*Neuroprotection in Multiple Sclerosis:Introduction

Multiple Sclerosis: PathogenesisDemyelinationAxonal damage/loss, neurodegenerationInflammation

Steinman L. Nat Immunol 2001;2:7624Inflammatory phaseDegenerative phaseThe Two Faces of MSReproduced with permission from Nature Publishing Group

Possible Pathogenic Mechanisms: The Role of the Immune SystemAdapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Inflammation: Possible MechanismsAdapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Demyelination: Possible MechanismsAdapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Pattern I

Pattern II

Pattern III

Pattern IVAntibodiesOligodendrocyte-DystrophyT-cells + Macrophages+ ComplementPrimary OG damageHeterogeneity of MS PathologyLucchinetti C et al. Ann Neurol 2000;47:70717

Myelin ScarringSclerosis(scarring)OligodendrocyteElectric pulseImage supplied by Dimitrios Karussis

Evidence for Neurodegeneration in MSAccumulation of APP in active lesionsAxonal ovoids/transected axons at the edge and the core of active lesionsOxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexesCD8 lymphocytes mediate axonal transectionAxons exposed to NO are vulnerable to degeneration

MS: HistopathologyAdapted with permission from Waxmann SG. N Engl J Med 1998;338:32325; and Trapp BD et al. N Engl J Med 1998;338:27885Copyright 1998 Massachusetts Medical Society. All rights reserved

Evidence for Neurodegeneration in MSAccumulation of APP in active lesionsAxonal ovoids/transected axons at the edge and the core of active lesionsOxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexesCD8 lymphocytes mediate axonal transectionAxons exposed to NO are vulnerable to degeneration

Axonal Loss in NAWMBjartmar C. Neurology 2001;57:124852Reproduced with permission

Evidence for Neurodegeneration in MSAccumulation of APP in active lesionsAxonal ovoids/transected axons at the edge and the core of active lesionsOxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexesCD8 lymphocytes mediate axonal transectionAxons exposed to NO are vulnerable to degeneration

Evidence for Neurodegeneration in MSImage supplied by Dimitrios Karussis

The Two Faces of MS: Inflammation and Degeneration/Axonal LossCompston A, Coles A. Lancet 2002;359:122131Reprinted with permission from Elsevier

Evidence for Neurodegeneration in MS: Is it a Distinct/Separate Process?Reduction in axonal density in NAWM in MSMore prominent reduction of axonal density in spinal cord NAWM in progressive MS patientsAxonal loss is not always related to inflammatory activityCorrelation between NAA reduction and disabilityTime from EDSS: 04, great variability; 47, very homogenic, indicating a degenerative pattern

Possible Neurotoxic Mechanisms in MSGlutamate-mediated cytotoxicityCD8 T-cell mediated toxicityInflammatory mediators, MMPsNO and reactive oxygen speciesCa++ and Na+ influxCa++-dependent enzymes

Inflammatory mechanisms:NOCD8 cytotoxicityTNFPro-inflammatory cytokinesAntibodiesOedemaExcitotoxic mechanisms:Glutamate overactivationCa++ influxNa+ influxApoptotic mechanisms:Caspase pathwayOtherDemyelination induced:Increased vulnerability to damage of demyelinated axons2.Dying back mechanismDepletion of growth factors:Depletion of stem cellsLack of inflammatory cells which may produce GFEnergy depletion:1. Mitochondrial dysfunction2. Free radicalsGenetic determination:1. Genetic programme2. DegenerationWhy and How a Neuron Dies: Degeneration of Axons

What is Neuroprotection?Neuroprotection Prevention of the original insultProtection of neurons and their processes Can be mediated or supported by exogenous or endogenous factors NeuroregenerationRecovery of neuronal cells (or functional neuronal connections) after injury May be stimulated (or inhibited) by exogenous or endogenous factors

How a Neuron/Axon Dies: Implications for NeuroprotectionInflammatory mechanisms:NOCD8 cytotoxicityTNFPro-inflammatory cytokinesAntibodiesOedemaExcitotoxic mechanisms:Glutamate overactivationCa++ influxNa+ influxApoptotic mechanisms:Caspase pathwayOtherDemyelination induced:Increased vulnerability to damage of demyelinated axons2.Dying back mechanismDepletion of growth factors:Depletion of stem cellsLack of inflammatory cells which may produce GFEnergy depletion:1. Mitochondrial dysfunction2. Free radicalsGenetic determination:1. Genetic programme2. Degeneration

Possible Neuroprotective Strategies in MSAnti-excitotoxic agents (e.g., glutamate receptor antagonists)iNOS inhibitorsCalpain inhibitorsFree radical scavengersAnti-apoptotic therapies (e.g. caspase inhibitors)Na+ channel- or Na+/Ca++-exchanger inhibitorsNeurotrophic factors/stem cellsInduction of protective inflammation?

NeuroprotectionAnti-inflammationThe Two Faces of Multiple Sclerosis: Need a Combined Therapy

Future Treatment of MS

We need more effective immunomodulation

Combine with neuroprotection strategies

Neuroprotective Treatment: When to Apply?Seems to be most needed in late SP and PP MS

Evidence that the changes observed in late stages are at least partially pre-determined by early (inflammatory) events

As early as possible?

***Steinman L Nat Immunol 2001;2:7624. Reproduced with permission from Nature Publishing Group*******Adapted with permission from Waxmann SG N Engl J Med 1998;338:32325; and Trapp BD, et al. N Engl J Med 1998;338:27885. Copyright 1998 Massachusetts Medical Society. All rights reserved

*****Compston A, Coles A. Lancet 2002;359:122131. Reprinted with permission from Elsevier

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