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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
Rep
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with
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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