Minocycline neuroprotects, reduces microgliosis, and inhibits caspase protease expression early after spinal cord injury

J Neurochem. 2006 Jun;97(5):1314-26. doi: 10.1111/j.1471-4159.2006.03799.x. Epub 2006 Apr 21.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Anti-Inflammatory Agents / pharmacology
  • Anti-Inflammatory Agents / therapeutic use
  • Apoptosis / drug effects
  • Apoptosis / physiology
  • Caspase 3
  • Caspase Inhibitors*
  • Caspases / genetics
  • Caspases / metabolism
  • Disease Models, Animal
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Female
  • Gliosis / physiopathology
  • Gliosis / prevention & control*
  • Injections, Intraperitoneal
  • Minocycline / pharmacology*
  • Minocycline / therapeutic use
  • Nerve Degeneration / drug therapy*
  • Nerve Degeneration / physiopathology
  • Nerve Degeneration / prevention & control
  • Neurons / drug effects
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Neuroprotective Agents / therapeutic use
  • Protein Synthesis Inhibitors / pharmacology
  • RNA, Messenger / drug effects
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Long-Evans
  • Rats, Sprague-Dawley
  • Spinal Cord / drug effects
  • Spinal Cord / metabolism
  • Spinal Cord / physiopathology
  • Spinal Cord Injuries / drug therapy*
  • Spinal Cord Injuries / metabolism
  • Spinal Cord Injuries / physiopathology
  • Tetracycline / pharmacology
  • Treatment Outcome
  • Tumor Necrosis Factor-alpha / drug effects
  • Tumor Necrosis Factor-alpha / metabolism

Substances

  • Anti-Inflammatory Agents
  • Caspase Inhibitors
  • Neuroprotective Agents
  • Protein Synthesis Inhibitors
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Casp3 protein, mouse
  • Casp3 protein, rat
  • Caspase 3
  • Caspases
  • Tetracycline
  • Minocycline