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Mechanisms underlying seizures and hypothermia during busulphan administration
Ibrahim El-Serafi1,2, Sofia Berglund3,4, Fadwa BenKessou5,3
1Experimental Cancer Medicine (ECM), Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden. i.elserafi@ajman.ac.ae.
Bone Marrow Transplantation
|May 3, 2025
Summary
Sulfolane, a busulphan metabolite, causes seizures and hypothermia by accumulating in the brain. This study identifies sulfolane as the primary culprit behind busulphan
Area of Science:
- Pharmacology
- Neuroscience
- Toxicology
Background:
- Busulphan (Bu) is a key agent in conditioning regimens before hematopoietic stem cell transplantation (HSCT).
- Neurotoxicity is a significant adverse effect associated with busulphan administration.
- Understanding busulphan's metabolism and its neurotoxic mechanisms is crucial for patient safety.
Purpose of the Study:
- To investigate the pharmacokinetic profile of busulphan and its metabolites in patients and mice.
- To elucidate the mechanisms underlying busulphan-induced central nervous system (CNS) toxicity in a murine model.
- To identify which specific busulphan metabolite is responsible for neurotoxic effects.
Main Methods:
- Quantification of busulphan and its metabolites (tetrahydothiophene, tetrahydrothiophene-1-oxide, sulfolane, 3-OH-sulfolane) in plasma and urine of patients and mice.
- Pharmacokinetic analysis comparing brain and plasma concentrations of metabolites in mice.
- Administration of busulphan or individual metabolites to mice to assess neurotoxic effects, including behavioral changes, seizures, hypothermia, and electrophysiological recordings.
- Measurement of calbindin-28k concentrations in the brain.
Main Results:
- Busulphan metabolites were detected up to 72 hours post-administration.
- Sulfolane levels peaked concurrently with reported seizure occurrences and showed the highest brain-to-plasma exposure ratio (AUCbrain/AUCplasma).
- Sulfolane administration in mice induced seizures, hypothermia, and a decrease in brain calbindin-28k levels, while lower doses caused behavioral changes without convulsions.
- Electrophysiological recordings revealed reduced spontaneous neuronal activity in pyramidal neurons upon sulfolane exposure.
Conclusions:
- Sulfolane is identified as the primary metabolite responsible for busulphan-induced seizures and hypothermia.
- Plasma sulfolane concentrations correlate with its brain levels, suggesting it as a reliable biomarker for CNS exposure.
- The role of calbindin-D28K in neurotoxicity and potential links to neurodegenerative diseases warrants further investigation.
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