The anti-inflammatory role of minocycline in alzheimer’s disease

Current Alzheimer Research

Volumn 13, Issue 12, 2016, Pages 1319-1329

  Budni, J ^a   Garcez, M L ^a   De Medeiros, J ^a   Cassaro, E ^a   Bellettini Santos, T ^a   Mina, F ^a   Quevedo, J ^a,b,c  

^a UNIVERSIDADE DO EXTREMO SUL CATARINENSE   (Brazil)

^b UNIVERSITY OF TEXAS MEDICAL SCHOOL   (United States)

^c UNIVERSITY OF TEXAS   (United States)

Author keywords

AD treatment; Alzheimer s disease; Cytokine; Microglial activation; Minocycline; Neuroinflammation

Indexed keywords

MINOCYCLINE;

ALZHEIMER DISEASE; ANIMAL; COMPLICATION; HUMAN; INFLAMMATION;

ALZHEIMER DISEASE; ANIMALS; HUMANS; INFLAMMATION; MINOCYCLINE;

EID: 84995877388     PISSN: 15672050     EISSN: 18755828     Source Type: Journal    
DOI: 10.2174/1567205013666160819124206     Document Type: Review

References (114)

1. Herrup K. Reimagining Alzheimer’s disease--an age-based hypothesis J Neurosci 30(50): 16755-62 (2010)
2. Ismail Z, Nguyen MQ, Fischer CE, Schweizer TA, Mulsant BH, Mamo D. Neurobiology of delusions in Alzheimer’s disease. Curr Psychiatr Rep 13(3): 211-8 (2011)
3. Cumming T, Brodtmann A. Dementia and stroke: the present and future epidemic. Int J Stroke 5(6): 453-4 (2010)
4. Schipper HM. Apolipoprotein E. implications for AD neurobiology, epidemiology and risk assessment. Neurobiol Aging 32(5): 778-90 (2011)
5. Liu C-C, Kanekiyo T, Xu H, Bu G. Apolipoprotein E and Alzheimer disease: risk, mechanisms and therapy. Nat Rev Neurol 9(2): 106-18 (2013)
6. Chouraki V, Seshadri S. Genetics of Alzheimer’s disease. Adv Genet 87: 245-94 (2014)
7. Multhaup G, Huber O, Buee L, Galas MC. Amyloid Precursor Protein (APP) Metabolites APP Intracellular Fragment (AICD), Abeta42, and Tau in Nuclear Roles. J Biol Chem 290(39): 23515-22 (2015)
8. Karch CM, Goate AM. Alzheimer’s disease risk genes and mechanisms of disease pathogenesis. Biol Psychiatry 77(1): 43-51 (2015)
9. Larson EB, Wang L, Bowen JD, McCormick WC, Teri L, Crane P, et al. Exercise is associated with reduced risk for incident dementia among persons 65 years of age and older. Ann Intern Med 144(2): 73-81 (2006)
10. Paradise M, Cooper C, Livingston G. Systematic review of the effect of education on survival in Alzheimer’s disease. Int Psychogeriatr 21(1): 25-32 (2009)
11. Alzheimer’s Association 2011 Alzheimer’s disease facts and figures. Alzheimer’s Dement 7(2): 208-44 (2011)
12. Durazzo TC, Mattsson N, Weiner MW. Smoking and increased Alzheimer’s disease risk: A review of potential mechanisms. Alzheimer’s Dement 10(3): S122-S45 (2014)
13. Chung SJ, Kim MJ, Kim J, Ryu HS, Kim YJ, Kim SY, et al. Association of type 2 diabetes GWAS loci and the risk of Parkinson’s and Alzheimer’s diseases. Parkinson Relat Disord 21(12): 1435-40 (2015)
14. Walter S, Marden JR, Kubzansky LD, Mayeda ER, Crane PK, Chang SC, et al. Diabetic phenotypes and late-life dementia risk: a mechanism-specific mendelian randomization study. Alzheimer Dis Assoc Disord 30(1): 15-20 (2016)
15. Zhao QF, Tan L, Wang HF, Jiang T, Tan MS, Tan L, et al. The prevalence of neuropsychiatric symptoms in Alzheimer’s disease: Systematic review and meta-analysis. J Affect Disord 190: 264-71 (2015)
16. Sadowsky CH, Galvin JE. Guidelines for the management of cognitive and behavioral problems in dementia. J Am Board Fam Med 25(3): 350-66 (2012)
17. Rogaev EI, Sherrington R, Rogaeva EA, Levesque G, Ikeda M, Liang Y, et al. Familial Alzheimer’s disease in kindreds with missense mutations in a gene on chromosome 1 related to the Alzheimer’s disease type 3 gene. Nature 376(6543): 775-8 (1995)
18. Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 375(6534): 754-760 (1995)
19. Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med 2(8): 864-70 (1996)
20. Coon KD, Myers AJ, Craig DW, Webster JA, Pearson JV, Lince DH, et al. A high-density whole-genome association study reveals that APOE is the major susceptibility gene for sporadic late-onset Alzheimer’s disease. J Clin Psychiatry 68(4): 613-8e (2007)
21. Holtzman DM, Fagan AM, Mackey B, Tenkova T, Sartorius L, Paul SM, et al. Apolipoprotein E facilitates neuritic and cerebrovascular plaque formation in an Alzheimer’s disease model. Ann Neurol 47(6): 739-47 (2000)
22. Grundke-Iqbal I, Iqbal K, Quinlan M, Tung YC, Zaidi MS, Wisniewski HM. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J Biol Chem 261(13): 6084-9 (1986)
23. Bell KF, Claudio Cuello A. Altered synaptic function in Alzheimer’s disease. Eur J Pharmacol 545(1): 11-21 (2006)
24. Buoso E, Lanni C, Schettini G, Govoni S, Racchi M. beta-Amyloid precursor protein metabolism: focus on the functions and degradation of its intracellular domain. Pharmacol Res 62(4): 308-17 (2010)
25. Citron M. Alzheimer’s disease: strategies for disease modification. Nat Rev Drug Discov 9(5): 387-98 (2010)
26. Sery O, Povova J, Misek I, Pesak L, Janout V. Molecular mechanisms of neuropathological changes in Alzheimer’s disease: a review. Folia Neuropathol 51(1): 1-9 (2013)
27. Moller C, Vrenken H, Jiskoot L, Versteeg A, Barkhof F, Scheltens P, et al. Different patterns of gray matter atrophy in early- and late- onset Alzheimer’s disease. Neurobiol Aging 34(8): 2014-22 (2013)
28. Liberto CM, Albrecht PJ, Herx LM, Yong VW, Levison SW. Pro-regenerative properties of cytokine-activated astrocytes. J Neurochem 89(5): 1092-100 (2004)
29. Fuller S, Steele M, Münch G. Activated astroglia during chronic inflammation in Alzheimer’s disease—Do they neglect their neurosupportive roles? Mut Res Fundam Mol Mech Mutagen 690(1-2): 40-49 (2010)
30. Benarroch EE. Neuron-astrocyte interactions: partnership for normal function and disease in the central nervous system. Mayo Clin Proc 80(10): 1326-38 (2005)
31. Bernardinelli Y, Magistretti PJ, Chatton JY. Astrocytes generate Na+-mediated metabolic waves. Proc Natl Acad Sci USA 101(41): 14937-42 (2004)
32. Singh P, Mann KA, Mangat HK, Kaur G. Prolonged glutamate excitotoxicity: effects on mitochondrial antioxidants and antioxidant enzymes. Mol Cell Biochem 243(1-2): 139-45 (2003)
33. Scott HA, Gebhardt FM, Mitrovic AD, Vandenberg RJ, Dodd PR. Glutamate transporter variants reduce glutamate uptake in Alzheimer’s disease. Neurobiol Aging 32(3): 553e1-53e11 (2011)
34. Esposito Z, Belli L, Toniolo S, Sancesario G, Bianconi C, Martorana A. Amyloid beta, glutamate, excitotoxicity in Alzheimer’s disease: are we on the right track? CNS Neurosci Ther 19(8): 549-55 (2013).
35. Liang J, Takeuchi H, Doi Y, Kawanokuchi J, Sonobe Y, Jin S, et al. Excitatory amino acid transporter expression by astrocytes is neuroprotective against microglial excitotoxicity. Brain Res 1210(0): 11-19 (2008)
36. Salminen A, Ojala J, Kauppinen A, Kaarniranta K, Suuronen T. Inflammation in Alzheimer’s disease: Amyloid-β oligomers trigger innate immunity defence via pattern recognition receptors. Prog Neurobiol 87(3): 181-94 (2009)
37. Ferreira ST, Clarke JR, Bomfim TR, De Felice FG. Inflammation, defective insulin signaling, and neuronal dysfunction in Alzheimer’s disease. Alzheimer’s Dement 10(1): S76-S83 (2014)
38. Czirr E, Wyss-Coray T. The immunology of neurodegeneration. J Clin Invest 122(4): 1156-63 (2012)
39. Britschgi M, Wyss-Coray T. Systemic and acquired immune responses in Alzheimer’s disease. Int Rev Neurobiol 82: 205-33 (2007)
40. Swardfager W, Lanctot K, Rothenburg L, Wong A, Cappell J, Herrmann N. A meta-analysis of cytokines in Alzheimer’s disease. Biol Psychiatry 68(10): 930-41 (2010)
41. Quintanilla RA, Orellana DI, Gonzalez-Billault C, Maccioni RB. Interleukin-6 induces Alzheimer-type phosphorylation of tau protein by deregulating the cdk5/p35 pathway. Exp Cell Res 295(1): 245-57 (2004)
42. Dheen ST, Kaur C, Ling EA. Microglial activation and its implications in the brain diseases. Curr Med Chem 14(11): 1189-97 (2007)
43. Latta CH, Sudduth TL, Weekman EM, Brothers HM, Abner EL, Popa GJ, et al. Determining the role of IL-4 induced neuroinflammation in microglial activity and amyloid-beta using BV2 microglial cells and APP/PS1 transgenic mice. J Neuroinflammation 12(1): 243 (2015)
44. Tang Y, Le W. Differential roles of M1 and M2 microglia in neurodegenerative diseases. Mol Neurobiol 53(2): 1181-94 (2016)
45. Heneka MT, Kummer MP, Latz E. Innate immune activation in neurodegenerative disease. Nat Rev Immunol 14(7): 463-77 (2014)
46. Ramirez-Bermudez J. Alzheimer’s disease: critical notes on the history of a medical concept. Arch Med Res 43(8): 595-9 (2012)
47. Shah RS, Lee HG, Xiongwei Z, Perry G, Smith MA, Castellani RJ. Current approaches in the treatment of Alzheimer’s disease. Biomed Pharmacother 62(4): 199-207 (2008)
48. Anand R, Gill KD, Mahdi AA. Therapeutics of Alzheimer’s disease: Past, present and future. Neuropharmacology 76: Part A(0): 27-50 (2014)
49. Reisberg B, Doody R, Stoffler A, Schmitt F, Ferris S, Mobius HJ. Memantine in moderate-to-severe Alzheimer’s disease. N Engl J Med 348(14): 1333-41 (2003)
50. Grossberg GT, Manes F, Allegri RF, Gutierrez-Robledo LM, Gloger S, Xie L, et al. The safety, tolerability, and efficacy of once-daily memantine (28 mg): a multinational, randomized, double-blind, placebo-controlled trial in patients with moderate-to-severe Alzheimer’s disease taking cholinesterase inhibitors. CNS Drugs 27(6): 469-78 (2013)
51. Da Re F, Rucci F, Isella V. Retrospective study on agitation provoked by memantine in dementia. J Neuropsychiatr Clin Neurosci 27(1): e10-3 (2015)
52. Tan CC, Yu JT, Wang HF, Tan MS, Meng XF, Wang C, et al. Efficacy and safety of donepezil, galantamine, rivastigmine, and memantine for the treatment of Alzheimer’s disease: a systematic review and meta-analysis. J Alzheimers Dis 41(2): 615-31 (2014)
53. Kroger E, Mouls M, Wilchesky M, Berkers M, Carmichael PH, van Marum R, et al. Adverse drug reactions reported with cholinesterase inhibitors: an analysis of 16 years of individual case safety reports from vigibase. Ann Pharmacother 49(11): 1197-206 (2015)
54. 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 9: 62 (2012)
55. Szekely CA, Zandi PP. Non-steroidal anti-inflammatory drugs and Alzheimer’s disease: the epidemiological evidence. CNS Neurol Disord Drug Targets 9(2): 132-9 (2010)
56. Kuang X, Scofield VL, Yan M, Stoica G, Liu N, Wong PK. Attenuation of oxidative stress, inflammation and apoptosis by minocycline prevents retrovirus-induced neurodegeneration in mice. Brain Res 1286: 174-84 (2009)
57. Wu DC, Jackson-Lewis V, Vila M, Tieu K, Teismann P, Vadseth C, et al. Blockade of microglial activation is neuroprotective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson disease. J Neurosci 22(5): 1763-71 (2002)
58. Zhu S, Stavrovskaya IG, Drozda M, Kim BY, Ona V, Li M, et al. Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice. Nature 417(6884): 74-8 (2002)
59. Chen M, Ona VO, Li M, Ferrante RJ, Fink KB, Zhu S, et al. Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease. Nat Med 6(7): 797-801 (2000)
60. Choi Y, Kim HS, Shin KY, Kim EM, Kim M, Kim HS, et al. Minocycline attenuates neuronal cell death and improves cognitive impairment in Alzheimer’s disease models. Neuropsycho-pharmacology 32(11): 2393-404 (2007)
61. Schieven GL. The biology of p38 kinase: a central role in inflammation. Curr Top Med Chem 5(10): 921-8 (2005)
62. Tikka T, Fiebich BL, Goldsteins G, Keinanen R, Koistinaho J. Minocycline, a tetracycline derivative, is neuroprotective against excitotoxicity by inhibiting activation and proliferation of microglia. J Neurosci 21(8): 2580-8 (2001)
63. Koistinaho M, Malm TM, Kettunen MI, Goldsteins G, Starckx S, Kauppinen RA, et al. Minocycline protects against permanent cerebral ischemia in wild type but not in matrix metalloprotease-9-deficient mice. J Cereb Blood Flow Metab 25(4): 460-7 (2005)
64. Hunter CL, Quintero EM, Gilstrap L, Bhat NR, Granholm AC. Minocycline protects basal forebrain cholinergic neurons from mu p75-saporin immunotoxic lesioning. Eur J Neurosci 19(12): 3305-16 (2004)
65. Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, Bandez MJ, Fernandez-Gomez FJ, Perez-Alvarez S, et al. Mitochondria and calcium flux as targets of neuroprotection caused by minocycline in cerebellar granule cells. Biochem Pharmacol 79(2): 239-50 (2010)
66. Gonzalez JC, Egea J, Del Carmen Godino M, Fernandez-Gomez FJ, Sanchez-Prieto J, Gandia L, et al. Neuroprotectant minocycline depresses glutamatergic neurotransmission and Ca(2+) signalling in hippocampal neurons. Eur J Neurosci 26(9): 2481-95 (2007)
67. 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 23(3): 739-50 (2009)
68. Hirashima Y, Kurimoto M, Nogami K, Endo S, Saitoh M, Ohtani O, et al. Correlation of glutamate-induced apoptosis with caspase activities in cultured rat cerebral cortical neurons. Brain Res 849(1-2): 109-18 (1999)
69. Wang J, Wei Q, Wang CY, Hill WD, Hess DC, Dong Z. Minocycline up-regulates Bcl-2 and protects against cell death in mitochondria. J Biol Chem 279(19): 19948-54 (2004).
70. Cai Z, Yan Y, Wang Y. Minocycline alleviates beta-amyloid protein and tau pathology via restraining neuroinflammation induced by diabetic metabolic disorder. Clin Interv Aging 8: 1089-95 (2013)
71. Parachikova A, Vasilevko V, Cribbs DH, LaFerla FM, Green KN. Reductions in amyloid-beta-derived neuroinflammation, with minocycline, restore cognition but do not significantly affect tau hyperphosphorylation. J Alzheimers Dis 21(2): 527-42 n (2010)
72. Forloni G, Colombo L, Girola L, Tagliavini F, Salmona M. Antiamyloidogenic activity of tetracyclines: studies in vitro. FEBS Lett 487(3): 404-7 (2001)
73. Berger-Sweeney J, Stearns NA, Murg SL, Floerke-Nashner LR, Lappi DA, Baxter MG. Selective immunolesions of cholinergic neurons in mice: effects on neuroanatomy, neurochemistry, and behavior. J Neurosci 21(20): 8164-73 (2001)
74. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia activation, Abeta deposition, and behavior in APP-tg mice. Glia 53(7): 776-82 (2006)
75. Bruno MA, Leon WC, Fragoso G, Mushynski WE, Almazan G, Cuello AC. Amyloid beta-induced nerve growth factor dysmetabolism in Alzheimer disease. J Neuropathol Exp Neurol 68(8): 857-69 (2009)
76. Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, et al. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297(5584): 1186-90 (2002)
77. Watson K, Fan GH. Macrophage inflammatory protein 2 inhibits beta-amyloid peptide (1-42)-mediated hippocampal neuronal apoptosis through activation of mitogen-activated protein kinase and phosphatidylinositol 3-kinase signaling pathways. Mol Pharmacol 67(3): 757-65 (2005)
78. Garwood CJ, Cooper JD, Hanger DP, Noble W. Anti-inflammatory impact of minocycline in a mouse model of tauopathy. Front Psychiatry 1: 136 (2010)
79. Sokolova A, Hill MD, Rahimi F, Warden LA, Halliday GM, Shepherd CE. Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer’s disease. Brain Pathol 19(3): 392-8 (2009)
80. Replogle JM, Chan G, White CC, Raj T, Winn PA, Evans DA, et al. A TREM1 variant alters the accumulation of Alzheimer-related amyloid pathology. Ann Neurol 77(3): 469-77 (2015)
81. Smits HA, Rijsmus A, van Loon JH, Wat JW, Verhoef J, Boven LA, et al. Amyloid-beta-induced chemokine production in primary human macrophages and astrocytes. J Neuroimmunol 127(1-2): 160-8 (2002)
82. Zhu M, Allard JS, Zhang Y, Perez E, Spangler EL, Becker KG, et al. Age-related brain expression and regulation of the chemokine CCL4/MIP-1beta in APP/PS1 double-transgenic mice. J Neuropathol Exp Neurol 73(4): 362-74 (2014)
83. 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 9(4): 187-98 (2012)
84. Cuello AC, Ferretti MT, Leon WC, Iulita MF, Melis T, Ducatenzeiler A, et al. Early-stage inflammation and experimental therapy in transgenic models of the Alzheimer-like amyloid pathology. Neurodegener Dis 7(1-3): 96-8 (2010)
85. Kumar V, Singh BK, Chauhan AK, Singh D, Patel DK, Singh C. Minocycline rescues from zinc-induced nigrostriatal dopaminergic neurodegeneration: biochemical and molecular interventions. Mol Neurobiol 13(5): 2761-71 (2016)
86. Jiang BP, Le L, Xu LJ, Xiao PG. Minocycline inhibits ICAD degradation and the NF-kappaB activation induced by 6-OHDA in PC12 cells. Brain Res 1586: 1-11 (2014)
87. DiCarlo G, Wilcock D, Henderson D, Gordon M, Morgan D. Intrahippocampal LPS injections reduce Abeta load in APP+PS1 transgenic mice. Neurobiol Aging 22(6): 1007-12 (2001)
88. Malm TM, Koistinaho M, Parepalo M, Vatanen T, Ooka A, Karlsson S, et al. Bone-marrow-derived cells contribute to the recruitment of microglial cells in response to beta-amyloid deposition in APP/PS1 double transgenic Alzheimer mice. Neurobiol Dis 18(1): 134-42 (2005)
89. Malm TM, Magga J, Kuh GF, Vatanen T, Koistinaho M, Koistinaho J. Minocycline reduces engraftment and activation of bone marrow-derived cells but sustains their phagocytic activity in a mouse model of Alzheimer’s disease. Glia 56(16): 1767-79 (2008)
90. Ito D, Imai Y, Ohsawa K, Nakajima K, Fukuuchi Y, Kohsaka S. Microglia-specific localisation of a novel calcium binding protein, Iba1. Mol Brain Res 57(1): 1-9 (1998)
91. Garcia-Alloza M, Ferrara BJ, Dodwell SA, Hickey GA, Hyman BT, Bacskai BJ. A limited role for microglia in antibody mediated plaque clearance in APP mice. Neurobiol Dis 28(3): 286-92 (2007)
92. Kreutzmann P, Wolf G, Kupsch K. Minocycline recovers MTT-formazan exocytosis impaired by amyloid beta peptide. Cell Mol Neurobiol 30(7): 979-84 (2010)
93. Isobe I, Michikawa M, Yanagisawa K. Enhancement of MTT, a tetrazolium salt, exocytosis by amyloid beta-protein and chloroquine in cultured rat astrocytes. Neurosci Lett 266(2): 129-32 (1999)
94. Shearman MS, Hawtin SR, Tailor VJ. The intracellular component of cellular 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide (MTT) reduction is specifically inhibited by beta-amyloid peptides. J Neurochem 65(1): 218-27 (1995)
95. Thoenen H. Neurotrophins and neuronal plasticity. Science 270(5236): 593-8 (1995)
96. Lee R, Kermani P, Teng KK, Hempstead BL. Regulation of cell survival by secreted proneurotrophins. Science 294(5548): 1945-8 (2001)
97. Chang RC, Wong AK, Ng HK, Hugon J. Phosphorylation of eukaryotic initiation factor-2alpha (eIF2alpha) is associated with neuronal degeneration in Alzheimer’s disease. Neuroreport 13(18): 2429-32 (2002)
98. Devi L, Ohno M. PERK mediates eIF2alpha phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer’s disease. Neurobiol Aging 35(10): 2272-81 (2014)
99. Kircik LH. Doxycycline and minocycline for the management of acne: a review of efficacy and safety with emphasis on clinical implications. J Drugs Dermatol 9(11): 1407-11 (2010)
100. Min DI, Burke PA, Lewis WD, Jenkins RL. Acute hepatic failure associated with oral minocycline: a case report. Pharmacotherapy 12(1): 68-71 (1992)
101. Andrade RJ, Tulkens PM. Hepatic safety of antibiotics used in primary care J Antimicrob Chemother 66(7): 1431-46 (2011)
102. Gordon PH, Moore DH, Gelinas DF, Qualls C, Meister ME, Werner J, et al. Placebo-controlled phase I/II studies of minocycline in amyotrophic lateral sclerosis. Neurology 62(10): 1845-7 (2004)
103. Group HS. Minocycline safety and tolerability in Huntington disease. Neurology 63(3): 547-9 (2004)
104. Levkovitz Y, Mendlovich S, Riwkes S, Braw Y, Levkovitch-Verbin H, Gal G, et al. A double-blind, randomized study of minocycline for the treatment of negative and cognitive symptoms in early-phase schizophrenia. J Clin Psychiatry 71(2): 138-49 (2010)
105. Oya K, Kishi T, Iwata N. Efficacy and tolerability of minocycline augmentation therapy in schizophrenia: a systematic review and meta-analysis of randomized controlled trials. Hum Psychopharmacol 29(5): 483-91 (2014)
106. Emadi-Kouchak H, Mohammadinejad P, Asadollahi-Amin A, Rasoulinejad M, Zeinoddini A, Yalda A, et al. Therapeutic effects of minocycline on mild-to-moderate depression in HIV patients: a double-blind, placebo-controlled, randomized trial. Int Clin Psychopharmacol 31(1): 20-6 (2016)
107. Cukras CA, Petrou P, Chew EY, Meyerle CB, Wong WT. Oral minocycline for the treatment of diabetic macular edema (DME): results of a phase I/II clinical study. Invest Ophthalmol Vis Sci 53(7): 3865-74 (2012)
108. London KSC. http://www.kcl.ac.uk/ioppn/depts/oldage/research/Pharmacological-Studies/Clinical-Trials/minocycline-in-alzheimers-disease-(MADE).aspx. 2014 (2015)
109. Sacktor N, Miyahara S, Evans S, Schifitto G, Cohen B, Haughey N, et al. Impact of minocycline on cerebrospinal fluid markers of oxidative stress, neuronal injury, and inflammation in HIV-seropositive individuals with cognitive impairment. J Neurovirol 20(6): 620-6 (2014)
110. Sacktor N, Miyahara S, Deng L, Evans S, Schifitto G, Cohen BA, et al. Minocycline treatment for HIV-associated cognitive impairment: results from a randomized trial. Neurology 77(12): 1135-42 (2011)
111. Nakasujja N, Miyahara S, Evans S, Lee A, Musisi S, Katabira E, et al. Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment. Neurology 80(2): 196-202 (2013)
112. Liu F, Guo X, Wu R, Ou J, Zheng Y, Zhang B, et al. Minocycline supplementation for treatment of negative symptoms in early-phase schizophrenia: a double blind, randomized, controlled trial. Schizophr Res 153(1-3): 169-76 (2014)
113. Chaudhry IB, Hallak J, Husain N, Minhas F, Stirling J, Richardson P, et al. Minocycline benefits negative symptoms in early schizophrenia: a randomised double-blind placebo-controlled clinical trial in patients on standard treatment. J Psychopharmacol 26(9): 1185-93 (2012)
114. Bonelli RM, Hodl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Huntington’s disease: a 2-year study on minocycline. Int Clin Psychopharmacol 19(6): 337-42 (2004)