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Prospects for Minocycline Neuroprotection
Jennifer M. Plane, PhD; Yan Shen, PhD; David E. Pleasure, MD; Wenbin Deng, PhD Minocyclineisaclinicallyavailableantibioticandanti-inflammatorydrugthatalso
demonstrates neuroprotective properties in a variety of experimental models of neu-rological diseases. There have thus far been more than 300 publications on mino-cycline neuroprotection including a growing number of human studies. Our ob- jective is to critically review the biological basis and translational potential of this action of minocyclineon the nervous system.
Arch Neurol. Published online August 9, 2010. The lack of robust treatment options avail- is warranted, as are guidelines on safe and able for neurodegenerative diseases, stroke, effective doses, routes of administration, all of which often involve both inflamma- tion and apoptotic cell death, has led to cline in suppression of both apoptosis and potential of established drugs for treat- ment of these conditions. Minocycline hy- cell death and by inhibiting microglial ac- drochloride is a second-generation tetra- tivation, the exact molecular targets of mi- clinical track record as an antibiotic and of action by which minocycline exerts its demonstrated neuroprotective qualities in models of neurological diseases, and dis- generative diseases including amyotro-phic lateral sclerosis, Huntington dis- MECHANISMS OF ACTION
ease, Parkinson disease, and multiplesclerosis. Thus, it is not surprising that sev-eral off-label minocycline clinical trials are under way for a variety of CNS diseases.
to be responsible for minocycline’s neu- mary target of this drug in the nervous sys- clinical practice for CNS diseases, whereas have focused on the anti-inflammatory, an- others (eg, in amyotrophic lateral sclero- tiapoptotic, and antioxidant properties of sis) have raised red flags. A thorough un- derstanding of minocycline’s modes of ac- of minocycline, which are involved in the tion and the targeted cellular mechanisms pathogenesis of several neurological dis-orders, include inhibition of microglial ac-tivation, attenuation of apoptosis, and sup- Author Affiliations: Departments of Cell Biology and Human Anatomy (Drs Plane,
Shen, and Deng), Pediatrics and Neurology (Dr Pleasure), University of California, Davis, School of Medicine; and the Institute for Pediatric Regenerative Medicine,Shriners Hospital and University of California, Davis, School of Medicine, 2010 American Medical Association. All rights reserved.
Figure. Signaling mechanisms involved in the neuroprotective actions of minocycline. See the text for detailed descriptions. AIF indicates apoptosis-inducing
factor; BCL-2, B-cell leukemia/lymphoma 2; CCR5, chemokine receptor type 5; CXCR3, chemokine (CXC motif ) receptor 3; GluR, glutamate receptor; IL,
interleukin; IIP-10, interferon-inducible protein 10; MAPK, mitogen-activated protein kinase; MIP-1␣,macrophage inflammatory protein 1␣; MMP,matrix
metalloprotease; PBR, peripheral benzodiazepine receptor; TNF, tumor necrosis factor; TUNEL, terminal deoxynucleotidyl transferase dUTP (2´-deoxyuridine,
5´-triphosphate)–biotin nick-end labeling.
proliferation/activation as well as subsequent release of other tetracyclines inhibited PARP-1 at nanomolar con- cytokines such as interleukins 1␤ and 6 and tumor ne- centrations, and minocycline protected neurons against crosis factor ␣.1,2 In addition, it decreases CNS expres- PARP-1–mediated toxicity. Other minocycline effects in- sion of chemokines and their receptors such as macro- clude inhibition of mitochondrial peripheral benzodiaz- phage inflammatory protein 1␣, interferon-inducible epine receptor (recently renamed 18-kDa translocator pro- protein 10, chemokine receptor type 5, and chemokine tein), increased phosphorylation, membranal insertion (CXC motif ) receptor 3 as well as suppressing the re- of glutamate receptor 1, and inhibition of mitogen acti- lease of lipids and the activity of matrix metalloprote- ases, which disrupt the blood-brain barrier.1,2 Further- Minocycline treatment provides neuroprotection more, minocycline inhibits T-cell migration into the CNS.
against excitotoxic insults in a number of experimental The neuroprotection afforded by minocycline treat- models. The neuroprotective effects of minocycline are ment of experimental disease models also appears to be evident after glutamate exposure, and oligodendrocyte related to p38 mitogen-activated protein kinase inhibi- survival is enhanced by minocycline treatment after li- tion, which both preserves neurons and inhibits microg- popolysaccharide-induced inflammation; all likely oc- cur as a result of decreased microglial activation.8 Over- The antiapoptotic effects of minocycline are exerted, all, although it is still unclear which of these mechanisms at least in part, on mitochondria. By reducing mitochon- plays the pivotal role in eliciting the neuroprotective prop- drial calcium overloading, minocycline stabilizes the erties of minocycline, the major targets for minocycline mitochondrial membrane and inhibits release of cyto- neuroprotection could lie within the complex signaling chrome c and other apoptotic factors into the cyto- network linking mitochondria, oxidative stress, excito- plasm, thus resulting in decreased caspase activation and toxicity, PARP-1, and apoptosis (Figure).
nuclear damage.4,5 Minocycline also exerts caspase-independent neuroprotective effects including upregu- STUDIES IN EXPERIMENTAL MODELS OF
HUMAN NEUROLOGICAL DISEASES
Minocycline possesses antioxidant properties in ad- dition to its antibiotic, antiapoptotic, and anti- Ischemic Injury
inflammatory properties. It directly scavenges free radi-cals and inhibits molecules such as cyclooxygenase 2, Yrjanheikki et al9 first published the neuroprotective ef- induced nitric oxide synthase, and nicotinamide ad- fects of minocycline on cerebral ischemia, prompting nu- enine dinucleotide phosphate oxidase. The antioxidant merous subsequent evaluations of minocycline on ex- activity of minocycline may be derived from its chemi- perimental models of stroke, neurodegenerative diseases, cal structure or its modulating effects on enzymes such and spinal cord injury (Table 1). Some of these studies
as nitric oxide synthase and lipoxygenases.
indicated substantial neuroprotective effects, while in oth- Poly (ADP [adenosine diphosphate]–ribose) poly- ers, minocycline was ineffective or even deleterious. These merase-1 (PARP-1) is activated by DNA damage and is studies varied widely in dosage, route of administra- critically involved in excitotoxicity, oxidative stress, and tion, timing of drug treatment, species, and experimen- inflammation. Activation of PARP-1 leads to transloca- tal model used. Several studies that tested multiple doses tion of apoptosis-inducing factor from the mitochon- of minocycline treatment after ischemia reported neu- dria to the nucleus and finally promotes cell death and roprotection with relatively low doses but observed tox- inflammation. Alano et al7 reported that minocycline and icity with high-dose minocycline treatment.6,10 Interest- 2010 American Medical Association. All rights reserved.
Table 1. Results of Experimental Studies on Minocycline Treatment for Neurological Diseases
Animal Model
Dose and Route
Reference
Stroke
MCAO
inhibited microglial activation, reduced COX-2 Low dose improved behavioral function, reduced infarct volume, decreased apoptosis, upregulated BCL-2; high dose increased behavioral deficit, increased infarct volume, increased apoptosis, Low dose increased neuron viability, decreased neuron death, increased BCL-2 expression; high dose decreased neuron and astrocyte viability, Decreased infarct volume in rats, increased Reduced white matter injury, reduced microglial Parkinson Disease
MPTP
Increased neuron death, inhibited microglial Huntington Disease
3-NP
Worsened behavioral function, increased neuron Delayed disease progression, inhibited caspase No change in behavioral function, no change in Improved behavioral function, decreased neuron Decreased neuron death, decreased microglial Alzheimer Disease
Tg-SwDI mice
Decreased microglial activation, decreased IL-6, Improved cognitive performance, decreased Multiple Sclerosis
EAE
Decreased clinical scores, decreased T-cell Amyotropic Lateral Sclerosis
SOD1 mice
Delayed disease onset, prolonged survival Abbreviations: 3-NP, nitropropionic acid; CoQ10, coenzyme Q10; COX-2, cyclooxygenase-2; EAE, experimental autoimmune encephalomyelitis; IL, interleukin; IP, intraperitoneal; IV, intravenous; MCAO, middle cerebral artery occlusion; MPTP, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine; OGD, oxygen glucosedeprivation; P, postnatal day; SC, subcutaneously; SOD1, superoxide dismutase 1.
ingly, minocycline treatment exacerbated injury in that, while low-dose minocycline was protective to neu- neonatal mouse models of stroke, whereas it attenuated rons in both in vivo and in vitro experimental models of injury in rats using a similar model and dosing para- stroke, it provided no protection to astrocytes in the same digm.10,11 Furthermore, minocycline exerts different ef- models.6 Yet, other studies describe decreased ischemia- fects on different types of cells. One recent study found induced astrogliosis and reduced white matter damage 2010 American Medical Association. All rights reserved.
Table 2. Summary of Human Trials of Minocycline Treatment for Neurological Diseases
Dosage, mg/d
Duration
Reference
Abbreviations: AIMS, Abnormal Involuntary Movement Scale; ALS, amyotropic lateral sclerosis; ALSFRS-R, ALS functional rating scale; ASIA, American Spinal Injury Association; BI, Barthel Index; FIM, Functional Independence Measure; MMSE, Mini-Mental State Evaluation; mRS, modified Rankin Scale; NIHSS, NationalInstitutes of Health Stroke Scale; SCIM, Spinal Cord Independence Measure; UHDRS, Unified Huntington Disease Rating Scale.
after ischemic injury following minocycline treat- necessary to confirm that these beneficial effects lead to ment.12,26 In addition, though most of these publica- tions addressed only the acute effects of minocycline treat-ment on ischemic injury, it will be important, from a Amyotrophic Lateral Sclerosis
translational point of view, to determine whether mino-cycline treatment confers long-term neuroprotection or Amyotrophic lateral sclerosis (ALS) is a neurodegenera- simply delays the onset of cell death. One promising ob- tive disease characterized by motor neuron death in the servation, in this respect, is that ischemia-induced be- spinal cord, brainstem, and motor cortex. Mutations in havioral deficits lessened after minocycline treatment.27 superoxide dismutase 1 account for a proportion of casesof familial ALS, and mutant superoxide dismutase 1 trans- Parkinson Disease
genic mice provide a useful tool for treatment-testing para-digms. Minocycline treatment improved the symptoms The effects of minocycline treatment on neurodegenera- of ALS in these mice via inhibition of cytochrome c re- tion in chemically induced Parkinson disease models have lease and caspase activation, thus delaying the onset of varied. While most studies found reduced microglial ac- degeneration and muscle strength decline.25 Owing to the tivation and neuronal cell death,13,14 others reported de- success of minocycline in these experimental trials, it creased microglial activation and enhanced neuron tox- quickly advanced to clinical trials but these yielded un- icity.15,16 In one genetic model, the Weaver mouse, expectedly poor results (see “Clinical Studies” section).
minocycline treatment resulted in nigrostriatal neuro-protection.17 Experimental Autoimmune Encephalomyelitis
Huntington Disease
Minocycline suppresses T-cell proliferation, migration,and cytokine production in an autoimmune animal model In a genetic model of Huntington disease (HD), the of multiple sclerosis, experimental autoimmune encepha- R6/2 mouse, one group reported that minocycline pro- lomyelitis, and delays the onset and diminishes the se- vided neuroprotection,15 another observed no clinical verity of clinical neurological disability.24,28 evidences of therapeutic efficacy,18 and a third reportedthat minocycline treatment was detrimental.19 Several Spinal Cord Injury
studies investigated the effects of minocycline treat-ment combined with other therapies. Treatment with In animal models of spinal cord injury, minocycline treat- minocycline and pyruvate or coenzyme Q10 afforded ment reduced microglial activation and astrogliosis and significant neuroprotection in mice with HD,20,21 sug- enhanced oligodendrocyte survival but reports of func- gesting that minocycline may best be used as a combi- CLINICAL STUDIES
Alzheimer Disease
The use of minocycline as an antibiotic as well as its ex- While minocycline treatment produced mixed results in cellent safety profile and penetration into the CNS spurred HD and Parkinson disease studies, it appears to be ben- interest in using this drug to treat neurological diseases.
eficial in experimental models of Alzheimer disease. Both Clinical trials are under way for the use of minocycline in vivo and in vitro studies report suppressed microglial to treat several neurological diseases such as stroke, mul- activation in Alzheimer disease models along with at- tiple sclerosis, spinal cord injury, Huntington disease, and tenuated neuronal cell death, astrogliosis, and im- Parkinson disease. Trials already completed have re- proved behavioral performance.22,23 Further studies are vealed both positive and negative effects (Table 2).
2010 American Medical Association. All rights reserved.
Brain Ischemia
18 months and patients were assessed for changes in thetotal Unified Parkinson Disease Rating Scale and a num- A number of completed clinical studies reported benefi- ber of other measures to identify disability and symp- cial effects of minocycline treatment without increased toms.32 The patients treated with minocycline showed nei- incidence of severe adverse events. In an open-label, evalu- ther a decline in symptoms nor any increase in adverse ator-blinded study, oral administration of 200 mg/d of minocycline for 5 days 6 to 24 hours after acute CNS in-farction caused no major complications, significantly de- Huntington Disease
creased scores on the National Institutes of Health StrokeScale and modified Rankin Scale, and increased Barthel An initial open-label study found no obvious toxicity and Index scores in treated patients at days 7, 30, and 90 of observed improvements in motor function in minocycline- follow-up. These observations suggest that the treat- treated patients with HD based on their Unified HD Rat- ment of acute stroke with minocycline at this stage is ing Scale and Mini-Mental State Examination after 6 associated with better clinical outcome.29 There are, how- months of treatment.33 In a 24-month follow-up, these ever, several limitations to this study including the open- authors reported stabilization of motor function and ame- label design and small sample size. Future studies of mi- lioration of psychiatric symptoms.38 The study included nocycline administration after CNS infarction should 14 patients, with only 11 included in the final analysis, include double-blind, controlled trials that use a broader making it difficult to draw firm conclusions. An 8-week, window of treatment time (especially earlier) as well as double-blind, randomized, placebo-controlled study by the Huntington Study Group in which patients with HDwere treated with the same dose (100 or 200 mg/d) as Spinal Cord Injury
the Bonelli group indicated that, although minocyclinewas well tolerated, it had no effect on Unified HD Rat- A small, phase 1/2 pilot study is under way to assess mi- ing Scale scores and actually worsened scores on the nocycline treatment in human patients after spinal cord Stroop Interference test.39 Another small pilot study re- injury. In this randomized, double-blind trial, patients ported similar findings of good tolerability but lack of receive 200 or 400 mg of minocycline intravenously twice motor improvement on the Unified HD Rating Scale af- daily for 7 days and are evaluated for 1 year. Results ob- tained thus far indicate that minocycline treatment en-hances recovery, as shown by improved scores on the Amyotrophic Lateral Sclerosis
American Spinal Injury Association examination, Func-tional Independence Measure, Spinal Cord Indepen-dence Measure, London Handicap Score, and Short Form– In a completed phase III clinical trial, patients with ALS 36. These improvements were limited to patients with received minocycline at up to 400 mg/d for 9 months; cervical spinal cord injury, whereas those with thoracic they were evaluated on the revised ALS functional rat- complete spinal cord injury showed no treatment effect.30 ing scale and for forced vital capacity, manual muscle test- The sample size in this study is small, so conclusions of ing, quality of life, survival, and drug safety. Patients treated with minocycline showed faster deterioration thanthe placebo group according to the ALS functional rat- Multiple Sclerosis
ing scale and trended toward a faster decline in forcedvital capacity and manual muscle testing scores. There Several small clinical trials found minocycline treatment was also a nonsignificant increase in mortality in the mi- to be effective in reducing lesion size and occurrence rate nocycline treatment group as well as gastrointestinal and in relapsing-remitting multiple sclerosis.36,37 More re- neurological adverse events. Despite the negative effect cently, a double-blind, placebo-controlled study was com- of minocycline treatment on disease progression and ad- pleted to evaluate the effects of minocycline combined with verse events, minocycline-treated patients described simi- glatiramer acetate treatment in patients with relapsing- lar quality-of-life scores to the placebo patients.35 The au- remitting multiple sclerosis. In this study, patients re- thors of this study concluded that minocycline is not a ceived 100 mg of minocycline twice daily combined with viable treatment for ALS and warned against its use to glatiramer acetate or glatiramer acetate/placebo for 9 months.
treat other neurodegenerative diseases. Among possible The combination of drugs reduced the total number of gado- reasons for this disappointing result are (1) that an in- linium-enhancing lesions, the total number of new and en- adequately low dosage schedule was used and (2) that larging lesions, and the total disease burden compared with the dosage of minocycline, by increasing glutamate re- glatiramer acetate/placebo treatment.31 Although the num- ceptor 1 phosphorylation and membrane insertion, pro- ber of patients in this study was relatively small, it pro- moted glutamate toxicity and motor neuron loss.40 vides support for the use of minocycline as a combinato-rial therapy for multiple sclerosis.
SUMMARY OF AVAILABLE
CLINICAL TRIALS DATA
Parkinson Disease
While the clinical trials mentioned reveal both benefi- In pilot clinical trials using minocycline treatment for Par- cial and deleterious results of minocycline treatment, all kinson disease, 200 mg/d of minocycline was given for hope is not lost regarding its use as a future therapeutic.
2010 American Medical Association. All rights reserved.
More studies are needed to confirm the appropriate tim- Foundation for Anemia Research, and Feldstein Medi- ing and dosage, which may vary by disease. Some re- cal Foundation (Dr Deng); the Shriners Hospitals for Chil- searchers speculate that doses of 100 to 200 mg/d, typi- dren (Drs Deng and Pleasure); and by grants R01 cally used in current clinical trials, may be ideal for NS059043, R01 ES015988 (Dr Deng), and R01 NS025044 humans to alleviate symptoms without toxic conse- (Dr Pleasure) from the National Institutes of Health.
quences. Others believe that this dose is too low, giventhat the typical dose for animal studies ranges from 10to 100 mg/kg/d, which would theoretically equal ap- proximately 3 to 7 g/d for humans. The dose of 200 mg/dprovided improvement for acute stroke, yet had no effect 1. Stirling DP, Koochesfahani KM, Steeves JD, Tetzlaff W. Minocycline as a neu- roprotective agent. Neuroscientist. 2005;11(4):308-322.
on Parkinson disease or patients with HD. Thus, the pos- 2. Kim HS, Suh YH. Minocycline and neurodegenerative diseases. Behav Brain Res.
sibility remains that increasing the dose of minocycline would improve its efficacy. In addition, minocycline treat- 3. Guo G, Bhat NR. p38alpha MAP kinase mediates hypoxia-induced motor neuron ment could be combined with other drug treatments in cell death: a potential target of minocycline’s neuroprotective action. Neuro- hopes of enhancing the beneficial effects without increas- chem Res. 2007;32(12):2160-2166.
4. Garcia-Martinez EM, Sanz-Blasco S, Karachitos A, et al. Mitochondria and cal- ing the risk of harmful adverse effects seen with high doses cium flux as targets of neuroprotection caused by minocycline in cerebellar gran- of minocycline treatment. This therapeutic strategy has ule cells. Biochem Pharmacol. 2010;79(2):239-250.
already proved useful in preliminary studies of multiple 5. Antonenko YN, Rokitskaya TI, Cooper AJ, Krasnikov BF. Minocycline chelates sclerosis and may be advantageous in a number of other Ca2ϩ, binds to membranes, and depolarizes mitochondria by formation of Ca2ϩ-dependent ion channels. J Bioenerg Biomembr. 2010;42(2):151-163.
6. Matsukawa N, Yasuhara T, Hara K, et al. Therapeutic targets and limits of mino- cycline neuroprotection in experimental ischemic stroke. BMC Neurosci. 2009; 7. Alano CC, Kauppinen TM, Valls AV, Swanson RA. Minocycline inhibits poly(ADP- The practical utility of the neuroprotective effects of mi- ribose) polymerase-1 at nanomolar concentrations. Proc Natl Acad Sci U S A. 2006;103(25):9685-9690.
nocycline, though based on a substantial body of prom- 8. Guimara˜es JS, Freire MA, Lima RR, Picanc¸o-Diniz CW, Pereira A, Gomes-Leal W.
ising in vitro and animal studies, continues to be a mat- Minocycline treatment reduces white matter damage after excitotoxic striatal injury.
ter of intense debate, with contradictory evidence ranging Brain Res. 2010;1329:182-193.
from neuroprotection to the exacerbation of toxicity in 9. Yrjänheikki J, Tikka T, Keinänen R, Goldsteins G, Chan PH, Koistinaho J. A tet- racycline derivative, minocycline, reduces inflammation and protects against fo- various experimental models and human trials. Studies cal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci U S A.
to date have clearly established that minocycline exerts neuroprotective effects but have also shown that the ac- 10. Tsuji M, Wilson MA, Lange MS, Johnston MV. Minocycline worsens hypoxic- tions of this drug are complex, and that its administra- ischemic brain injury in a neonatal mouse model. Exp Neurol. 2004;189(1): tion can, under certain circumstances, also have neuro- 11. Carty ML, Wixey JA, Colditz PB, Buller KM. Post-insult minocycline treatment toxic consequences. More studies, both clinical and attenuates hypoxia-ischemia-induced neuroinflammation and white matter in- preclinical, and both combinatorial and sequential strat- jury in the neonatal rat: a comparison of two different dose regimens. Int J Dev egies, should be carried out to ascertain the therapeutic Neurosci. 2008;26(5):477-485.
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13. Du Y, Ma Z, Lin S, et al. Minocycline prevents nigrostriatal dopaminergic neu- Accepted for Publication: June 15, 2010.
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14. Radad K, Moldzio R, Rausch WD. Minocycline protects dopaminergic neurons against long-term rotenone toxicity. Can J Neurol Sci. 2010;37(1):81-85.
Correspondence: Wenbin Deng, PhD, Department of Cell
15. Diguet E, Fernagut PO, Wei X, et al. Deleterious effects of minocycline in animal Biology and Human Anatomy, University of California, models of Parkinson’s disease and Huntington’s disease. Eur J Neurosci. 2004; Davis, School of Medicine, 2425 Stockton Blvd, Sacra- mento, CA 95817 (wbdeng@ucdavis.edu).
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Author Contributions: Drs Plane and Shen had full ac-
17. Peng J, Xie L, Stevenson FF, Melov S, Di Monte DA, Andersen JK. Nigrostriatal cess to all of the materials in the study and take respon- dopaminergic neurodegeneration in the weaver mouse is mediated via neuroin- sibility for the integrity of the data and the accuracy of flammation and alleviated by minocycline administration. J Neurosci. 2006; the data analysis. Study concept and design: Plane, Shen, Pleasure, and Deng. Acquisition of data: Plane, Shen, Plea- 18. Chen M, Ona VO, Li M, et al. Minocycline inhibits caspase-1 and caspase-3 ex- pression and delays mortality in a transgenic mouse model of Huntington disease.
sure, and Deng. Analysis and interpretation of data: Plane, Shen, Pleasure, and Deng. Drafting of the manuscript: Plane, 19. Smith DL, Woodman B, Mahal A, et al. Minocycline and doxycycline are not ben- Shen, Pleasure, and Deng. Critical revision of the manu- eficial in a model of Huntington’s disease. Ann Neurol. 2003;54(2):186-196.
script for important intellectual content: Plane, Shen, Plea- 20. Stack EC, Smith KM, Ryu H, et al. Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington’s disease mice. Biochim Biophys sure, and Deng. Statistical analysis: Pleasure. Obtained funding: Plane, Shen, Pleasure, and Deng. Administra- 21. Ryu JK, Choi HB, McLarnon JG. Combined minocycline plus pyruvate treatment tive, technical, and material support: Plane, Shen, Plea- enhances effects of each agent to inhibit inflammation, oxidative damage, and sure, and Deng. Study supervision: Pleasure and Deng.
neuronal loss in an excitotoxic animal model of Huntington’s disease. Neuroscience.
Financial Disclosure: None reported.
22. Fan R, Xu F, Previti ML, et al. Minocycline reduces microglial activation and im- Funding/Support: This study was supported in part by
proves behavioral deficits in a transgenic model of cerebral microvascular amyloid.
grants from the National Multiple Sclerosis Society, Roche J Neurosci. 2007;27(12):3057-3063.
2010 American Medical Association. All rights reserved.
23. Seabrook TJ, Jiang L, Maier M, Lemere CA. Minocycline affects microglia acti- remitting multiple sclerosis: results of a Canadian, multicenter, double-blind, pla- vation, Abeta deposition, and behavior in APP-tg mice. Glia. 2006;53(7):776- cebo-controlled trial. Mult Scler. 2009;15(10):1183-1194.
32. NINDS NET-PD Investigators. A pilot clinical trial of creatine and minocycline in 24. Nikodemova M, Lee J, Fabry Z, Duncan ID. Minocycline attenuates experimental early Parkinson disease: 18-month results. Clin Neuropharmacol. 2008;31 autoimmune encephalomyelitis in rats by reducing T cell infiltration into the spi- nal cord. J Neuroimmunol. 2010;219(1-2):33-37.
33. Bonelli RM, Heuberger C, Reisecker F. Minocycline for Huntington’s disease: an 25. Zhu S, Stavrovskaya IG, Drozda M, et al. Minocycline inhibits cytochrome c re- open label study. Neurology. 2003;60(5):883-884.
lease and delays progression of amyotrophic lateral sclerosis in mice. Nature.
34. Thomas M, Ashizawa T, Jankovic J. Minocycline in Huntington’s disease: a pilot study. Mov Disord. 2004;19(6):692-695.
26. Cai ZY, Yan Y, Chen R. Minocycline reduces astrocytic reactivation and neuro- 35. Gordon PH, Moore DH, Miller RG, et al; Western ALS Study Group. Efficacy of inflammation in the hippocampus of a vascular cognitive impairment rat model.
minocycline in patients with amyotrophic lateral sclerosis: a phase III ran- Neurosci Bull. 2010;26(1):28-36.
domised trial. Lancet Neurol. 2007;6(12):1045-1053.
27. Liu Z, Fan Y, Won SJ, et al. Chronic treatment with minocycline preserves adult 36. Zabad RK, Metz LM, Todoruk TR, et al. The clinical response to minocycline in new neurons and reduces functional impairment after focal cerebral ischemia.
multiple sclerosis is accompanied by beneficial immune changes: a pilot study.
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29. Lampl Y, Boaz M, Gilad R, et al. Minocycline treatment in acute stroke: an open- 38. Bonelli RM, Hödl AK, Hofmann P, Kapfhammer HP. Neuroprotection in Hunting- label, evaluator-blinded study. Neurology. 2007;69(14):1404-1410.
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