Veratridine

The Journal of Physiology,1975, 247(3):617-655.

Effects of potassium, veratridine, and scorpion venom on calcium accumulation and transmitter release by nerve terminals in vitro.[Reference: WebLink]

METHODS AND RESULTS:
1. 45-Ca uptake by pinched-off nerve terminals (synaptosomes) of rat brain incubated in standard physiological saline (including 132 mM-Na + 5mM-K + 1-2 mM-Ca) at 30 degrees C averages about 0-5 mumole Ca per g protein per minute. This may be equivalent to a Ca influx of about 0-03 p-mole/cm-2 sec. 2. The rate of 45-Ca uptake is increased when the concentration of K in the medium is increased above 15-20 mM, K replacing Na isosmotically. Maximum stimulation, a three- to six-fold increase in the rate of Ca uptake, occurs when [K]o is about 60 mM. The effect of increased [K]o is reversible. 3. The K-stimulated Ca uptake is associated primarily with the nerve terminal fraction of brain homogenates. The entering Ca is not accompanied by extracellular markers such as mannitol or inulin. Replacement of external chloride by methylsulphate or sulphate does not prevent the stimulation by K. 4. The effects of external K are quantitatively mimicked by Rb. Caesium also stimulates Ca uptake, but is only about one fifth as effective as K or Rb; Li is ineffective. 5. Two other depolarizing agents also stimulate Ca uptake by synaptosomes: Veratridine (7-5 times 10- minus 6 to 7-5 times 10- minus 5 M) and scorpion (Leirus quinquestriatus) venom (6-7 times 10- minus 7 to 6-7 times 10- minus g/ml.). The stimulatory effects of Veratridine and scorpion venom, but not of increased [K] are blocked by 2 times 10- minus 7 M tetrodotoxin. 6. Internal K also influences the rate of 45-Ca uptake by synaptosomes: lowering [K]i reduces the stimulatory effect of external K and Veratridine. 7. Replacement of external Na by choline markedly inhibits the response to Veratridine, but has a much smaller effect on the response to increased [K]o. 8. The Ca uptake mechanism has an apparent dissociation constant for Ca (KCa) of about 0-8 mM. Increasing [K]o increases the maximal rate of Ca uptake, but has no effect on KCa. The K-induced 45-Ca uptake is competitively inhibited by Mg-2+, Mn-2+ and La-3+. 9. The release of acetylcholine and noradrenaline was also studied. Increasing [K]o stimulates external Ca-dependent acetylcholine release. Scorpion venom stimulates noradrenaline release from synaptosomes; this effect could be prevented by adding tetrodotoxin or removing external Ca. 10.
CONCLUSIONS:
These results indicate that synaptosomes may increase their permeability to Ca, accumulate Ca and release neural transmitter substances, when stimulated by depolarizing agents under appropriate physiological conditions.

British Journal of Pharmacology, 2000, 130(7):1496-1504.

Veratridine induces apoptotic death in bovine chromaffin cells through superoxide production.[Reference: WebLink]

The molecular mechanisms involved in Veratridine-induced chromaffin cell death have been explored.
METHODS AND RESULTS:
We have found that exposure to Veratridine (30 microM, 1 h) produces a delayed cellular death that reaches 55% of the cells 24 h after Veratridine exposure. This death has the features of apoptosis as DNA fragmentation can be observed. Calcium ions play an important role in Veratridine-induced chromaffin cell death because the cell permeant Ca(2+) chelator BAPTA-AM and extracellular Ca(2+) removal completely prevented Veratridine-induced toxicity. Following Veratridine treatment, there is a decrease in mitochondrial function and an increase in superoxide anion production. Veratridine-induced increase in superoxide production was blocked by tetrodotoxin (TTX; 10 microM), extracellular Ca(2+) removal and the mitochondrial permeability transition pore blocker cyclosporine A (10 microM). Veratridine-induced death was prevented by different antioxidant treatments including catalase (100 IU ml(-1)), N-acetyl cysteine (100 microM), allopurinol (100 microM) or vitamin E (50 microM). Veratridine-induced DNA fragmentation was prevented by TTX (10 microM). Veratridine produced a time-dependent increase in caspase activity that was prevented by Ca(2+) removal and TTX (10 microM). In addition, calpain and caspases inhibitors partially prevented Veratridine-induced death.
CONCLUSIONS:
These results indicate that chromaffin cells share with neurons the molecular machinery involved in apoptotic death and might be considered a good model to study neuronal death during neurodegeneration.

Neuroscience letters, 1994, 177(1):95-99.

Neuroprotective effects of riluzole on N-methyl-D-aspartate- or veratridine-induced neurotoxicity in rat hippocampal slices.[Reference: WebLink]

The neuroprotective activity of riluzole has been studied on N-methyl-D-aspartate (NMDA)- or Veratridine-induced toxicity in immature rat hippocampal slices.
METHODS AND RESULTS:
Neurodegeneration was assessed by the measurement of LDH release and histology. Veratridine-induced LDH release can be inhibited by 100 microM riluzole (-90% and by tetrodotoxin (1 microM). Riluzole markedly reduced (-59%) the NMDA-induced LDH release and this protective effect was confirmed by histology. Riluzole inhibited the NMDA-induced LDH release in the presence of tetrodotoxin. Moreover, a pretreatment with pertussis toxin (1 microgram/ml) abolished the effect of riluzole against NMDA-induced neurotoxicity.
CONCLUSIONS:
These results support the view that the neuroprotective properties of riluzole could be exerted via two distinct mechanisms of action.