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An In Vivo Assessment of Blood-Brain Barrier Disruption in a Rat Model of Ischemic Stroke
Published on: March 11, 2018
Effects of 2,4-dinitrophenol on ischemia-induced blood-brain barrier disruption
1Department of Neurosurgery, University of Michigan Medical School, Ann Arbor, Michigan 48109-0532, USA.
Abstract:
This study examines the effect of 2,4-dinitrophenol (DNP), a mitochondrial uncoupling agent, during focal brain ischemia induced by middle cerebral artery (MCA) occlusion. Blood-brain barrier (BBB) disruption was assessed after 2 hours of occlusion with 2 hours of reperfusion or 4 hours of permanent occlusion by measurement of the influx rate constant (K(i)) for 3H-inulin in the MCA territory ipsi- and contralateral to the occlusion. Three experimental groups were examined: vehicle and 1 and 5 mg/kg DNP treated animals (given 30 minutes prior to occlusion). Four hours of permanent MCA occlusion only induced a modest increase in the K(i) for inulin in vehicle-treated animals (0.09 +/- 0.01 vs. 0.07 +/- 0.01 microL/g/min in contralateral tissue). Although 5 mg/kg DNP significantly increased this disruption (p < 0.01), this effect was relatively minor (0.14 +/- 0.02 microL/g/min). In contrast, DNP treatment in transient ischemia markedly increased barrier disruption. The ipsilateral K(i) for 3H-inulin were 0.15 +/- 0.04, 0.37 +/- 0.06, and 0.79 +/- 0.17 microL/g/min in vehicle, 1 mg/kg DNP and 5 mg/kg DNP groups, respectively. DNP did not induce barrier disruption in the contralateral hemisphere. Thus, while there is evidence that DNP can be neuroprotective, it has adverse effects on the BBB during ischemia, particularly with reperfusion. Considering the importance of naturally- or therapeutically-induced reperfusion in limiting brain damage, this may limit the utility of DNP and mitochondrial uncouplers as therapeutic agents.
Insights
2,4-dinitrophenol (DNP) may harm the blood-brain barrier (BBB) during focal brain ischemia, especially with reperfusion. This finding could limit DNP
Area of Science:
- Neuroscience
- Biochemistry
- Pharmacology
Background:
- Focal brain ischemia, often caused by middle cerebral artery (MCA) occlusion, leads to neuronal damage.
- Mitochondrial uncoupling agents like 2,4-dinitrophenol (DNP) have shown potential neuroprotective effects.
- The impact of DNP on the blood-brain barrier (BBB) integrity during ischemic conditions requires further investigation.
Purpose of the Study:
- To investigate the effects of 2,4-dinitrophenol (DNP) on blood-brain barrier (BBB) disruption during focal brain ischemia.
- To assess whether DNP exacerbates BBB permeability in transient and permanent middle cerebral artery (MCA) occlusion models.
- To evaluate the potential therapeutic limitations of DNP due to its effects on BBB integrity.
Main Methods:
- Induction of focal brain ischemia via middle cerebral artery (MCA) occlusion in animal models.
- Administration of varying doses of 2,4-dinitrophenol (DNP) or vehicle control prior to ischemia.
- Assessment of blood-brain barrier (BBB) disruption using the influx rate constant (K(i)) for 3H-inulin in the ischemic (ipsilateral) and contralateral brain hemispheres.
- Comparison of BBB integrity under permanent ischemia versus transient ischemia with reperfusion.
Main Results:
- Permanent MCA occlusion caused a modest increase in BBB permeability (K(i) for inulin).
- High-dose DNP (5 mg/kg) significantly increased BBB disruption during permanent ischemia, though the effect was minor.
- Transient MCA occlusion combined with DNP treatment markedly increased BBB disruption in a dose-dependent manner, with significant effects observed at 1 and 5 mg/kg DNP.
- DNP did not affect BBB integrity in the non-ischemic (contralateral) hemisphere.
Conclusions:
- While 2,4-dinitrophenol (DNP) may offer neuroprotection, it significantly disrupts blood-brain barrier (BBB) integrity, particularly under conditions of reperfusion following transient ischemia.
- The adverse effects of DNP on BBB permeability may limit its therapeutic utility in treating ischemic stroke, where reperfusion is crucial for limiting brain damage.
- Further research is needed to balance potential neuroprotective benefits against the detrimental effects on BBB integrity for mitochondrial uncouplers like DNP.
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