L4 - Parkinsons

Chapter 1: Introduction to Parkinson's Disease

• Focus of Lecture: Pathophysiology, motor circuit changes, treatments.

• Background on Parkinson's Disease:

  • Chronic progressive disorder of the central nervous system.

  • Second most common neurodegenerative disease after dementia.

  • Approximately 200,000 people in Australia and around 10 million globally live with the disease.

  • Main risk factor: age; some rare cases involve genetic mutations.

• Key Motor Symptoms:

  • Muscle tremors: Often starting in hands at rest.

  • Bradykinesia: Slowing of movement impacting daily tasks.

  • Muscle rigidity: Stiff muscles creating mobility challenges.

  • Altered posture: Stooped or hunched appearance.

• Pathophysiology:

  • Degeneration of dopamine-producing neurons in the substantia nigra affects movement control.

  • Lower dopamine levels impair initiation and control of movement.

  • Alpha-synuclein protein misfolding: Forms Lewy bodies that contribute to neuronal dysfunction and cell death.

• Progression of Symptoms:

  • Initially in substantia nigra, later spreading to cortical regions, affecting cognition, mood, and autonomic functions.

Chapter 2: Dopamine and Acetylcholine in Parkinson's Disease

• Dopamine loss affects more than just the basal ganglia, leading to autonomic dysfunction (e.g., blood pressure instability).

• Dopamine's Role:

  • Acts as a neurotransmitter to inhibit movement through the basal ganglia.

  • Loss of inhibitory control contributes to excessive cholinergic excitation, resulting in tremors and rigidity.

• Pharmacological Targets:

  • Treatment strategies focus on restoring the balance between dopamine and acetylcholine.

  • Direct and indirect pathways of basal ganglia regulate movement:

    • Direct pathway: Facilitates movement via excitatory signals.

    • Indirect pathway: Suppresses unwanted movement through inhibition.

Chapter 3: Postsynaptic Dopamine Receptors

• Cholinergic neurons exert excitatory effects, disrupting normal movement patterns.

• Treatment Strategies:

  • Aim to replenish dopamine levels or reduce cholinergic activity with anticholinergic medications.

  • No current treatments stop neurodegeneration; they only manage symptoms.

Key Treatment Options:

• L-DOPA (Levodopa):

  • Converts to dopamine within the brain; gold standard treatment but can lead to side effects (nausea, behavior changes, dyskinesias).

• Dopamine Agonists:

  • Mimic dopamine action and stimulate recycled receptors; useful early in disease progression or in combination with L-DOPA.

• Monoamine Oxidase B Inhibitors:

  • Prevent dopamine breakdown, enhancing availability.

• NMDA Receptor Antagonists:

  • If used, they help provoke dopamine release and may enhance L-DOPA effects but with considerable side effects.

Chapter 4: DOPA to Dopamine and Beyond

• Challenges of L-DOPA:

  • Peripheral breakdown necessitates co-administration with dopa carboxylase inhibitors.

  • Long-term issues include nausea and compulsive behavior.

• Dopamine Agonists:

  • Direct stimulation of dopamine receptors, however can cause hallucinations and nausea.

• Other Medication Categories:

  • COMT Inhibitors: Enhance effects of L-DOPA by preventing its breakdown; limited by side effects.

  • Muscarinic Antagonists: Rarely used today; aim to rebalance acetylcholine and dopamine.

Chapter 5: Conclusion

• Summary of Parkinson's Disease impact on millions worldwide.

• Current treatments focus on symptom management, restoring the balance of neurotransmitters, primarily dopamine and acetylcholine.

• Need for ongoing research into disease-modifying therapies that can halt neurodegeneration.

• Emerging therapies should address specific cellular mechanisms while commonalities across patients remain targets for broader treatment approaches.