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Use of minocycline in viral infections.

"The most fruitful basis for the discovery of a new drug is to start with an old drug".

James W. Black

Nobel Prize in Physiology or Medicine (1988)

Minocycline: from bacterial infections to neurodegenerative diseases

Minocycline is a semi-synthetic second generation tetracycline that has now been in use for more than 40 years. It was synthesized in 1967 by the erstwhile Lederle Laboratories (part of American Cyanamid that was subsequently bought by American Home Products Corp. in 1994 which in turn became a part of Pfizer Inc. in 2009), and became commercially available from 1972 under the brand name of Minocin, after getting United States Food and Drug Administration (FDA) approval in June 1971. Minocycline was originally developed to treat a wide array of diseases such as susceptible bacterial infections of both Gram-negative and Gram-positive organisms and is currently recommended for the treatment of anthrax (inhalational, cutaneous, and gastrointestinal), moderate-to-severe acne, meningococcal (asymptomatic) carrier state, Rickettsial diseases (including Rocky Mountain spotted fever, Q fever), nongonococcal urethritis, gonorrhoea, acute intestinal amoebiasis, respiratory tract infection, skin/soft tissue infections, and chlamydial infections (1-3). Apart from the approved uses, minocycline is being used to treat rheumatoid arthritis (4) and has even been tried for the treatment of leprosy (5).

Owing to its relatively small size (495 Da) and highly lipophilic nature, minocycline crosses the blood-brain barrier (BBB) with ease and has been shown to penetrate the cerebrospinal fluid (CSF) of human beings better than doxycycline and other tetracyclines (6,7). Owing to these properties it had been suspected that minocycline may play a role in neurological processes. In a landmark study in 1998, Yrjanheikki et al (8) reported that minocycline was neuroprotective in an experimental model of ischaemia. Since then, there has been several reports linking minocycline with neurological diseases such as haemorrhagic and ischaemic stroke (9), multiple sclerosis (10), spinal-cord injury (11), Parkinson's disease (12), Huntington's disease (HD) (13), and amyotrophic lateral sclerosis (ALS) (14), leading to various clinical trials. Clinical trials of minocycline administration in ALS (15) and HD16 have been completed with positive outcome and are in progress for traumatic brain injury cases (17). Recently, a double-blinded randomized clinical trial has begun which aims to explore the possibilities of using minocycline as an adjunctive therapy for schizophrenia (18).

Minocycline in viral infections

The earliest available report of antiviral activity of minocycline came when Lemaitre et al (19) reported in 1990 that it imparts protection against human immunodeficiency virus (HIV) in human acute lymphoblastic T-cell leukemia (CEM) cells. They showed that minocycline (and doxycycline) prevented HIV-mediated cytopathic effects in vitro, 7-14 days post-infection. However, during this time frame, virus production was not inhibited, that indicated dissociation between protection against cell death and suppression of virus growth. However, the protected cells could be maintained in culture for 6-7 wk after which there was complete cessation of virus production in the cells, even in the absence of the drug. Later on it was reported that minocycline was also effective in adjunct therapy for acquired immunodeficiency syndrome (AIDS) dementia by virtue of its anti-inflammatory effect on the microglial cells thereby inhibiting their activation and also inhibiting virus production from these cells (20). In 2005, a group of investigators from John Hopkins University School of Medicine reported that minocycline imparted significant neuroprotection in a simian immunodeficiency virus (SIV) model of HIV-associated central nervous system (CNS) disease (21). It was the first report of its kind demonstrating anti-inflammatory and neuroprotective activity of an antibiotic against a highly pathogenic virus infection and it was also reported that minocycline suppresses HIV and SIV replication in lymphocytes and macrophages, the main target cells, in vivo. Minocycline was thus found to be responsible for the reduction of severity of encephalitis, suppressed viral load in the brain, and decrease in the expression of CNS inflammatory markers. Minocycline was also found to inhibit SIV and HIV replication in vitro (21). They went on to show that the protective effect is mediated by the suppression of p38MAPK and JNK levels in the brain thereby leading to inhibition of activation of apoptosis signal-regulating kinase-1 (ASK1) (22). Thus it seemed that minocyclines' anti-HIV role is based on its ability to suppress inflammatory reactions in the brain that is associated with the infection. It is also to be noted that minocycline was originally not engineered to target any specific viral proteins. However, a non-clinical, computational docking with molecular dynamics simulation method-based study has proposed that minocycline has a very high predicted binding affinity against HIV-1 integrase (23), the key protein in the integration of the viral DNA into the host genome. Inhibition of the viral integrase could have therapeutic implications, though actual wet lab studies are yet to be performed to evaluate the efficacy of minocycline in such process. It has also been recently reported that the anti-HIV efficacy of minocycline may be attributed to the suppression of cellular activation in human CD4+ T cells (24). The study proposes that instead of directly targeting the virus, minocycline acts by altering the cellular environment, thereby placing minocycline in the class of anticellular anti-HIV drugs.

Cognitive impairments associated with HIV infection has been an additional concern. The term 'NeuroAIDS' encompasses those neurologic disorders that are a primary consequence of damage to the central and peripheral nervous system by HIV. The clinical syndromes identified include sensory neuropathy, myelopathy, HIV dementia, and cognitive/motor disorder. It is believed that minocycline, when administered in adjunct to conventional antiretroviral therapy, may help in ameliorating cognitive dysfunctions associated with HIV infection. A recent study (25) reports that oral administration of minocycline is effective in alleviating neuronal damage in an animal model of neuroAIDS following infection with SIV. Using proton resonance spectroscopy it was shown that neuronal integrity was maintained following minocycline administration in SIV infected experimental animals (25). These observations are significant in the current context as a clinical trial is currently in progress in Uganda, to evaluate this hypothesis (26).

Moving away from retroviruses, it has been shown that minocycline is also effective against flaviviral infections. A study published in 2007 claimed that minocycline significantly inhibited West Nile virus replication in cultured human neuronal cells and subsequently prevented virus-induced apoptosis (27). We reported that minocycline was also protective in case of Japanese encephalitis virus (JEV) infection. Using animal models it was shown that this protective role was attributed to reduction in neuronal apoptosis, microglial activation, active caspase activity, proinflammatory mediators released in the brain, and viral titre. Minocycline was also found to be effective in vitro, when JEV-infected neuroblastoma cells were protected from virus-induced death (28). Minocyclines' antioxidative property has also been shown to significantly ameliorate the oxidative stress generated as a result of JEV infection (29) and also imparts protection to the blood brain barrier by decreasing the expression of various adhesion molecules in the brain as well as downplaying the activity of matrix metalloproteinase 9 (MMP-9) (30). The observed protective role of minocycline in JE has led to the initiation of a randomized phase II clinical trial to be conducted in Chhatrapati Shahuji Maharaj Medical University (formerly King George's Medical College, Lucknow). The trial has been approved by the Drug Controller General of India and currently going through the preparatory stages (31).

Fatal encephalomyelitis caused by alphavirus has also been shown to be countered by minocycline. In animal models, minocycline confers protection against alphavirus infection by inhibiting microglial activation in the brain and diminishing production of interleukin 1 beta in the CNS (32). However, minocycline's protective action in case of reovirus infections is attributed to its anti-apoptotic activity rather than inhibition of microglial activation (33).

According to an estimate, it takes about 10-15 years of research and nearly US$2 billion to bring a single new drug to market. Trying out existing drugs for conditions other than what they were originally intended for, is therefore, cost-effective and comparatively easy, as the drugs have approval from regulatory bodies and with known pharmacokinetics and safety profile (34). The use of minocycline as an antiviral drug is thus an ideal case of 'repurposing' an old drug. As seen from the experimental studies, minocycline's antiviral efficacy is mostly based on its anti-apoptotic or anti-inflammatory activities; yet, actual inhibition of viral replication cannot be ruled out. It would also be fruitful to look into other tetracycline derivatives that may have similar activities. It may also be possible in the future to create a network database linking the mechanism of action of all tetracycline derivatives in different viral infections that would create a new vista of antiviral drug research.


The work in the National Brain Research Centre, Manesar, Haryana, was funded by the grant from the Department of Biotechnology (Award#BT/PR/5799/MED/14/698/ 2005 and BT/PR8682/Med/14/1273/ 2007), and the Council of Scientific and Industrial Research (27(0173)/07/EMR-II), Government of India. The first author (KD) is recipient of Research Associateship in Biotechnology and Life Sciences from the Department of Biotechnology, Government of India.

Received June 2, 2010


(1.) Smilack JD. The tetracyclines. Mayo Clin Proc 1999; 74 : 727-9.

(2.) Goulden V. Guidelines for the management of acne vulgaris in adolescents. Paediatr Drugs. 2003; 5 : 301-13.

(3.) -Comprehensive Information on Prescription Drugs. (Updated: January 07, 2010). Available from: http:// accessed on June 18, 2010.

(4.) Tilley BC, Alarcon GS, Heyse SP, Trentham DE, Neuner R, Kaplan DA, et al. Minocycline in rheumatoid arthritis. A 48-week, double-blind, placebo-controlled trial. MIRA Trial Group. Ann Intern Med 1995; 122 : 81-9.

(5.) Gelber RH, Fukuda K, Byrd S, Murray LP, Siu P, Tsang M, et al. A clinical trial of minocycline in lepromatous leprosy. BMJ 1992; 304 : 91-2.

(6.) Macdonald H, Kelly RG, Allen ES, Noble JF, Kanegis LA. Pharmacokinetic studies on minocycline in man. Clin Pharmacol Ther 1973; 14 : 852-61.

(7.) Carney S, Butcher RA, Dawborn JK, Pattison G. Minocycline excretion and distribution in relation to renal function in man. Clin Exp Pharmacol Physiol 1974; 1 : 299-308.

(8.) Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J. Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 1998; 95 : 15769-74.

(9.) Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, et al. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 2007; 69 : 1404-10.

(10.) Zabad RK, Metz LM, Todoruk TR, Zhang Y, Mitchell JR, Yeung M, et al. The clinical response to minocycline in multiple sclerosis is accompanied by beneficial immune changes: a pilot study. Mult Scler 2007; 13 : 517-26.

(11.) Kwon BK, Okon E, Hillyer J, Mann C, Baptiste D, Weaver LC, et al. A systematic review of non-invasive pharmacologic neuroprotective treatments for acute spinal cord injury. J Neurotrauma (In Press) 2010.

(12.) Thomas M, Le WD. Minocycline: neuroprotective mechanisms in Parkinson's disease. Curr Pharm Des 2004; 10 : 679-86.

(13.) Huntington Study Group. Minocycline safety and tolerability in Huntington disease. Neurology 2004; 63 : 547-9.

(14.) Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz LM. The promise of minocycline in neurology. Lancet Neurol 2004; 3 : 744-51.

(15.) Gordon PH, Moore DH, Miller RG, Florence JM, Verheijde JL, Doorish C, et al. Efficacy of minocycline in patients with amyotrophic lateral sclerosis: a phase III randomised trial. Lancet Neurol 2007; 6 : 1045-53.

(16.) A service of the U.S. National Institutes of Health. Minocycline in patients with Huntington's disease. (Updated: June 23, 2005). Available from: http://clinicaltrials. gov/ct2/show/NCT00029874; accessed on June 21, 2010.

(17.) A service of the U.S. National Institutes of Health. Safety and Feasibility of Minocycline in the Treatment of Traumatic Brain Injury (TBI). (Updated: February 11, 2010). Available from: NCT01058395, accessed on June 21, 2010.

(18.) A service of the U.S. National Institutes of Health. Safety and Minocycline as an Adjunctive Therapy for Schizophrenia: a Randomized Controlled Study. (Updated: May 26, 2010) Available from: http://, accessed on June 21, 2010.

(19.) Lemaitre M, Guetard D, Henin Y, Montagnier L, Zerial A. Protective activity of tetracycline analogs against the cytopathic effect of the human immunodeficiency viruses in CEM cells. Res Virol 1990; 141 : 5-16.

(20.) Si Q, Cosenza M, Kim MO, Zhao ML, Brownlee M, Goldstein H, et al. A novel action of minocycline: inhibition of human immunodeficiency virus type 1 infection in microglia. J Neurovirol 2004; 10 : 284-92.

(21.) Zink MC, Uhrlaub J, DeWitt J, Voelker T, Bullock B, Mankowski J, et al. Neuroprotective and anti-human immunodeficiency virus activity of minocycline. JAMA 2005; 293 : 2003-11.

(22.) Follstaedt SC, Barber SA, Zink MC. Mechanisms of minocycline-induced suppression of simian immunodeficiency virus encephalitis: inhibition of apoptosis signal-regulating kinase 1. J Neurovirol 2008; 14 : 376-88.

(23.) Jenwitheesuk E, Samudrala R. Identification of potential HIV-1 targets of minocycline. Bioinformatics 2007; 23 : 2797-9.

(24.) Szeto GL, Brice AK, Yang HC, Barber SA, Siliciano RF, Clements JE. Minocycline attenuates HIV infection and reactivation by suppressing cellular activation in human CD4+ T cells. J Infect Dis, 2010; 201 : 1132-40.

(25.) Ratai EM, Bombardier JP, Joo CG, Annamalai L, Burdo TH, Campbell J, et al. Proton magnetic resonance spectroscopy reveals neuroprotection by oral minocycline in a nonhuman primate model of accelerated NeuroAIDS. PLoS One 2010; 5 : e10523.

(26.) A service of the U.S. National Institutes of Health. Minocycline for HIV+ Cognitive Impairment in Uganda. (Updated: May 26, 2010). Available from: http://, accessed on June 21, 2010.

(27.) Michaelis M, Kleinschmidt MC, Doerr HW, Cinatl J Jr. Minocycline inhibits West Nile virus replication and apoptosis in human neuronal cells. J Antimicrob Chemother 2007; 60 : 981-6.

(28.) Mishra MK, Basu A. Minocycline neuroprotects, reduces microglial activation, inhibits caspase 3 induction, and viral replication following Japanese encephalitis. J Neurochem 2008; 105 : 1582-95.

(29.) Mishra MK, Ghosh D, Duseja R, Basu A.Antioxidant potential of minocycline in Japanese Encephalitis virus infection in murine neuroblastoma cells: correlation with membrane fluidity and cell death. Neurochem Int 2009; 54 : 464-70.

(30.) Mishra MK, Dutta K, Saheb SK, Basu A. Understanding the molecular mechanism of blood-brain barrier damage in an experimental model of Japanese encephalitis: correlation with minocycline administration as a therapeutic agent. Neurochem Int 2009; 55 : 717-23.

(31.) Clinical Trials Registry- India. A service of the Indian Council of Medical Research. Randomised Double Blind Controlled Trial of Minocycline in Japanese encephalitis. (Updated: January 11, 2011). Available from: http://ctri.nic. in/Clinicaltrials/showallp.php?mid1=2529&EncHid=&user Name=minocycline, accessed on April 18, 2011.

(32.) Irani DN, Prow NA. Neuroprotective interventions targeting detrimental host immune responses protect mice from fatal alphavirus encephalitis. J Neuropathol Exp Neurol 2007; 66 : 533-44.

(33.) Richardson-Burns SM, Tyler KL. Minocycline delays disease onset and mortality in reovirus encephalitis. Exp Neurol 2005; 192 : 331-9.

(34.) Chong CR, Sullivan DJ Jr. New uses for old drugs. Nature 2007; 448 : 645-6.

Kallol Dutta & Anirban Basu

National Brain Research Centre, Manesar, Haryana, India

Reprint requests: Dr Anirban Basu, National Brain Research Centre, Manesar, Haryana 122 050, India

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Author:Dutta, Kallol; Basu, Anirban
Publication:Indian Journal of Medical Research
Article Type:Report
Geographic Code:9INDI
Date:May 1, 2011
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