Neuroprotectant effects of iso-osmolar D-mannitol to prevent Pacific ciguatoxin-1 induced alterations in neuronal excitability: a comparison with other osmotic agents and free radical scavengers

Neuropharmacology. 2005 Oct;49(5):669-86. doi: 10.1016/j.neuropharm.2005.04.024.


The basis for the neuroprotectant effect of D-mannitol in reducing the sensory neurological disturbances seen in ciguatera poisoning, is unclear. Pacific ciguatoxin-1 (P-CTX-1), at a concentration 10 nM, caused a statistically significant swelling of rat sensory dorsal root ganglia (DRG) neurons that was reversed by hyperosmolar 50 mM D-mannitol. However, using electron paramagnetic resonance (EPR) spectroscopy, it was found that P-CTX-1 failed to generate hydroxyl free radicals at concentrations of toxin that caused profound effects on neuronal excitability. Whole-cell patch-clamp recordings from DRG neurons revealed that both hyper- and iso-osmolar 50 mM D-mannitol prevented the membrane depolarisation and repetitive firing of action potentials induced by P-CTX-1. In addition, both hyper- and iso-osmolar 50 mM D-mannitol prevented the hyperpolarising shift in steady-state inactivation and the rise in leakage current through tetrodotoxin (TTX)-sensitive Na(v) channels, as well as the increased rate of recovery from inactivation of TTX-resistant Na(v) channels induced by P-CTX-1. D-Mannitol also reduced, but did not prevent, the inhibition of peak TTX-sensitive and TTX-resistant I(Na) amplitude by P-CTX-1. Additional experiments using hyper- and iso-osmolar D-sorbitol, hyperosmolar sucrose and the free radical scavenging agents Trolox and L-ascorbic acid showed that these agents, unlike D-mannitol, failed to prevent the effects of P-CTX-1 on spike electrogenesis and Na(v) channel gating. These selective actions of D-mannitol indicate that it does not act purely as an osmotic agent to reduce swelling of nerves, but involves a more complex action dependent on the Na(v) channel subtype, possibly to alter or reduce toxin association.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Algorithms
  • Ascorbic Acid / pharmacology
  • Cell Size
  • Chromans / pharmacology
  • Ciguatoxins / antagonists & inhibitors*
  • Ciguatoxins / toxicity*
  • Diuretics / chemistry
  • Diuretics / pharmacology*
  • Electron Spin Resonance Spectroscopy
  • Electrophysiology
  • Free Radical Scavengers / pharmacology*
  • Ganglia, Spinal / cytology
  • Ganglia, Spinal / drug effects
  • Ion Channel Gating / drug effects
  • Mannitol / chemistry
  • Mannitol / pharmacology*
  • Membrane Potentials / drug effects
  • Neurons, Afferent / drug effects*
  • Neurons, Afferent / ultrastructure
  • Neuroprotective Agents*
  • Osmolar Concentration
  • Patch-Clamp Techniques
  • Sodium Channel Blockers / pharmacology
  • Sodium Channels / drug effects
  • Sorbitol / pharmacology
  • Tetrodotoxin / pharmacology


  • Chromans
  • Diuretics
  • Free Radical Scavengers
  • Neuroprotective Agents
  • Sodium Channel Blockers
  • Sodium Channels
  • Ciguatoxins
  • Mannitol
  • Tetrodotoxin
  • Sorbitol
  • Ascorbic Acid
  • 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid