Lack of evidence of direct mitochondrial involvement in the neuroprotective effect of minocycline

Cornet, Sylvie; Spinnewyn, B.; Delaflotte, Sylvie; Charnet, Christelle; Roubert, Véronique; Favre, C.; Hider, Hamida; Chabrier, P; Auguet, Michel

doi:10.1016/j.ejphar.2004.10.039

Cited by 28 publications

(22 citation statements)

References 34 publications

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“…Minocycline increased the swelling response to Ca 2+ at lower doses and longer incubations, an effect more pronounced in spinal cord mitochondria. A similar finding has been demonstrated in isolated liver mitochondria where concentrations ≥10 µM minocycline induced swelling (Cornet et al, 2004). In energized mitochondria, Ca 2+ -induced mPT (measured e.g.…”

Section: Discussionsupporting

confidence: 67%

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Månsson¹,

Hansson²,

Morota³

et al. 2007

Neurobiology of Disease

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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.

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Section: Discussionsupporting

confidence: 67%

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Månsson¹,

Hansson²,

Morota³

et al. 2007

Neurobiology of Disease

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“…This observation may perhaps be an explanation for the observed detrimental effects of MC [16,[18][19][20] and requires further clarification.…”

Section: +mentioning

confidence: 99%

“…Furthermore, neuroprotective potency of MC has been observed in experimental models of acute cerebral ischemia [10,11], spinal cord- [12][13][14] and traumatic brain injury [15]. But, also contradictory and even detrimental effects of MC were reported recently [16][17][18][19][20], pointing at the importance of a thorough understanding of the detailed cellular and molecular mechanisms triggered by MC.…”

Section: Introductionmentioning

confidence: 99%

Inhibitory modulation of the mitochondrial permeability transition by minocycline

Gieseler

Schultze

Kupsch

et al. 2009

Biochemical Pharmacology

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The semisynthetic tetracycline derivative minocycline exerts neuroprotective properties in various animal models of neurodegenerative disorders. Although antiinflammatory and anti-apoptotic effects are reported to contribute to the neuroprotective action, the exact molecular mechanisms underlying the beneficial properties of minocycline remain to be clarified. We analyzed the effects of Additionally, we provide evidence for the high antioxidant potential of MC in our model. In conclusion, the present data substantiate the beneficial properties of minocycline as promising neuroprotectant by its inhibitory activity on the mitochondrial permeability transition pore.

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“…A reduced micromolar range of minocycline was investigated, as many research groups have already studied the effects of minocycline on isolated mitochondria at concentrations up to 100-200 μM (e.g. Zhu et al 2002;Cornet et al 2004;Fernandez-Gomez et al 2005;Kupsch et al 2009;Antonenko et al 2010;GarciaMartinez et al 2010;Mansson et al 2010). Since the concentrations might be difficult to obtain in vivo and some of the studies report their deleterious effects on energy Fig.…”

Section: In the Presence Of Vdac Minocycline Protects Yeast Cells Agamentioning

confidence: 99%

Cytoprotective activity of minocycline includes improvement of mitochondrial coupling: the importance of minocycline concentration and the presence of VDAC

Karachitos

Jordan

Kmita

2012

J Bioenerg Biomembr

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biotic of the tetracycline family, has cytoprotective properties due to a direct interaction with mitochondria. Yet, the data in the case of isolated mitochondria suggest discrepant or even detrimental effect(s) of the interaction. We have studied the cytoprotective activity displayed by minocycline in the case of the yeast Saccharomyces cerevisiae cells pretreated with H 2 O 2 . We demonstrated that the activity of minocycline required the presence of VDAC (voltage-dependent anion-selective channel) and provided distinct improvement of mitochondrial coupling. In the case of isolated mitochondria, we verified that minocycline exhibited uncoupler activity when applied in micromolar concentrations. However, when added in nanomolar concentrations, minocycline was able to improve the level of coupling for isolated mitochondria. The coupling improvement effect was observed in mitochondria containing VDAC but not in Δpor1 mitochondria (depleted of VDAC1, termed here VDAC) and in both types of mitoplasts. Thus, properly low concentrations of minocycline within the cell in the vicinity of VDAC-containing mitochondria enable the improvement of energy coupling of mitochondria that contributes to cytoprotective activity of minocycline.

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Lack of evidence of direct mitochondrial involvement in the neuroprotective effect of minocycline

Cited by 28 publications

References 34 publications

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Re-evaluation of mitochondrial permeability transition as a primary neuroprotective target of minocycline

Inhibitory modulation of the mitochondrial permeability transition by minocycline

Cytoprotective activity of minocycline includes improvement of mitochondrial coupling: the importance of minocycline concentration and the presence of VDAC

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