Neuroprotection in Multiple Sclerosis: Introduction

Multiple Sclerosis: Pathogenesis

Inflammation Demyelination

Axonal damage/loss, neurodegeneration

The Two Faces of MS

Inflammatory phase

Degenerative phase

Steinman L. Nat Immunol 2001;2:7624

Possible Pathogenic Mechanisms: The Role of the Immune System

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Inflammation: Possible Mechanisms

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Demyelination: Possible Mechanisms

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:93852

Heterogeneity of MS Pathology
Antibodies

T-cells + Macrophages

OligodendrocyteDystrophy

Pattern I Pattern II Pattern III Pattern IV

Primary OG damage + Complement

Lucchinetti C et al. Ann Neurol 2000;47:70717

Myelin Scarring
Electric pulse Oligodendrocyte

Sclerosis (scarring)

Image supplied by Dimitrios Karussis

Evidence for Neurodegeneration in MS

Accumulation of APP in active lesions Axonal ovoids/transected axons at the edge and the core of active lesions Oxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexes CD8 lymphocytes mediate axonal transection Axons exposed to NO are vulnerable to degeneration

MS: Histopathology
Copyright 1998 Massachusetts Medical Society. All rights reserved

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

Evidence for Neurodegeneration in MS

Accumulation of APP in active lesions Axonal ovoids/transected axons at the edge and the core of active lesions Oxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexes CD8 lymphocytes mediate axonal transection Axons exposed to NO are vulnerable to degeneration

Axonal Loss in NAWM

Bjartmar C. Neurology 2001;57:124852

Reproduced with permission

Evidence for Neurodegeneration in MS

Accumulation of APP in active lesions Axonal ovoids/transected axons at the edge and the core of active lesions Oxidative damage in mitochondrial DNA and impaired activity of mitochondrial enzyme complexes CD8 lymphocytes mediate axonal transection Axons exposed to NO are vulnerable to degeneration

Evidence for Neurodegeneration in MS

Image supplied by Dimitrios Karussis

The Two Faces of MS: Inflammation and Degeneration/Axonal Loss

Reprinted with permission from Elsevier

Compston A, Coles A. Lancet 2002;359:122131

Evidence for Neurodegeneration in MS: Is it a Distinct/Separate Process?

Reduction in axonal density in NAWM in MS More prominent reduction of axonal density in spinal cord NAWM in progressive MS patients Axonal loss is not always related to inflammatory activity

Correlation between NAA reduction and disability

Time from EDSS: 04, great variability; 47, very homogenic, indicating a degenerative pattern

Possible Neurotoxic Mechanisms in MS

Glutamate-mediated cytotoxicity CD8 T-cell mediated toxicity Inflammatory mediators, MMPs NO and reactive oxygen species Ca++ and Na+ influx Ca++-dependent enzymes

Why and How a Neuron Dies: Degeneration of Axons

Inflammatory mechanisms: 1. NO 2. CD8 cytotoxicity 3. TNF 4. Pro-inflammatory cytokines 5. Antibodies 6. Oedema Excitotoxic mechanisms: 1. Glutamate overactivation 2. Ca++ influx 3. Na+ influx Energy depletion: 1. Mitochondrial dysfunction 2. Free radicals

Demyelination induced: 1. Increased vulnerability to damage of demyelinated axons 2. Dying back mechanism

Genetic determination: 1. Genetic programme 2. Degeneration Apoptotic mechanisms: 1. Caspase pathway 2. Other

Depletion of growth factors: 1. Depletion of stem cells 2. Lack of inflammatory cells which may produce GF

What is Neuroprotection?
Neuroprotection
Prevention of the original insult

Protection of neurons and their processes

Can be mediated or supported by exogenous or endogenous factors

Neuroregeneration
Recovery 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 Neuroprotection

Excitotoxic mechanisms: Inflammatory mechanisms: 1. Glutamate overactivation 1. NO 2. Ca++ influx 2. CD8 cytotoxicity 3. Na+ influx Energy depletion: 3. TNF 1. Mitochondrial dysfunction 4. Pro-inflammatory cytokines 2. Free radicals 5. Antibodies 6. Oedema

Demyelination induced: 1. Increased vulnerability to damage of demyelinated axons 2. Dying back mechanism

Genetic determination: 1. Genetic programme 2. Degeneration Apoptotic mechanisms: 1. Caspase pathway 2. Other

Depletion of growth factors: 1. Depletion of stem cells 2. Lack of inflammatory cells which may produce GF

Possible Neuroprotective Strategies in MS

Anti-excitotoxic agents (e.g., glutamate receptor antagonists)

iNOS inhibitors
Calpain inhibitors Free radical scavengers Anti-apoptotic therapies (e.g. caspase inhibitors) Na+ channel- or Na+/Ca++-exchanger inhibitors

Neurotrophic factors/stem cells

Induction of protective inflammation?

The Two Faces of Multiple Sclerosis: Need a Combined Therapy

Anti-inflammation

Neuroprotection

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?