A 68-year-old man with a history of Parkinson disease is hospitalized for pneumonia and sepsis. The patient is treated with intravenous (IV) fluids and antibiotics. He is also started on an infusion of IV dopamine for hemodynamic support. Although the manifestations of Parkinson disease are attributed to dopaminergic neuron degeneration in the substantia nigra, IV dopamine does not improve this patient's Parkinson symptoms. Which of the following cell structures accounts for this lack of responsiveness?
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This patient's Parkinson symptoms do not improve with intravenous dopamine infusion because dopamine is unable to cross the blood-brain barrier. The blood-brain barrier is formed by tight junctions between nonfenestrated capillary endothelial cells that prevent the paracellular passage of fluid and solutes. Tight junctions, also known as zonulae occludentes, are composed of transmembrane proteins (eg, claudins and occludins) that associate with actin filaments, forming a beltlike seal around the apical intercellular space. This seal only permits the passage of substances from the blood to the brain via transcellular movement.
Transcellular movement of dopamine is limited by the molecule's low lipid solubility and the lack of dopamine-specific transport carriers in capillary endothelial cells of the blood-brain barrier. L-DOPA (dopamine precursor) also has low lipid solubility, but it is able to enter the brain due to its high affinity for the large neutral amino acid transporter.
(Choice A) Desmosomes (maculae adherentes) are spotlike junctions that anchor adjacent cells together via keratin intermediate filament interactions. Autoantibodies against desmosomes in the stratum spinosum of the skin cause pemphigus vulgaris.
(Choice B) Fenestrae are small pores within endothelial cells that allow free fluid exchange between the intravascular and extravascular spaces. They are found in capillaries perfusing the intestine, renal tubules, and endocrine glands.
(Choice C) Gap junctions are composed of connexin proteins that create channels between cells, permitting the free passage of small ions (eg, Ca2+) and molecules.
(Choice D) Hemidesmosomes are similar to desmosomes but bind the basal layer of epithelial cells to the basement membrane. Autoantibodies against hemidesmosomes in the skin cause bullous pemphigoid.
(Choice E) Intermediate junctions (zonula adherens or belt desmosomes) are located below tight junctions and form a beltlike anchor between adjacent cells in association with actin microfilaments.
Educational objective:
The blood-brain barrier is formed by tight junctions between nonfenestrated capillary endothelial cells that prevent the paracellular passage of fluid and solutes. This barrier only permits the passage of substances from the blood to the brain via transcellular movement across the endothelial plasma membrane, which is limited by diffusion or carrier-mediated transport.