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Updated: Jul 3, 2026
Rat Model of Blood-brain Barrier Disruption to Allow Targeted Neurovascular Therapeutics
Published on: November 30, 2012
Different effects of KCa and KATP agonists on brain tumor permeability between syngeneic and allogeneic rat models
Keith L Black1, Dali Yin, Bindu M Konda
1Department of Neurosurgery, Maxine Dunitz Neurosurgical Institute, Cedars-Sinai Medical Center, 8631 West Third Street, Suite 800 E., Los Angeles, California 90048, USA. keith.black@cshs.org
Abstract:
The blood-brain tumor barrier (BTB) significantly limits delivery of effective concentrations of chemotherapeutic drugs to brain tumors. Previous studies suggest that BTB permeability may be modulated via alteration in the activity of potassium channels. In this study, we studied the relationship of BTB permeability increase mediated by potassium channel agonists to channel expression in two rat brain tumor models. Intravenous infusion of KCO912 (K(ATP) agonist), minoxidil sulfate (K(ATP) agonist) or NS1619 (K(Ca) agonist) increased tumor permeability more in the 9L allogeneic brain tumor model than in the syngeneic brain tumor model. Consistently, expression of both K(ATP) and K(Ca) channels in 9L tumors was increased to a significantly greater extent in Wistar rats (allogeneic) as compared to Fischer rats (syngeneic). Furthermore, as a preliminary effort to understand clinical implication of potassium channels in brain tumor treatment, we determined the expression of K(ATP) in surgical specimens. K(ATP) mRNA was detected in glioblastoma multiforme (GBM) from nineteen patients examined, with a wide range of expression levels. Interestingly, in paired GBM tissues from seven patients before and after vaccination therapy, increased levels of K(ATP) were detected in five patients after vaccination that had positive response to chemotherapy after vaccination. The present study indicates that the effects of potassium channel agonists on BTB permeability are different between syngeneic and allogeneic models which have different expression levels of potassium channels. The expression of potassium channels in brain tumors is variable, which may be associated with different tumor permeability to therapeutic agents among patients.
Insights
Potassium channel agonists increase blood-brain tumor barrier permeability differently in models with varying channel expression. This suggests variable potassium channel expression in brain tumors impacts drug delivery.
Area of Science:
- Neuroscience
- Pharmacology
- Oncology
Background:
- The blood-brain tumor barrier (BTB) restricts chemotherapy delivery to brain tumors.
- Potassium channel activity may modulate BTB permeability.
Purpose of the Study:
- To investigate the relationship between potassium channel expression and BTB permeability modulation by channel agonists in brain tumor models.
- To explore the clinical relevance of potassium channels in glioblastoma multiforme (GBM) treatment.
Main Methods:
- Administered potassium channel agonists (KCO912, minoxidil sulfate, NS1619) to two rat brain tumor models (syngeneic and allogeneic).
- Quantified BTB permeability and K(ATP)/K(Ca) channel expression in tumors.
- Analyzed K(ATP) mRNA expression in human GBM surgical specimens.
Main Results:
- Potassium channel agonists increased tumor permeability more in the allogeneic (9L) model than the syngeneic model.
- Higher K(ATP) and K(Ca) channel expression was observed in the allogeneic model.
- K(ATP) mRNA was detected in all GBM samples, with increased levels post-vaccination in responders.
Conclusions:
- BTB permeability modulation by potassium channel agonists differs between syngeneic and allogeneic models, correlating with channel expression levels.
- Variable potassium channel expression in brain tumors may influence therapeutic agent permeability.
- K(ATP) channel expression shows potential association with chemotherapy response in GBM patients.
