and Demyelination Saline Magnified pictures of cross sections of axons showing saline and FK506 FK506 Gold et al, J Neurosci Res, 2004

Without FK506 With FK506 Neurons Neurons Neurite Neurite Magnifed pictures of neurons and neurites from the work of Dr. Bruce Gold Courtesy of Dr. Bruce Gold

MS and Remyelination Adams, A Colour Atlas of Multiple Sclerosis, 1989 Picture of remyelination from the Colour Atlas of MS Adams, A Colour Atlas of Multiple Sclerosis, 1989

MS and Remyelination Adams, A Colour Atlas of Multiple Sclerosis, 1989 Picture of remyelination from the Colour Atlas of MS Adams, A Colour Atlas of Multiple Sclerosis, 1989

Obstacles It is uncertain how we should be studying neuroprotective therapies MRI measurements Slowing of clinical disability Experience in other neurologic diseases with neuroprotective therapies is discouraging Stroke ALS PD CMSC, June 2004

Conclusions We should continue to treat early and develop highly effective anti-inflammatory regimens Neuroprotective and neuroregenerative therapies need to be tested in MS CMSC, June 2004