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.
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.
Birinyi-Strachan
Liesl C
LC
Neurotoxin Research Group, Department of Health Sciences, University of Technology, Sydney, Broadway, NSW, Australia.
Davies
Michael J
MJ
Lewis
Richard J
RJ
Nicholson
Graham M
GM
D000465:Algorithms; D001205:Ascorbic Acid / Q000494:pharmacology; D048429:Cell Size; D002839:Chromans / Q000494:pharmacology; D002922:Ciguatoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D004232:Diuretics / Q000737:chemistry / Q000494:pharmacology*; D004578:Electron Spin Resonance Spectroscopy; D004594:Electrophysiology; D016166:Free Radical Scavengers / Q000494:pharmacology*; D005727:Ganglia, Spinal / Q000166:cytology / Q000187:drug effects; D015640:Ion Channel Gating / Q000187:drug effects; D008353:Mannitol / Q000737:chemistry / Q000494:pharmacology*; D008564:Membrane Potentials / Q000187:drug effects; D009475:Neurons, Afferent / Q000187:drug effects* / Q000648:ultrastructure; D018696:Neuroprotective Agents; D009994:Osmolar Concentration; D018408:Patch-Clamp Techniques; D026941:Sodium Channel Blockers / Q000494:pharmacology; D015222:Sodium Channels / Q000187:drug effects; D013012:Sorbitol / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology
D002839:Chromans; D004232:Diuretics; D016166:Free Radical Scavengers; D018696:Neuroprotective Agents; D026941:Sodium Channel Blockers; D015222:Sodium Channels; D002922:Ciguatoxins; D008353:Mannitol; D013779:Tetrodotoxin; D013012:Sorbitol; D001205:Ascorbic Acid; C010643:6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid