Lesson 16: Neurodegenerative Diseases (CEU, 2024/25) PDF

Lesson 16 Neurodegenerative diseases 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1.NEURODEGENERATIVE DISEASES 2.MECHANISMS OF NEURONAL DEATH 3.DRUGS FOR NEURODEGENERATIVE DISEASES 2  1. NEURODEGE...

Lesson 16 Neurodegenerative diseases 3° Medicine Professor: Vittoria Carrabs PhD Academic year: 2024/25 SUMMARY 1.NEURODEGENERATIVE DISEASES 2.MECHANISMS OF NEURONAL DEATH 3.DRUGS FOR NEURODEGENERATIVE DISEASES 2  1. NEURODEGENERATIVE DISEASES A neurodegenerative disease is a condition characterized by the progressive degeneration or death of neurons in the CNS. Result in the loss of cognitive and motor functions and can lead to disability and death over time. Common neurodegenerative diseases include Alzheimer's disease, Parkinson's disease, Amyotrophic Lateral Sclerosis (ALS), and Huntington's disease. 3  1. NEURODEGENERATIVE DISEASES - In the adult CNS, dead neurons are not replaced. - Interrupted axons cannot regenerate their terminals. - Limited neuronal regeneration → unpromising area for pharmacological intervention. 4  1. NEURODEGENERATIVE DISEASES Protein misfolding and aggregation is the initial step in many neurodegenerative diseases. Aggregates gradually accumulate with age, forming amyloid deposits. As occurs in Alzheimer's disease, these plaques disrupt neuronal communication and trigger inflammatory responses, which contribute to the neurodegenerative process. 5 1. NEUROEGENERATIVE DISEASES 6  1. NEURODEGENERATIVE DISEASES The body has protective mechanisms to counteract the damage caused by misfolded proteins. These mechanisms include: 1. Production of chaperone proteins: - Chaperone proteins bind to misfolded proteins and assist in helping them fold correctly. This is crucial to prevent the formation of toxic protein aggregates, which can harm neurons. 7  1. NEURODEGENERATIVE DISEASES The body has protective mechanisms to counteract the damage caused by misfolded proteins. These mechanisms include: 2. Ubiquitination reaction: - “Ubiquitination” is a cellular process that tags defective or damaged proteins with a small protein called ubiquitin. This tag signals the protein for destruction within the proteasome, a cellular complex that degrades and recycles damaged proteins, helping maintain cellular health. These mechanisms are essential for maintaining protein balance within cells and preventing the accumulation of misfolded proteins, which is a key factor in many neurodegenerative diseases. 8 INDEX 1. NEUROEGENERATIVE DISEASES 2. MECHANISMS OF NEURONAL DEATH 3. DRUGS FOR NEURODEGENERATIVE DISEASES 10 2. MECHANISMS OF NEURONAL DEATH NECROSIS: Due to acute injury to cells. – inflammatory response. neurodegenerative disorders Necrosis: is an uncontrolled form of cell death that occurs in response to injury, infection, or insufficient blood supply. 11 2. MECHANISMS OF NEURONAL DEATH EXCITOTOXICITY Glutamate and Ca2+ are the two most ubiquitous chemical signals, extracellular and intracellular. Glutamate is highly toxic to neurons. is highly toxic to neurons and is widely used as a taste-enhancing food additive, which raises concerns Calcium overload: a crucial factor in excitotoxicity, contributing significantly to neuronal death. 12  2. MECHANISMS OF NEURONAL DEATH APOPTOSIS Mitochondrial energy metabolism: one line of defence – impaired mitochondrial function can cause apoptosis. Activation of a family of proteases (caspases), may be involved in apoptosis. – Neural apoptosis is prevented by neuronal growth factors, including: nerve growth factor and brain-derived neurotrophic factor. Mitochondrial integrity is essential for Apoptosis is a programmed, controlled process of neuronal survival. cell death, where cells shrink and are safely Mitochondrial dysfunction is considered a removed without triggering inflammation. It is essential for normal development and tissue major factor in many neurodegenerative maintenance. disorders. 13  2. MECHANISMS OF NEURONAL DEATH OXIDATIVE STRESS High Energy Needs: The brain requires a lot of energy, which it gets by producing ATP Oxygen Reduction: During ATP production, oxygen (O2) is reduced to water (H2O) Reactive Oxygen Species (ROS): This process can generate highly reactive molecules like oxygen and hydroxyl free radicals, and hydrogen peroxide (H2O2) Oxidative Stress: When the production of ROS exceeds the cells’ ability to neutralize them with antioxidants, oxidative stress occurs. This imbalance can lead to significant cellular damage and contribute to the development of neurodegenerative diseases such as Alzheimer’s and Parkinson’s 14  2. MECHANISMS OF NEURONAL DEATH ISCHAEMIC BRAIN DAMAGE After heart disease and cancer, strokes are the commonest cause of death in Europe and North America Interruption of blood supply to the brain initiates the cascade of neuronal events Pathophysiology Ischaemia causes: – depolarisation of neurons, and the release of large amounts of glutamate. Ca2+ accumulation occurs, partly as a result of glutamate acting on NMDA receptors. – Nitric oxide is also produced in amounts much greater than result from normal neuronal activity 15  2. MECHANISMS OF NEURONAL DEATH ALZHEIMER’S DISEASE Pathogenesis Alzheimer’s disease (AD) is a common age-related dementia Main Pathological Features: Amyloid Plaques: Deposits of beta-amyloid proteins that accumulate in neurons. Neurofibrillary Tangles: Abnormal aggregates of the Tau protein inside neurons. Loss of Neurons: Reduction in the number of neurons in the brain. Genetic Mutations: ApoE4: Mutations in the ApoE4 lipoprotein gene are associated with a higher risk of developing AD. Tau: Intracellular aggregates of the Tau protein contribute to neuronal degeneration. Loss of Cholinergic Neurons: The loss of these neurons is believed to account for much of the learning and memory deficits observed in AD. 16 INDEX 1. NEUROEGENERATIVE DISEASES 2. MECHANISMS OF NEURONAL DEATH 3. DRUGS FOR NEURODEGENERATIVE DISEASES 17 3. DRUGS FOR NEURODEGENERATIVE DISEASES inhibite Ach esterase = enhance Ach Currently, cholinesterase inhibitors (Donezepil, Rivastigmine) and Memantine are the only drugs approved for treating AD. Why??? 18  3. DRUGS FOR NEURODEGENERATIVE DISEASES Memantine an orally active weak antagonist at NMDA receptors: a potential inhibitor of excitotoxicity. It produces a modest cognitive improvement in moderate or severe AD, but does not appear to be neuroprotective. It has a long half-life ADRs: headache, dizziness, drowsiness, constipation, shortness of breath and hypertension. name !! block Ach esterase and Ach degradaition 3. DRUGS FOR NEURODEGENERATIVE DISEASES 20  3. DRUGS FOR NEURODEGENERATIVE DISEASES CLINICAL USE OF DRUGS IN DEMENTIA: Acetylcholinesterase Inhibitors and NMDA Antagonists: Improve cognitive impairment in clinical trials. Limited clinical use due to significant adverse effects. Not shown to retard neurodegeneration. Periodically monitored in individual patients. Continued administration only if drugs are effective. ACETYLCHOLINESTERASE INHIBITORS: Donepezil, Galantamine, Rivastigmine. Tacrine is also effective, but may cause liver damage. Unwanted cholinergic effects may be troublesome. Used in mild to moderate Alzheimer’s disease. NMDA RECEPTOR ANTAGONISTS: Memantine Used in moderate to severe Alzheimer’s disease. 21