Neuroprotective effects of tetracyclines: molecular targets, animal models and human disease.
Tetracyclines are a class of antibiotics which could play a therapeutic role in several neurological disorders. Minocycline, extensively studied in animal models, decreased the size of ischaemic and haemorrhagic infarct. In Parkinson's disease models minocycline protected the nigrostriatal pathway, and in Huntington's disease and motoneuron disease models delayed the progression of disease extending the lifespan. Finally, in human diseases such as stroke and multiple sclerosis tetracyclines seem to play some neuroprotective role. The main biological effects of tetracyclines are the inhibition of microglial activation, the attenuation of apoptosis, and the suppression of reactive oxygen species production. These mechanisms are involved in the pathogenesis of several neurodegenerative disorders. Several reports showed that minocycline reduced mitochondrial Ca(2+) uptake, stabilized mitochondrial membranes, and reduced the release into the cytoplasm of apoptotic factors. Other effects include up-regulation of mitochondrial bcl-2 (an antiapoptotic protein), direct scavenging of reactive oxygen species, and inhibition of mitogen activated protein kinases. It is still unclear which of these mechanisms plays the pivotal role in neuroprotective properties of tetracyclines. The anti-apoptotic effect of tetracyclines probably involves the mitochondrion. The major target for tetracyclines in neurodegeneration could lie within the complex network that links mitochondria, oxidative stress, poly (ADP-ribose) polymerase-1 and apoptosis. Here, we review the neuroprotective effects of tetracyclines in animal models and in human disease, and we focus on their possible mechanism(s) of action, with special regard to mitochondrial dysfunction in neurodegeneration.
Orsucci
D
D
Department of Neuroscience, Neurological Clinic, University of Pisa, Italy. d.orsucci@sssup.it
Calsolaro
V
V
Mancuso
M
M
Siciliano
G
G
D000818:Animals; D004195:Disease Models, Animal; D016503:Drug Delivery Systems / Q000379:methods*; D006801:Humans; D009422:Nervous System Diseases / Q000378:metabolism / Q000517:prevention & control*; D018696:Neuroprotective Agents / Q000008:administration & dosage* / Q000378:metabolism; D013754:Tetracyclines / Q000008:administration & dosage* / Q000378:metabolism
D018696:Neuroprotective Agents; D013754:Tetracyclines