Neuroprotection by tetracyclines

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Neuroprotection by tetracyclines
  Research Focus Neuroprotection by tetracyclines Marı´a Domercq and Carlos Matute Departamento de Neurociencias, Universidad del Paı´s Vasco, E-48940 Leioa, Vizcaya, Spain The neuroprotective properties of tetracyclines havebeen clearly established in rodent models of acute andchronic neurodegeneration during the past few years.Recent findings have provided novel insights into themolecular and cellular mechanisms of protection ofneurons and oligodendrocytes by tetracyclines. Theseadvances have prompted several clinical trials withminocycline, the most effective tetracycline, which arestill in their early phases. Thus, tetracyclines hold greatpromise as therapeutic agents for the treatment ofhuman neurodegenerative diseases. Tetracyclines are bacteriostatic agents that bind to the30S ribosomal subunit of bacteria and inhibit proteinsynthesis. Semi-synthetic second-generation tetracyclinesincluding minocycline and doxycycline are used currentlyas typical antibiotics in humans. In addition to theirefficacy in thetreatment of multidrug-resistant infections,these antibiotics have a good clinical safety record andeasily penetrate the blood–brain barrier. The discovery of their anti-inflammatory properties prompted their appli-cation for the treatment of other diseases such as acne vulgaris and rheumatoid arthritis. A pioneer study byClark and colleagues in 1994 demonstrated that doxycy-cline improved recovery in a rabbit model offocal ischemia[1] and, subsequently, Koistinaho’s group showed thatdoxycycline and minocycline were neuroprotective in ratglobal brain ischemia [2]. Since then, there has been anexplosion of studies showing that tetracyclines haveremarkable neuroprotective properties in models of cerebral ischemia, spinal cord injury, Parkinson’s disease(PD), Huntington’s disease (HD), amyotrophic lateralsclerosis (ALS) and multiple sclerosis (MS). The mechan-isms that underlie these therapeutic effects are nowbeginningtobeunderstoodandinitialresultsfromclinicaltrials using minocycline in chronic neurological disordershave just been published [3–6]. In the light of these newfindingsfromanimalmodelsandhumanpatients,itseemsappropriate to evaluate the prospects of these drugs forthe treatment of neurodegenerative pathologies. Molecular and cellular mechanisms of neuroprotectionby tetracyclines Tetracyclines prevent cell death in a wide range of   in vitro and  in vivo  models by at least two mechanisms: attenu-ation of innate and adaptive immunity and blockade of apoptotic cascades (Figure 1). The CNS is an immune-privileged tissue, exhibiting a robust innate immuneresponse that is mediated by microglia. Activation of microglia, a common feature of most neurodegenerativediseases, leads to the release of pro-inflammatorymediators and other injury response factors that ulti-mately compromise neuronal and oligodendroglial viabi-lity. Minocycline inhibits: (i) microglial activation andproliferation (Figure 1a); (ii) the induction of caspase-1and inducible nitric oxide syntihase (iNOS) followingischemic insults, exposure to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or excitotoxicity; and (iii) theinduction of cyclooxygenase 2 (COX-2) secondary toischemia [2,7–10]. Minocycline also attenuates adaptiveimmunity by reducing the expression and activity of matrix metalloproteinases (MMPs) [11,12], which alterblood–brain barrier permeability, enabling T-cellmigration into the CNS, and myelin degradation(Figure 1a).Tetracyclinescanalsoactdirectlytoblockneuronalandoligodendroglial cell death (Figure 1b). Minocyclineinhibits caspase-dependent and -independent cell deathinduced by different stimuli such as glutamate, hydrogenperoxide (H 2 O 2 ), thapsigargin, a mixture of tumornecrosis factor  a  (TNF- a ) and cycloheximide, 3-nitro-propionic acid (a mitochondrial toxin) and etoposide(a DNA-damaging agent)  in vitro  [13,14]. A key targetfor the broad-spectrum neuroprotective actions of minocy-cline is the mitochondrion (Figure 1b). Minocycline blocksthereleaseofthepro-apoptoticfactorscytochrome c ,SMAC(Diablo) and apoptosis-inducing factor (AIF) [13,14] by atleast two mechanisms (Figure 1b). In isolated cell-freemitochondrion preparations, minocycline inhibits mito-chondrial depolarization and prevents the opening of thepermeability transition pore by direct interaction with themitochondrial membrane [13,14]. By contrast, in whole-cell preparations, minocycline upregulates Bcl-2, whichaccumulates in mitochondria and facilitates protectiveeffects by antagonizing Bax, Bak and Bid [15], a family of death-promoting factors that facilitate the release of cytochrome  c  through the outer mitochondrial membrane(Figure 1b). In turn, cell death signals mediated by thesefactorsleadultimatelytoactivationofcaspase-3,aprocessthat is also blocked by minocycline [13,14]. Tetracycline-mediated protection in models of acuteneurodegeneration  AcuteinsultstotheCNSsuchasischemia,traumaorspinalcord injury cause immediate primary damage and asubsequent secondary degenerative response that developsover several days post-injury. This secondary response isamenable to therapeutic intervention and is characterized Corresponding author:  Carlos Matute ( Update  TRENDS in Pharmacological Sciences   Vol.25 No.12 December 2004 0165-6147/$ - see front matter Q 2004 Elsevier Ltd. All rights reserved. doi:10.1016/  by inflammation and delayed neuronal death. Minocy-cline and doxycycline markedly reduce the size of infarction in both focal and global transient ischemia inthe adult rat [1,2,7,16] (Table 1). By contrast, tetracycline, which is less able to cross the blood–brain barrier to enterthe CNS, is not neuroprotective at the same dose [2].Minocycline also protects against neonatal hypoxic–ischemia damage in rats [17,18], but exacerbates injuryin a similar experimental paradigm in mice [18]. Thesestriking species differences could be due to the oppositeeffects of minocycline on the modulation of COX-2expression in both species [18] and underline the need toperform further animal studies before clinical applicationof this tetracycline. In addition, recent studies indicatethat oligodendrocyte apoptosis, demyelination and axonaldamage, which can be caused by excitotoxicity [19],determine the outcome of acute injury, and that minocy-cline limits deterioration of these tissue components andmitigates associated functional deficits [20–22] (Table 1). Importantly, functional recovery in models of spinal cordinjury after minocycline treatment correlates with thepreservation of white matter [22]. This indicates thatoligodendrocyte survival is crucial to minimize functionalloss. Indeed, the lack of success in translating neuro-protective agents from animal models of acute diseases tothe human scenario might be due largely to the lack of prevention of white matter damage, which in humansconstitutes approximately half of the CNS and is extre-mely vulnerable to traumatic and ischemic insults [19].Together, the aforementioned studies indicate thatminocycline is a solid candidate for clinical trials in stroketherapy and spinal cord injury. An additional favorablefeature of this tetracycline in terms of its potential use inhumans is its broad therapeutic window as a neuropro-tectant, which ranges from 1 h after spinal cord injury to5 h post-ischemia [16,22]. Tetracycline-mediated protection in models of chronicneurodegenerative diseases Neuroprotection by tetracyclines in animal models of chronic neurodegenerative disorders has been associatedwith the anti-inflammatory and anti-apoptotic propertiesof tetracyclines (Table 1). In ALS transgenic mice,administration of minocycline delays the onset of diseaseand slows its progression. Moreover, it increases motorperformance and extends survival by 2–3 weeks compared Bid Bcl-2MMPs  (a) (b) Blood–brainbarrier T cell RestingmicrogliaActivatedmicrogliaCelldeathCelldeathNeuronOligodendrocyteIL-1 β ,NO,PGE 2 Caspase-1NucleusCell deathExecutionercaspaseApoptosomeAIFSMAC(Diablo)Cytochrome c  Bax, BaktBidIAPAPAF1Caspase-9MinocyclineMinocyclineMinocyclineMitochondria TRENDS in Pharmacological Sciences Figure 1.  Mechanisms of neuroprotection by tetracyclines.  (a)  Tetracyclines attenuate both innate and adaptive immune responses. Thus, tetracyclines reduce microglialactivation and thereby reduce transcription of the downstream pro-inflammatory mediators caspase-1, inducible nitric oxide synthase and cyclooxygenase 2 and thesubsequent release of interleukin 1 b  (IL-1 b ), nitric oxide (NO) and prostaglandin E 2  (PGE 2 ), which are associated with cell death. Tetracyclines also inhibit the expression andactivity of matrix metalloproteinases (MMPs), which regulate blood–brain barrier permeability and, consequently, peripheral cell infiltration and ensuing demyelination.Activated MMPs can also directly contribute to myelin degradation by myelin basic protein (MBP) digestion.  (b)  Minocycline interferes with different molecular elements inthe programmed cell death pathway. Thus, minocycline inhibits the release of the pro-apoptotic factors apoptosis-inducing factor (AIF), SMAC (Diablo) and cytochrome  c  from mitochondria by controlling mitochondrial permeability. Minocycline upregulates Bcl-2, which antagonizes the death-promoting factors Bax, Bak and Bid (inducers of cytochrome c  release).Furthermore,minocyclinealsoinhibitstheactivationofcaspase-1,preventingcleavageofBidtotruncatedBid(tBid).Abbreviations:APAF1,apoptosisprotease-activating factor 1; IAP, inhibitor of apoptosis. Update  TRENDS in Pharmacological Sciences   Vol.25 No.12 December 2004610  withnon-treatedALStransgenicmice[13,23].Inaddition,minocycline attenuates loss of acetylcholine-containingneurons and cognitive impairment induced by mu p75-saporin in mice, a novel immunotoxin used to model Alzheimer’s disease [24]. By contrast, conflicting evidenceregarding theefficacyof tetracyclineshas beenreportedinanimal models of HD and PD (Table 1). Thus, the effects of minocycline in animals with HD-like symptoms rangefrom beneficial [25] to ineffective [26] or deleterious [27]. Furthermore, minocycline can have variable and evenharmful effects in the MPTP model of PD [8,10,27,28].Clearly, additional experimental work is needed to clarifytheneuroprotectivemechanismsof tetracyclinesandtheirclinical potential in HD and PD.The dual effects of tetracyclines as immunomodulatorsand as anti-apoptotic agents hold great promise for thetreatment of MS, an autoimmune and neurodegenerativedisease that involves the loss of oligodendrocytes, myelinandaxons,togetherwithanelevatedexpressionandactivityof MMPs. The latter permits infiltration of activated Tcellsinto the brain and myelin degradation. In the chronicrelapsingformofexperimentalautoimmuneencephalomye-litis,thebestcharacterizedmodelofMS,minocyclinedelaysepisode onset and ameliorates neurological symptoms,precisely by inhibiting MMP2 and MMP9 [12] (Table 1). Moreover, recent findings indicate that massive oligoden-drocyte apoptosis triggered by unknown mechanisms is anearly feature in the formation of MS lesions [29]. Becauseminocycline has well established anti-apoptotic properties,it is conceivable that its administration to MS patientsmight contribute to the reduction in the formation of newlesions and thus lead to a significant clinical improvement. Therapeutic prospects of tetracyclines Together, the studies described in this article indicate thatminocycline and doxycycline are solid candidates for thetreatmentofmajorneurodegenerativediseases.Moreover,both of these tetracyclines readily cross the blood–brainbarrier regardless of the dose and route of administration[30]. However, the dose of minocycline required to elicitneuroprotection in the absence of undesirable side-effects remains a crucial issue because in mostexperimental models the dose required can be as muchas 50–90 mg kg K 1 daily.The first clinical trials and pilot studies, the results of which were published during the past few months, wereaimed primarily at assessing the safety and tolerability of minocycline in ALS [3], HD [4,5] and MS [6]. In all trials, minocycline was well tolerated at 200 mg day K 1 over6 months and no side-effects or negative interactions withother simultaneously administered drugs were observed.The small sample size and limited duration of these trialsdid not enable any definitive conclusions to be drawnregarding the efficacy of the treatment. In particular, nonoticeable changes in different clinical scores weremeasured during the treatment of HD patients [4,5]. Bycontrast, MS patients who had received minocyclineexperienced a sharp reduction in the number of activelesions during the first 6 months of treatment comparedwiththe run-inperiod in whichthere was no treatment[6].Nevertheless, it is unclear whether the reduced magneticresonance imaging (MRI) activity observed was due to theneuroprotectiveproperties ofminocyclineor toits immuno-modulatory properties. Thus, the results of a longer follow-up of these patients are eagerly awaited. Concluding remarks The neuroprotective nature of tetracyclines is now wellestablished. Recent studies have contributed greatly toour understanding of the molecular and cellular mechan-isms that underlie neuroprotection mediated by thesebacteriostatic agents. In addition, the protective Table 1. Tetracycline-mediated protection in animal models of neurodegenerative diseases a Model Species Refs Neuroprotective Neurotoxic Clinical trialor RefsIschemia  NoGlobal ischemia Mongolian gerbil [2] Yes NoFocal ischemia Sprague-Dawley rat [7,16] Yes NoNeonatal hypoxic–ischemia Sprague-Dawley rat [17,18] Yes NoNeonatal hypoxic–ischemia C57BL/6 mouse [18] No Yes Spinal cord injury  NoExtradural compression CD-1 mouse [20] Yes NoT10 contusion injury Sprague-Dawley rat [22] Yes NoC7–C8 transection Wistar rat [21] Yes No Huntington’s disease  Yes; [4,5]R6/2 transgene C57BL/6 mouse [14,25] Yes NoR6/2 transgene C57BL/6 mouse [26] No No3-Nitropropionic acid C57BL/6 mouse [27] No Yes ALS  Yes; [3] SOD1 G93A transgene C57BL/6 mouse [13] Yes No SOD1 G37A transgene C57BL/6 mouse [23] Yes No Parkinson’s disease  NoMPTP C57BL/6 mouse [8,10] Yes NoMPTP C57BL/6 mouse [28] No YesMPTP Cinomolgus monkey [27] No Yes Multiple sclerosis  Yes; [6]Relapse-remitting EAE Dark Agouti rats [11] Yes NoChronic EAE C57BL/6 mouse [12] Yes No a Abbreviations: ALS, amyotrophic lateral sclerosis; EAE, experimental autoimmune encephalomyelitis; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine;  SOD  , geneencoding superoxide dismutase. Update  TRENDS in Pharmacological Sciences   Vol.25 No.12 December 2004 611  properties of these molecules have been extended tooligodendrocytes and to white matter as a whole, empha-sizing the relevance of these regions for the clinicalconsequences of brain and spinal cord damage. The safetyandtolerabilityoftetracyclinesinhumansatdosesthatarerelevant to neuroprotection are encouraging. It thus seemsthat a new, multifaceted agent to treat major neuro-degenerative disorders is about to emerge. This is indeedwelcome because there are few, if any, available to date. Acknowledgements We thank A. Verkhratsky, D.J. Fogarty, G. Linazasoro, F. Pe´rez-Cerda´and J.M. Delgado for critical reading of the manuscript. We also aregrateful to the Gobierno Vasco, the Universidad del Paı´s Vasco, theFundacio´ La Caixa and the Ministerio de Sanidad y Consumo for fundingsupport. M.D. holds a fellowship from the Gobierno Vasco. References 1 Clark, W.M.  et al . (1994) Reduction of central nervous systemreperfusion injury in rabbits using doxycycline treatment.  Stroke  25,1411–14152 Yrjanheikki, J.  et al . (1998) Tetracyclines inhibit microglial activationand are neuroprotective in global brain ischemia.  Proc. Natl. Acad. Sci. U. S. A.  95, 15769–157743 Gordon, P.H.  et al . (2004) Placebo-controlled phase I/II studies of minocyclineinamyotrophiclateralsclerosis.  Neurology 62,1845–18474 Thomas, M.  et al . (2004) Minocycline in Huntington’s disease: a pilotstudy.  Mov. Disord.  19, 692–6955 HuntingtonStudyGroup.(2004)MinocyclinesafetyandtolerabilityinHuntington disease.  Neurology  63, 547–5496 Metz, L.M.  et al . (2004) Minocycline reduces gadolinium-enhancingmagnetic resonance imaging lesions in multiple sclerosis.  Ann. Neurol.  55, 7567 Yrjanheikki, J.  et al . (1999) A tetracycline derivative, minocycline,reduces inflammation and protects against focal cerebral ischemiawith a wide therapeutic window.  Proc. Natl. Acad. Sci. U. S. A.  96,13496–135008 Du, Y.  et al . (2001) Minocycline prevents nigrostriatal dopaminergicneurodegeneration in the MPTP model of Parkinson’s disease.  Proc. Natl. Acad. Sci. U. S. A.  98, 14669–146749 Tikka, T.  et al . (2001) Minocycline, a tetracycline derivative, isneuroprotective against excitotoxicity by inhibiting activation andproliferation of microglia.  J. Neurosci.  21, 2580–258810 Wu, D.C.  et al . (2002) Blockade of microglial activation is neuropro-tective in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mousemodel of Parkinson disease.  J. Neurosci.  22, 1763–177111 Popovic, N.  et al . (2002) Inhibition of autoimmune encephalomyelitisby a tetracycline.  Ann. Neurol.  51, 215–22312 Brundula, V.  et al . (2002) Targeting leukocyte MMPs and transmigra-tion: minocycline as a potential therapy for multiple sclerosis.  Brain 125, 1297–130813 Zhu, S.  et al . (2002) Minocycline inhibits cytochrome c release anddelays progression of amyotrophic lateral sclerosis in mice.  Nature 417, 74–7814 Wang, X.  et al . (2003) Minocycline inhibits caspase-independent and -dependent mitochondrial cell death pathways in models of Hunting-ton’s disease.  Proc. Natl. Acad. Sci. U. S. A.  100, 10483–1048715 Wang, J.  et al . (2004) Minocycline up-regulates Bcl-2 and protectsagainst cell death in mitochondria.  J. Biol. Chem.  279, 19948–1995416 Xu, L.  et al . (2004) Low dose intravenous minocycline is neuroprotec-tive after middle cerebral artery occlusion-reperfusion in rats.  BMC Neurol.  4, 1–717 Arvin, K.L.  et al . (2002) Minocycline markedly protects the neonatalbrain against hypoxic-ischemic injury.  Ann. Neurol.  52, 54–6118 Tsuji, M.  et al . (2004) Minocycline worsens hypoxic-ischemic braininjury in a neonatal mouse model.  Exp. Neurol.  189, 58–6519 Matute, C.  et al . (2001) The link between excitotoxic oligodendroglialdeath and demyelinating diseases.  Trends Neurosci.  24, 224–23020 Wells, J.E.A.  et al . (2003) Neuroprotection by minocyclinefacilitates significant recovery from spinal cord injury in mice.  Brain  126, 1628–163721 Stirling, D.P.  et al . (2004) Minocycline treatment reduces delayedoligodendrocyte death, attenuates axonal dieback, and improvesfunctionaloutcomeafterspinalcordinjury.  J.Neurosci. 24,2182–219022 Teng, Y.D.  et al . (2004) Minocycline inhibits contusion-triggeredmitochondrial cytochrome c release and mitigates functional deficitsafter spinal cord injury.  Proc. Natl. Acad. Sci. U. S. A.  101, 3071–307623 Kriz, J.  et al . (2002) Minocycline slows disease progression in a mousemodel of amyotrophic lateral sclerosis.  Neurobiol. Dis.  10, 268–27824 Hunter, C.L.  et al . (2004) Minocycline protects basal forebraincholinergic neurons from mu p75-saporin immunotoxic lesioning.  Eur. J. Neurosci.  19, 3305–331625 Chen, M.  et al . (2000) Minocycline inhibits caspase-1 and caspase-3expression and delays mortality in a transgenic mouse model of Huntington disease.  Nat. Med.  6, 797–80126 Smith, D.L.  et al . (2003) Minocycline and doxycycline are notbeneficial in a model of Huntington’s disease.  Ann. Neurol.  54,186–19627 Diguet, E.  et al . (2004) Deleterious effects of minocycline in animalmodels of Parkinson’s disease and Huntington’s disease.  Eur. J. Neurosci.  19, 3266–327628 Yang, L.  et al . (2003) Minocycline enhances MPTP toxicity todopaminergic neurons.  J. Neurosci. Res.  74, 278–28529 Barnet, M.H. and Prineas, J.W. (2004) Relapsing and remittingmultiple sclerosis: pathology of the newlyforminglesion.  Ann.Neurol. 55, 458–46830 Fagan, S.C.  et al . (2004) Optimal delivery of minocycline to the brain:implication for human studies of acute neuroprotection.  Exp. Neurol. 186, 248–251 Therapeutic Target Database (TTD) Modern drug discovery is based primarily on the search for drug leads that act on pre-selected therapeutic targets. Advances ingenomics, the identification of protein structures and the elucidation of disease mechanisms have fuelled increasing interest infinding new targets. Knowledge of existing targets is helpful for the molecular dissection of the mechanism of action of drugs, theprediction of features that guide new drug design and the search for new targets. Analysis of these targets, particularly those of recently approved and patented drugs, alsoprovides useful information aboutgeneral trends,current focuses of research, areasof successes and difficulties in the exploration of therapeutic targets for the discovery of drugs for specific diseases.The Therapeutic Target Database (TTD) is a resource for comprehensive information about currently explored targets. TTDcontains 1174 distinct proteins (including subtypes) and 35 nucleic acids. These include 280 successful targets (those for marketeddrugs) and 894 research targets (those for investigational agents). Information and crosslinks are provided about thenomenclature, sequence, structure, function, therapeutic applications, disease classes, drug usage and effects, and drug-ligandbinding properties for each target. US patent information is also provided for some of the targets.TTD is publicly accessible free of charge for non-commercial purposes at: more information, please contact Y.Z. Chen ( Update  TRENDS in Pharmacological Sciences   Vol.25 No.12 December 2004612
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