Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline
Roland Månsson1, Magnus J Hansson, Saori Morota
1Laboratory for Experimental Brain Research, Department of Clinical Sciences, Lund University, Sweden. roland.mansson@med.lu.se
Abstract:
Minocycline has been shown to be neuroprotective in ischemic and neurodegenerative disease models and could potentially be relevant for clinical use. We revisited the hypothesis that minocycline acts through direct inhibition of calcium-induced mitochondrial permeability transition (mPT) resulting in reduced release of cytochrome c (cyt c). Minocycline, at high dosage, was found to prevent calcium-induced mitochondrial swelling under energized conditions similarly to the mPT inhibitor cyclosporin A (CsA) in rodent mitochondria derived from the CNS. In contrast to CsA, minocycline dose-dependently reduced mitochondrial calcium retention capacity (CRC) and respiratory control ratios and was ineffective in the de-energized mPT assay. Further, minocycline did not inhibit calcium- or tBid-induced cyt c release. We conclude that the neuroprotective mechanism of minocycline is likely not related to direct inhibition of mPT and propose that the mitochondrial effects of minocycline may contribute to toxicity rather than tissue protection at high dosing in animals and humans.
Insights
Minocycline's neuroprotective effects are not due to direct inhibition of mitochondrial permeability transition (mPT). High doses may cause toxicity by negatively impacting mitochondrial function, challenging its therapeutic potential.
Area of Science:
- Neuroscience
- Mitochondrial Biology
- Pharmacology
Background:
- Minocycline exhibits neuroprotective properties in models of ischemic and neurodegenerative diseases.
- Its potential clinical relevance is linked to its proposed mechanism of inhibiting calcium-induced mitochondrial permeability transition (mPT).
Purpose of the Study:
- To investigate whether minocycline directly inhibits calcium-induced mPT and subsequent cytochrome c release.
- To clarify the mitochondrial mechanisms underlying minocycline's neuroprotective effects.
Main Methods:
- Assessing minocycline's effect on calcium-induced mitochondrial swelling in rodent CNS mitochondria.
- Measuring mitochondrial calcium retention capacity (CRC) and respiratory control ratios.
- Evaluating minocycline's impact on calcium- or tBid-induced cytochrome c release.
Main Results:
- Minocycline prevented calcium-induced mitochondrial swelling at high doses, similar to cyclosporin A (CsA).
- Unlike CsA, minocycline reduced CRC and respiratory control dose-dependently and failed in de-energized mPT assays.
- Minocycline did not inhibit calcium- or tBid-induced cytochrome c release.
Conclusions:
- Minocycline's neuroprotective mechanism is unlikely to involve direct inhibition of mPT.
- High-dose minocycline's mitochondrial effects may contribute to toxicity rather than protection.
- Further research is needed to understand minocycline's complex role in neuroprotection and potential toxicity.
