Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial

Gordon, Paul H.; Moore, Dan H.; Miller, Robert G.; Florence, Julaine; Verheijde, Joseph L.; Doorish, Carolyn; Hilton, Joan F.; Spitalny, G. Mark; MacArthur, Robert B.; Mitsumoto, Hiroshi; Neville, Hans E.; Boylan, Khrista; Mozaffar, Tahseen; Belsh, Jerry M.; Ravits, John; Bedlack, Richard; Graves, Michael C.; McCluskey, Leo; Barohn, Richard J.; Tandan, Rup

doi:10.1016/s1474-4422(07)70270-3

Cited by 595 publications

(383 citation statements)

References 45 publications

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“…Since activation of NMDA receptors responsible for excitotoxicity imposes a high energetic demand on the in situ mitochondria [51] one could hypothesize that minocycline exerts its neuroprotective effect by affecting bioenergetic functions of mitochondria. Indeed, this effect could be responsible for the recent report showing that minocycline has a harmful effect on patients with ALS [52]. Accordingly, it was proposed by Kupsch et al [53] that minocycline impairs mitochondria functions causing dissipation.…”

Section: Discussionmentioning

confidence: 98%

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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Section: Discussionmentioning

confidence: 98%

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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“…In a later study comparing riluzole serum levels to both survival and MMT muscle testing, no effect of riluzole concentration was found on either measure [5]. In a phase III study of minocycline in ALS, a statistically significant trend toward faster progression in the ALS Functional Rating Scale-revised (ALSFRS-R) in patients treated with minocycline versus placebo; there was a trend in the same direction for MMT, but this was not significant [6]. A large, phase II trial of TCH346 in ALS showed a trend toward detriment on most outcome measures assessed but no effect on MMT [7].…”

Section: Methods Of Strength Assessment Manual Muscle Testingmentioning

confidence: 94%

Strength Testing in Motor Neuron Diseases

Shefner

2017

Neurotherapeutics

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Loss of muscle strength is a cardinal feature of all motor neuron diseases. Functional loss over time, including respiratory dysfunction, inability to ambulate, loss of ability to perform activities of daily living, and others are due, in large part, to decline in strength. Thus, the accurate measurement of limb muscle strength is essential in therapeutic trials to best understand the impact of therapy on vital function. While qualitative strength measurements show declines over time, the lack of reproducibility and linearity of measurement make qualitative techniques inadequate. A variety of quantitative measures have been developed; all have both positive attributes and limitations. However, with careful training and reliability testing, quantitative measures have proven to be reliable and sensitive indicators of both disease progression and the impact of experimental therapy. Quantitative strength measurements have demonstrated potentially important therapeutic effects in both amyotrophic lateral sclerosis and spinobulbar muscular atrophy, and have been shown feasible in children with spinal muscular atrophy. The spectrum of both qualitative and quantitative strength measurements are reviewed and their utility examined in this review.

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“…While much of the information points toward significant microglial contribution to disease, other reports have argued otherwise 52. Similarly, minocycline, a tetracycline derivative that has anti‐inflammatory properties in addition to off‐target inhibition of microglial activation, showed promise in preclinical models of ALS but failed in clinical trial 53, 54…”

Section: Status Of Neuroinflammation In Als and Smamentioning

confidence: 99%

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

Deguise

Kothary

2017

Ann Clin Transl Neurol

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Spinal muscular atrophy (SMA) is a neuromuscular disorder characterized by motor neuron degeneration, although defects in multiple cell types and tissues have also been implicated. Three independent laboratories recently identified immune organ defects in SMA. We therefore propose a novel pathogenic mechanism contributory to SMA, resulting in higher susceptibility to infection and exacerbated disease progression caused by neuroinflammation. Overall, compromised immune function could significantly affect survival and quality of life of SMA patients. We highlight the recent findings in immune organ defects, their potential consequences on patients, our understanding of neuroinflammation in SMA, and new research hypotheses in SMA pathogenesis.

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Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial

Cited by 595 publications

References 45 publications

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

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

Strength Testing in Motor Neuron Diseases

New insights into SMA pathogenesis: immune dysfunction and neuroinflammation

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