Multiple Sclerosis Introduction.ppt

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Neuroprotection in Multiple Sclerosis:Introduction

Neuroprotection in Multiple Sclerosis:Introduction

Multiple Sclerosis: PathogenesisMultiple Sclerosis: Pathogenesis

Demyelination

Axonal damage/loss, neurodegeneration

Inflammation

Steinman L. Nat Immunol 2001;2:762–4

Inflammatory phase

Degenerative phase

The Two Faces of MSThe Two Faces of MS

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Possible Pathogenic Mechanisms: The Role of the Immune SystemPossible Pathogenic Mechanisms: The Role of the Immune System

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:938–52

Inflammation: Possible MechanismsInflammation: Possible Mechanisms

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:938–52

Demyelination: Possible MechanismsDemyelination: Possible Mechanisms

Adapted from Noseworthy JH et al. N Engl J Med 2000;343:938–52

Pattern I

Pattern II

Pattern III

Pattern IV

Antibodies Oligodendrocyte-Dystrophy

T-cells + Macrophages

+ Complement

Primary OG damage

Heterogeneity of MS PathologyHeterogeneity of MS Pathology

Lucchinetti C et al. Ann Neurol 2000;47:707–17

Myelin ScarringMyelin Scarring

Sclerosis(scarring)

Oligodendrocyte

Electric pulse

Image supplied by Dimitrios Karussis

Evidence for Neurodegeneration in MSEvidence 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: HistopathologyMS: Histopathology

Adapted with permission from Waxmann SG. N Engl J Med 1998;338:323–25; and Trapp BD et al. N Engl J Med 1998;338:278–85

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Evidence for Neurodegeneration in MSEvidence 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 NAWMAxonal Loss in NAWM

Bjartmar C. Neurology 2001;57:1248–52

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Evidence for Neurodegeneration in MSEvidence 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 MSEvidence for Neurodegeneration in MS

Image supplied by Dimitrios Karussis

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

Compston A, Coles A. Lancet 2002;359:1221–31

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Evidence for Neurodegeneration in MS: Is it a Distinct/Separate Process?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: 0–4, great variability; 4–7, very homogenic, indicating a degenerative pattern

Possible Neurotoxic Mechanisms in MSPossible 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

Inflammatory mechanisms:1. NO2. CD8 cytotoxicity3. TNF4. Pro-inflammatory cytokines5. Antibodies6. Oedema

Excitotoxic mechanisms:1. Glutamate overactivation2. Ca++ influx3. Na+ influx

Apoptotic mechanisms:1. Caspase pathway2. Other

Demyelination induced:1. Increased vulnerability to damage of demyelinated axons2. Dying back mechanism

Depletion of growth factors:1. Depletion of stem cells2. Lack of inflammatory cells which may produce GF

Energy depletion:1. Mitochondrial dysfunction2. Free radicals

Genetic determination:1. Genetic programme2. Degeneration

Why and How a Neuron Dies: Degeneration of AxonsWhy and How a Neuron Dies: Degeneration of Axons

What is Neuroprotection?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 NeuroprotectionHow a Neuron/Axon Dies: Implications for Neuroprotection

Inflammatory mechanisms:1. NO2. CD8 cytotoxicity3. TNF4. Pro-inflammatory cytokines5. Antibodies6. Oedema

Excitotoxic mechanisms:1. Glutamate overactivation2. Ca++ influx3. Na+ influx

Apoptotic mechanisms:1. Caspase pathway2. Other

Demyelination induced:1. Increased vulnerability to damage of demyelinated axons2. Dying back mechanism

Depletion of growth factors:1. Depletion of stem cells2. Lack of inflammatory cells which may produce GF

Energy depletion:1. Mitochondrial dysfunction2. Free radicals

Genetic determination:1. Genetic programme2. Degeneration

Possible Neuroprotective Strategies in MSPossible 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?

NeuroprotectionAnti-inflammation

The Two Faces of Multiple Sclerosis: Need a Combined TherapyThe Two Faces of Multiple Sclerosis: Need a Combined Therapy

Future Treatment of MSFuture Treatment of MS

• We need more effective immunomodulation

• Combine with neuroprotection strategies

Neuroprotective Treatment: When to Apply?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?