1. 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

2. 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

3. 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

4. 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

5. 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

6. 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

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

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

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

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

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

12. 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

13. 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

14. 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

15. 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

16. 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

17. 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

18. 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

19. 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

20. 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

21. 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