Therapeutics

Minocycline

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Overview

Name: Minocycline
Synonyms: Solodyn, Arestin, Minocin, Dynacin
Therapy Type: Small Molecule (timeline)
Target Type: Other (timeline)
Condition(s): Alzheimer's Disease
U.S. FDA Status: Alzheimer's Disease (Discontinued)

Background

This second-generation tetracycline antibiotic has been in use for more than 30 years. It also has anti-inflammatory activity, crosses the blood-brain barrier, and inhibits microglia activation. Based on these properties, and the central role of microglia in Alzheimer’s, this drug was considered a repurposing candidate for evaluation in AD (Corbett et al., 2015; Appleby and Cummings 2013).

Preclinically, minocycline prevented Aβ fibrillization and Aβ-induced microglial activation in vitro (Familian et al. 2006). In mouse and rat models of AD, minocycline inhibition of microglial activation led to reduced amyloid and tau deposition, protection of hippocampal neurogenesis, and improved cognition (Seabrook et al. 2006; Choi et al., 2007; Nobel et al., 2009; Biscaro et al., 2012).

Minocycline displayed neuroprotective activity in preclinical models of multiple other neurologic conditions, but subsequently failed to show efficacy in clinical trials for Huntington’s and Parkinson's diseases, multiple systems atrophy, schizophrenia, multiple sclerosis, and traumatic brain injury.  In people with amyotrophic lateral sclerosis, minocycline accelerated deterioration (Gordon et al., 2007).

Findings

In May, 2014, a Phase 2, multicenter trial began enrolling people with mild AD from National Health Service memory clinics in Scotland and England. Participation required a clinical diagnosis and a standardized MMSE score above 24. The 544 participants took 200 or 400 mg minocycline per day, or placebo, for two years. The primary outcomes in this pragmatic trial were change from baseline in MMSE and Bristol Activities of Daily living, assessed every six months.

Full trial results are published (Nov 2019 news on Howard et al., 2019). After 24 months, minocycline on neither dose slowed cognitive or functional decline relative to placebo. The high dose was poorly tolerated: around 60 percent of the low-dose and placebo groups completed the trial, fewer than 30 percent of the high-dose group did. The most common reasons for withdrawal were gastrointestinal side and skin problems, and dizziness.

This trial was listed in the EU Clinical Trials Register. For more trials on minocycline, see clinicaltrials.gov.

Last Updated: 06 Dec 2019

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References

News Citations

  1. Minocycline Does Not Work in Mild Alzheimer’s Disease

Paper Citations

  1. Howard R, Zubko O, Bradley R, Harper E, Pank L, O'Brien J, Fox C, Tabet N, Livingston G, Bentham P, McShane R, Burns A, Ritchie C, Reeves S, Lovestone S, Ballard C, Noble W, Nilforooshan R, Wilcock G, Gray R, Minocycline in Alzheimer Disease Efficacy (MADE) Trialist Group. Minocycline at 2 Different Dosages vs Placebo for Patients With Mild Alzheimer Disease: A Randomized Clinical Trial. JAMA Neurol. 2019 Nov 18; PubMed.
  2. Corbett A, Williams G, Ballard C. Drug repositioning in Alzheimer's disease. Front Biosci (Schol Ed). 2015 Jun 1;7:184-8. PubMed.
  3. Appleby BS, Cummings JL. Discovering New Treatments for Alzheimer's Disease by Repurposing Approved Medications. Curr Top Med Chem. 2013;13(18):2306-27. PubMed.
  4. Familian A, Boshuizen RS, Eikelenboom P, Veerhuis R. Inhibitory effect of minocycline on amyloid beta fibril formation and human microglial activation. Glia. 2006 Feb;53(3):233-40. PubMed.
  5. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia. 2006 May;53(7):776-82. PubMed.
  6. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Park CH, Jeong YH, Yoo J, Lee JP, Chang KA, Kim S, Suh YH. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer's disease models. Neuropsychopharmacology. 2007 Nov;32(11):2393-404. PubMed.
  7. Noble W, Garwood C, Stephenson J, Kinsey AM, Hanger DP, Anderton BH. Minocycline reduces the development of abnormal tau species in models of Alzheimer's disease. FASEB J. 2009 Mar;23(3):739-50. Epub 2008 Nov 11 PubMed.
  8. Biscaro B, Lindvall O, Tesco G, Ekdahl CT, Nitsch RM. Inhibition of microglial activation protects hippocampal neurogenesis and improves cognitive deficits in a transgenic mouse model for Alzheimer's disease. Neurodegener Dis. 2012;9(4):187-98. PubMed.
  9. Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, Hilton JF, Spitalny GM, Macarthur RB, Mitsumoto H, Neville HE, Boylan K, Mozaffar T, Belsh JM, Ravits J, Bedlack RS, Graves MC, McCluskey LF, Barohn RJ, Tandan R, . Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol. 2007 Dec;6(12):1045-53. PubMed.

External Citations

  1. EU Clinical Trials Register
  2. clinicaltrials.gov

Further Reading

Papers

  1. Schneider LS. Pragmatic Trials and Repurposed Drugs for Alzheimer Disease. JAMA Neurol. 2019 Nov 18; PubMed.
  2. Ferretti MT, Allard S, Partridge V, Ducatenzeiler A, Cuello AC. Minocycline corrects early, pre-plaque neuroinflammation and inhibits BACE-1 in a transgenic model of Alzheimer's disease-like amyloid pathology. J Neuroinflammation. 2012;9:62. PubMed.