Parkinson’s disease (PD) is chronic progressive neurodegenerative disease, characterized by motor symptoms, but also non-motor symptoms. Pathophysiology The complex interplay of genetic, environmental, and cellular factors is believed to contribute to the pathophysiology of IS.
Zepbound (tirzepatide ) is a prescription medication used to help certain adults with weight control. It comes in a liquid solution in prefilled injection pens and is injected subcutaneously (just beneath the skin) once a week.
Loss of Dopaminergic Neurons
- Site: Substantia nigra pars compacta in the midbrain.
- Consequence: Decreased striatal release of dopamine, which is an important part of the basal ganglia that controls movement. This inversion affects the balance between excitatory and inhibitory pathways in motor circuits, confounding voluntary motor control.
Formation of Lewy Bodies
- Composition: Proteins misfolded alpha-synuclein and ubiquitin.
- Pathological Role:
- Existence of alpha-synuclein results in cellular degeneration.
- Inhibition of protein degradation pathways, such as the ubiquitin-proteasome system and autophagy, worsens neuronal injury.
Neuroinflammation
- Microglial activation: The brains of people with depression show microglial overactivation that promotes the release of various pro-inflammatory cytokines (e.g., TNF-α, IL-1β) which can result in neuronal damage.
- Oxidative Stress: Enhanced generation of reactive oxygen species (ROS) and impaired antioxidant defenses lead to cellular damage.
Mitochondrial Dysfunction
- Pathophysiology Defective mitochondrial complexes (most notably Complex I in the electron transport chain) lead to reduced ATP production and increased oxidative stress.
- Energy shortages are detrimental to cellular operations and lead to sensitivity to apoptosis.
Excitotoxicity
- Dopaminergic inhibition loss subsequently leads to hyperactivity of glutamatergic neurons, causing excitotoxic neuronal damage.
- Inhibited Neural Networks in the Basal Ganglia
- Disruption of signaling in the direct and indirect pathways:
- Direct Pathway (movement): Activity decreased (dopamine sparing).
- Indirect Pathway (inhibition of movement): Overactivity from lower direct pathway inhibition = rigidity, bradykinesia.
Genetic Contributions
- Mutations in genes like SNCA (for alpha-synuclein), LRRK2, PINK1, PARKIN, and DJ-1 are linked to familial as well as sporadic forms of the disease.
- They alter pathways like protein aggregation, mitochondrial function, and cellular stress responses.
Clinical Implications
- The dynamic of such mechanisms results in the classic motor features of Parkinson’s disease:
- Bradykinesia (slowness of movement)
- Rigidity (muscle stiffness)
- Tremor (resting tremor)
- Postural instability (problems with balance)
- Cognitive decline, autonomic dysfunction, sleep and mood disorders are collectively termed as non-motor symptoms.
Knowledge of these mechanisms is key to devising targeted therapeutic interventions to slow or arrest disease progression. Current therapies are mainly dopamine replacement (eg, levodopa) based, while newer approaches seek to target underlying pathophysiologic processes such as alpha-synuclein aggregation and mitochondrial dysfunction.
- Hypoglycemia (low blood sugar): Especially in combination with diabetes medications.
- Cardiovascular effects: Tachycardia, episodes of sinus tachycardia.
- Pancreas problems: A few reports of acute pancreatitis, cholelithiasis (gallstones) have been reported.
- Injection site reactions: Redness, swelling, or pain at the injection site (areas where it is administered).
- Hypersensitivity reactions: such as urticaria (hives) and rarely anaphylaxis.
- Neuropsychiatric symptoms: Including shakiness, slurring of speech or altered mental state
Conclusion
To summarise, Zepbound (tirzepatide) is a novel therapy indicated for weight loss and glycaemic control in certain populations. Although these are effective, they can also have side effects which may include mild gastrointestinal side effects all the way up to pancreatitis, cardiovascular effects and hypersensitivity reactions.
Monitoring for these side effects can also help you follow the advice of the attending physician and report unusual symptoms to the doctor.
