Research Focus
Neuroprotection by tetracyclines

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The neuroprotective properties of tetracyclines have been clearly established in rodent models of acute and chronic neurodegeneration during the past few years. Recent findings have provided novel insights into the molecular and cellular mechanisms of protection of neurons and oligodendrocytes by tetracyclines. These advances have prompted several clinical trials with minocycline, the most effective tetracycline, which are still in their early phases. Thus, tetracyclines hold great promise as therapeutic agents for the treatment of human neurodegenerative diseases.

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Molecular and cellular mechanisms of neuroprotection by tetracyclines

Tetracyclines prevent cell death in a wide range of in vitro and in vivo models by at least two mechanisms: attenuation of innate and adaptive immunity and blockade of apoptotic cascades (Figure 1). The CNS is an immune-privileged tissue, exhibiting a robust innate immune response that is mediated by microglia. Activation of microglia, a common feature of most neurodegenerative diseases, leads to the release of pro-inflammatory mediators and other injury response factors that ultimately

Tetracycline-mediated protection in models of acute neurodegeneration

Acute insults to the CNS such as ischemia, trauma or spinal cord injury cause immediate primary damage and a subsequent secondary degenerative response that develops over several days post-injury. This secondary response is amenable to therapeutic intervention and is characterized by inflammation and delayed neuronal death. Minocycline and doxycycline markedly reduce the size of infarction in both focal and global transient ischemia in the adult rat 1, 2, 7, 16 (Table 1). By contrast,

Tetracycline-mediated protection in models of chronic neurodegenerative diseases

Neuroprotection by tetracyclines in animal models of chronic neurodegenerative disorders has been associated with the anti-inflammatory and anti-apoptotic properties of tetracyclines (Table 1). In ALS transgenic mice, administration of minocycline delays the onset of disease and slows its progression. Moreover, it increases motor performance and extends survival by 2–3 weeks compared with non-treated ALS transgenic mice 13, 23. In addition, minocycline attenuates loss of

Therapeutic prospects of tetracyclines

Together, the studies described in this article indicate that minocycline and doxycycline are solid candidates for the treatment of major neurodegenerative diseases. Moreover, both of these tetracyclines readily cross the blood–brain barrier regardless of the dose and route of administration [30]. However, the dose of minocycline required to elicit neuroprotection in the absence of undesirable side-effects remains a crucial issue because in most experimental models the dose required can be as

Concluding remarks

The neuroprotective nature of tetracyclines is now well established. Recent studies have contributed greatly to our understanding of the molecular and cellular mechanisms that underlie neuroprotection mediated by these bacteriostatic agents. In addition, the protective properties of these molecules have been extended to oligodendrocytes and to white matter as a whole, emphasizing the relevance of these regions for the clinical consequences of brain and spinal cord damage. The safety and

Acknowledgements

We thank A. Verkhratsky, D.J. Fogarty, G. Linazasoro, F. Pérez-Cerdá and J.M. Delgado for critical reading of the manuscript. We also are grateful to the Gobierno Vasco, the Universidad del País Vasco, the Fundació La Caixa and the Ministerio de Sanidad y Consumo for funding support. M.D. holds a fellowship from the Gobierno Vasco.

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