tetracycline and Nerve-Degeneration

Minocycline, a clinically used tetracycline for over 40 years, crosses the blood-brain barrier and prevents caspase up-regulation. It reduces apoptosis in mouse models of Huntington's disease and familial amyotrophic lateral sclerosis (ALS) and is in clinical trial for sporadic ALS. Because apoptosis also occurs after brain and spinal cord (SCI) injury, its prevention may be useful in improving recovery. We analyzed minocycline's neuroprotective effects over 28 days following contusion SCI and found significant functional recovery compared to tetracycline. Histology, immunocytochemistry, and image analysis indicated statistically significant tissue sparing, reduced apoptosis and microgliosis, and less activated caspase-3 and substrate cleavage. Since our original report in abstract form, others have published both positive and negative effects of minocycline in various rodent models of SCI and with various routes of administration. We have since found decreased tumor necrosis factor-alpha, as well as caspase-3 mRNA expression, as possible mechanisms of action for minocycline's ameliorative action. These results support reports that modulating apoptosis, caspases, and microglia provide promising therapeutic targets for prevention and/or limiting the degree of functional loss after CNS trauma. Minocycline, and more potent chemically synthesized tetracyclines, may find a place in the therapeutic arsenal to promote recovery early after SCI in humans.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Caspase 3; Caspase Inhibitors; Caspases; Disease Models, Animal; Enzyme Activation; Female; Gliosis; Injections, Intraperitoneal; Minocycline; Nerve Degeneration; Neurons; Neuroprotective Agents; Protein Synthesis Inhibitors; Rats; Rats, Long-Evans; Rats, Sprague-Dawley; RNA, Messenger; Spinal Cord; Spinal Cord Injuries; Tetracycline; Treatment Outcome; Tumor Necrosis Factor-alpha

Genetic evidence indicates that several mutations in tau, including G272V, are linked to frontotemporal dementia with parkinsonism. We expressed this mutation in mouse brains by combining a prion protein promoter-driven expression system with an autoregulatory transactivator loop that resulted in high expression of human G272V tau in neurons and in oligodendrocytes. We show that G272V tau can form filaments in murine oligodendrocytes. Electron microscopy established that the filaments were either straight or had a twisted structure; these were 17-20 nm wide and had a periodicity of approximately 75 nm. Filament formation was associated with tau phosphorylation at distinct sites, including the AT8 epitope 202/205 in vivo. Immunogold electron microscopy of sarcosyl-extracted spinal cords from G272V transgenic mice using phosphorylation-dependent antibodies AT8 or AT100 identified several sparsely gold-labelled 6-nm filaments. In the spinal cord, fibrillary inclusions were also identified by thioflavin-S fluorescent microscopy in oligodendrocytes and motor neurons. These results establish that expression of the G272V mutation in mice causes oligodendroglial fibrillary lesions that are similar to those seen in human tauopathies.

Topics: Animals; Central Nervous System; Cytoskeleton; Disease Models, Animal; Immunohistochemistry; Mice; Mice, Transgenic; Microscopy, Electron; Mutation; Nerve Degeneration; Neurodegenerative Diseases; Neurofibrillary Tangles; Neurons; Oligodendroglia; Phosphorylation; Solubility; tau Proteins; Tetracycline; Trans-Activators