Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical‐scavenging activity

Minocycline is neuroprotective in animal models of a number of acute CNS injuries and neurodegenerative diseases. While anti‐inflammatory and anti‐apoptotic effects of minocycline have been characterized, the molecular basis for the neuroprotective effects of minocycline remains unclear. We report here that minocycline and a number of antioxidant compounds protect mixed neuronal cultures in an oxidative stress assay. To evaluate the role of minocycline's direct antioxidant properties in neuroprotection, we determined potencies for minocycline, other tetracycline antibiotics, and reference antioxidant compounds using a panel of in vitro radical scavenging assays. Data from in vitro rat brain homogenate lipid peroxidation and 2,2‐diphenyl‐1‐picrylhydrazyl (DPPH) radical scavenging assays show that minocycline, in contrast to tetracycline, is an effective antioxidant with radical scavenging potency similar to vitamin E. Our findings suggest that the direct antioxidant activity of minocycline may contribute to its neuroprotective effects in some cell‐based assays and animal models of neuronal injury.

[1]  Dong-Kug Choi,et al.  Blockade of Microglial Activation Is Neuroprotective in the 1-Methyl-4-Phenyl-1,2,3,6-Tetrahydropyridine Mouse Model of Parkinson Disease , 2002, The Journal of Neuroscience.

[2]  S. Paul,et al.  Minocycline blocks nitric oxide-induced neurotoxicity by inhibition p38 MAP kinase in rat cerebellar granule neurons , 2001, Neuroscience Letters.

[3]  T. Murphy,et al.  Immature cortical neurons are uniquely sensitive to glutamate toxicity by inhibition of cystine uptake , 1990, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[4]  J. Brotchi,et al.  Clinical potential of minocycline for neurodegenerative disorders , 2004, Neurobiology of Disease.

[5]  Betty Y. S. Kim,et al.  Minocycline inhibits cytochrome c release and delays progression of amyotrophic lateral sclerosis in mice , 2002, Nature.

[6]  C. Behl Vitamin E protects neurons against oxidative cell death in vitro more effectively than 17-β estradiol and induces the activity of the transcription factor NF-κB , 2000, Journal of Neural Transmission.

[7]  C. Rice-Evans,et al.  Factors influencing the antioxidant activity determined by the ABTS.+ radical cation assay. , 1997, Free radical research.

[8]  J. Steeves,et al.  Minocycline Treatment Reduces Delayed Oligodendrocyte Death, Attenuates Axonal Dieback, and Improves Functional Outcome after Spinal Cord Injury , 2004, The Journal of Neuroscience.

[9]  S. Paul,et al.  Minocycline prevents nigrostriatal dopaminergic neurodegeneration in the MPTP model of Parkinson's disease , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[10]  Y. Oh,et al.  Minocycline inhibits apoptotic cell death via attenuation of TNF‐α expression following iNOS/NO induction by lipopolysaccharide in neuron/glia co‐cultures , 2004, Journal of neurochemistry.

[11]  D. Hess,et al.  Low dose intravenous minocycline is neuroprotective after middle cerebral artery occlusion-reperfusion in rats , 2004, BMC neurology.

[12]  T. Russo,et al.  Gene regulation by reactive oxygen species. , 1997, Current topics in cellular regulation.

[13]  R. Dodel,et al.  Minocycline blocks 6-hydroxydopamine-induced neurotoxicity and free radical production in rat cerebellar granule neurons. , 2003, Life sciences.

[14]  K. Lee,et al.  Vitamin C equivalent antioxidant capacity (VCEAC) of phenolic phytochemicals. , 2002, Journal of agricultural and food chemistry.

[15]  E. Melamed,et al.  Antioxidant Therapy in Acute Central Nervous System Injury: Current State , 2002, Pharmacological Reviews.

[16]  I. Gülçin,et al.  Determination of in vitro antioxidant and radical scavenging activities of propofol. , 2005, Chemical & pharmaceutical bulletin.

[17]  M. E. Eichler,et al.  Minocycline inhibits contusion-triggered mitochondrial cytochrome c release and mitigates functional deficits after spinal cord injury. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[18]  W. Robberecht,et al.  Minocycline delays disease onset and mortality in a transgenic model of ALS , 2002, Neuroreport.

[19]  N. Holbrook,et al.  Cellular response to oxidative stress: Signaling for suicide and survival * , 2002, Journal of cellular physiology.

[20]  P. Beart,et al.  A reliable procedure for comparison of antioxidants in rat brain homogenates. , 1998, Journal of pharmacological and toxicological methods.

[21]  INTERNATIONAL SOCIETY FOR NEUROCHEMISTRY , 1976 .

[22]  P. Chan,et al.  A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[23]  Ming-tao Li,et al.  Minocycline prevents glutamate‐induced apoptosis of cerebellar granule neurons by differential regulation of p38 and Akt pathways , 2004, Journal of neurochemistry.

[24]  Y. Kawaoka,et al.  Epidermal immunization by a needle-free powder delivery technology: Immunogenicity of influenza vaccine and protection in mice , 2000, Nature Medicine.

[25]  A. Caswell,et al.  Selectivity of cation chelation to tetracyclines: evidence for special conformation of calcium chelate. , 1971, Biochemical and biophysical research communications.

[26]  C. Behl,et al.  The antioxidant neuroprotective effects of estrogens and phenolic compounds are independent from their estrogenic properties. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[27]  J. Koistinaho,et al.  Minocycline Provides Neuroprotection Against N-Methyl-d-aspartate Neurotoxicity by Inhibiting Microglia1 , 2001, The Journal of Immunology.

[28]  C. Sen,et al.  Cellular and mitochondrial changes in glutamate-induced HT4 neuronal cell death , 2000, Neuroscience.

[29]  S. Imamura,et al.  Effect of antibiotics on the generation of reactive oxygen species. , 1986, The Journal of investigative dermatology.

[30]  C. Behl,et al.  Protective Activity of Aromatic Amines and Imines against Oxidative Nerve Cell Death , 2001, Biological chemistry.

[31]  M. Gyamfi,et al.  Antioxidant properties of Thonningianin A, isolated from the African medicinal herb, Thonningia sanguinea. , 2002, Biochemical pharmacology.

[32]  Carlos Matute,et al.  Neuroprotection by tetracyclines. , 2004, Trends in pharmacological sciences.

[33]  S. Hersch,et al.  Minocycline inhibits caspase-1 and caspase-3 expression and delays mortality in a transgenic mouse model of Huntington disease , 2000, Nature Medicine.

[34]  Rachel L Neve,et al.  In vitro model of oxidative stress in cortical neurons. , 2002, Methods in enzymology.

[35]  Robert M Friedlander,et al.  Apoptosis and caspases in neurodegenerative diseases. , 2003, The New England journal of medicine.