Clinical potential of minocycline for neurodegenerative disorders

Blum, David; Chtarto, Abdelwahed; Tenenbaum, Liliane; Brotchi, Jacques; Levivier, Marc

doi:10.1016/j.nbd.2004.07.012

Cited by 150 publications

(99 citation statements)

References 109 publications

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“…Minocycline, an antibiotic that like dox is a member of the tetracycline family, has well documented protective effects against neurodegeneration. 33 It is possible that dox has similar neuroprotective effects that could contribute to some extent to the protection we observe when suppressing the transgene in rTg4510 mice. However, the literature on the protective effects of dox is inconclusive.…”

Section: Discussionmentioning

confidence: 93%

Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Spires

Orne

SantaCruz

et al. 2006

The American Journal of Pathology

363

333

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Neurofibrillary tangles form in a specific spatial and temporal pattern in Alzheimer's disease. Although tangle formation correlates with dementia and neuronal loss, it remains unknown whether neurofibrillary pathology causes cell death. Recently, a mouse model of tauopathy was developed that reversibly expresses human tau with the dementia-associated P301L mutation. This model (rTg4510) exhibits progressive behavioral deficits that are ameliorated with transgene suppression. Using quantitative analysis of PHF1 immunostaining and neuronal counts, we estimated neuron number and accumulation of neurofibrillary pathology in five brain regions. Accumulation of PHF1-positive tau in neurons appeared between 2.5 and 7 months of age in a region-specific manner and increased with age. Neuron loss was dramatic and region-specific in these mice, reaching over 80% loss in hippocampal area CA1 and dentate gyrus by 8.5 months. We observed regional dissociation of neuronal loss and accumulation of neurofibrillary pathology, because there was loss of neurons before neurofibrillary lesions appeared in the dentate gyrus and, conversely, neurofibrillary pathology appeared without major cell loss in the striatum. Finally, suppressing the transgene prevented further neuronal loss without removing or preventing additional accumulation of neurofibrillary pathology. Together, these results imply that neurofibrillary tangles do not necessarily lead to neuronal death. (Am J Pathol

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Section: Discussionmentioning

confidence: 93%

Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Spires

Orne

SantaCruz

et al. 2006

The American Journal of Pathology

363

333

View full text Add to dashboard Cite

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“…The therapeutic doses of minocycline, approved by the FDA, for the diseases described above are 100-200 mg/day . In animals, minocycline is lethal at very high doses (LD 50 :3600 mg/kg; Blum et al, 2004;Smith et al, 2003). In humans, long-term treatment with minocycline up to 200 mg/day is generally safe and well tolerated as In recent years, minocycline has been reported to have neuroprotective effects in various experimental neurodegenerative disease models such as cerebral ischemia (Yrjanheikki et al, 1999), traumatic brain injury (Sanchez Mejia et al, 2001), ALS (Zhu et al, 2002), PD (Wu et al, 2002), and HD (Chen et al, 2000;Wang et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Choi

Kim

Shin

et al. 2007

Neuropsychopharmacol

259

179

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Minocycline is a semi-synthetic tetracycline antibiotic that effectively crosses the blood-brain barrier. Minocycline has been reported to have significant neuroprotective effects in models of cerebral ischemia, traumatic brain injury, amyotrophic lateral sclerosis, and Huntington's and Parkinson's diseases. In this study, we demonstrate that minocycline has neuroprotective effects in in vitro and in vivo Alzheimer's disease models. Minocycline was found to attenuate the increases in the phosphorylation of double-stranded RNAdependent serine/threonine protein kinase, eukaryotic translation initiation factor-2 a and caspase 12 activation induced by amyloid b peptide 1-42 treatment in NGF-differentiated PC 12 cells. In addition, increases in the phosphorylation of eukaryotic translation initiation factor-2 a were attenuated by administration of minocycline in Tg2576 mice, which harbor mutated human APP695 gene including the Swedish double mutation and amyloid b peptide 1-42 -infused rats. We found that minocycline administration attenuated deficits in learning and memory in amyloid b peptide 1-42 -infused rats. Increased phosphorylated state of eukaryotic translation initiation factor-2 a is observed in Alzheimer's disease patients' brains and may result in impairment of cognitive functions in Alzheimer's disease patients by decreasing the efficacy of de novo protein synthesis required for synaptic plasticity. On the basis of these results, minocycline may prove to be a good candidate as an effective therapeutic agent for Alzheimer's disease.

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“…Minocycline, a semi-synthetic derivate of tetracycline, is under scientific debate as a potential therapeutic agent in neurological disease processes (for review see [1,2]. Support for this new application of a time-tested antibiotic comes from observations that minocycline readily crosses the blood-brain barrier to the greatest extent of all of the tetracyclines and is well tolerated.…”

Section: Introductionmentioning

confidence: 99%

“…Support for this new application of a time-tested antibiotic comes from observations that minocycline readily crosses the blood-brain barrier to the greatest extent of all of the tetracyclines and is well tolerated. It affords neuroprotection in experimental models of Parkinson's disease, Huntington's disease, multiple sclerosis, amyotrophic lateral sclerosis (ALS), and acute inflammation after brain trauma or cerebral ischemia [1,3]. Although there are inconsistent reports that show detrimental effects in different models of neurodegeneration [4,5], numerous studies have focused on the mechanisms underlying minocycline-mediated cell protection.…”

Section: Introductionmentioning

confidence: 99%

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

García-Martínez

Sanz-Blasco

Karachitos

et al. 2010

Biochemical Pharmacology

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. A c c e p t e d M a n u s c r i p t 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 Garcia-Martinez EM et al., 2 AbstractMinocycline, an antibiotic of the tetracycline family, has attracted considerable interest for its theoretical therapeutic applications in neurodegenerative diseases. However, the mechanism of action underlying its effect remains elusive. Here we have studied the effect of minocycline under excitotoxic conditions. Fluorescence and bioluminescence imaging studies in rat cerebellar granular neuron cultures using fura-2/AM and mitochondria-targeted aequorin revealed that minocycline, at concentrations higher than those shown to block inflammation and inflammation-induced neuronal death, inhibited NMDA-induced cytosolic and mitochondrial rises in Ca 2+ concentrations in a reversible manner. Moreover, minocycline added in the course of NMDA stimulation decreased Ca 2+ intracellular levels, but not when induced by depolarization with a high K + medium. We also found that minocycline, at the same concentrations, partially depolarized mitochondria by about 5-30 mV, prevented mitochondrial Ca 2+ uptake under conditions of environmental stress, and abrogated NMDAinduced reactive oxygen species (ROS) formation. Consistently, minocycline also abrogates the rise in ROS induced by 75 M Ca 2+ in isolated brain mitochondria. In search for the mechanism of mitochondrial depolarization, we found that minocycline markedly inhibited state 3 respiration of rat brain mitochondria, although distinctly increased oxygen uptake in state 4. Minocycline inhibited NADH-cytochrome c reductase and cytochrome c oxidase activities, whereas the activity of succinate-cytochrome c reductase was not modified, suggesting selective inhibition of complex I and IV. Finally, minocycline affected activity of voltage-dependent anion channel (VDAC) as determined in the reconstituted system. Taken together, our results indicate that mitochondria are a critical factor in minocycline-mediated neuroprotection.

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Clinical potential of minocycline for neurodegenerative disorders

Cited by 150 publications

References 109 publications

Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Region-specific Dissociation of Neuronal Loss and Neurofibrillary Pathology in a Mouse Model of Tauopathy

Minocycline Attenuates Neuronal Cell Death and Improves Cognitive Impairment in Alzheimer's Disease Models

Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells

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