Abstract
We demonstrated that β-bungarotoxin (β-BuTX), a snake presynaptic neurotoxin, exhibited a potent cytotoxic effect on cultured cerebellar granule neurons. The mechanism of action of β-BuTX and the cytoprotective agents against β-BuTX were studied. The neuronal death of cerebellar granule neurons induced by β-BuTX was manifested with apoptosis and necrosis processes as revealed by neurite fragmentation, morphological alterations, and staining apoptotic bodies with the fluorescent dye Hoechst 33258. By means of microspectrofluorimetry and fura-2, we measured intracellular Ca2+ concentration, [Ca2+]i and found that [Ca2+]i was increased markedly prior to the morphological changes and cytotoxicity. The downstream pathway of the increased [Ca2+]i was investigated: there was increased production of free radicals, decreased mitochondrial membrane potential, and depleted cellular ATP content. MK801 and suramin effectively suppressed these detrimental effects of β-BuTX. Furthermore, the [3H]MK801 binding was reduced by unlabeled MK801, β-BuTX, and suramin. Thus, activation of N-methyl-D-aspartate (NMDA) receptors appeared to play a crucial role in the cytotoxic effects following βBuTX exposure. In conclusion, the novel finding of this study was that a polypeptide β-BuTX exerted a potent cytotoxic effect through sequential events, including activating NMDA receptors followed by increasing [Ca2+]i, ROS production, and impaired mitochondrial energy metabolism. Suramin, clinically used as a trypanocidal agent, was an effective antagonist against β-BuTX. Data suggest that suramin might have value to detect the possible pathway of certain neuropathological disorders.
| Original language | English |
|---|---|
| Pages (from-to) | 45-55 |
| Number of pages | 11 |
| Journal | Toxicology and Applied Pharmacology |
| Volume | 189 |
| Issue number | 1 |
| DOIs | |
| Publication status | Published - 2003 May 15 |
Fingerprint
All Science Journal Classification (ASJC) codes
- Toxicology
- Pharmacology
Cite this
}
Suramin inhibits β-bungarotoxin-induced activation of N-methyl-D-aspartate receptors and cytotoxicity in primary neurons. / Tseng, Wen Pei; Lin-Shiau, Shoei Yn.
In: Toxicology and Applied Pharmacology, Vol. 189, No. 1, 15.05.2003, p. 45-55.Research output: Contribution to journal › Article
TY - JOUR
T1 - Suramin inhibits β-bungarotoxin-induced activation of N-methyl-D-aspartate receptors and cytotoxicity in primary neurons
AU - Tseng, Wen Pei
AU - Lin-Shiau, Shoei Yn
PY - 2003/5/15
Y1 - 2003/5/15
N2 - We demonstrated that β-bungarotoxin (β-BuTX), a snake presynaptic neurotoxin, exhibited a potent cytotoxic effect on cultured cerebellar granule neurons. The mechanism of action of β-BuTX and the cytoprotective agents against β-BuTX were studied. The neuronal death of cerebellar granule neurons induced by β-BuTX was manifested with apoptosis and necrosis processes as revealed by neurite fragmentation, morphological alterations, and staining apoptotic bodies with the fluorescent dye Hoechst 33258. By means of microspectrofluorimetry and fura-2, we measured intracellular Ca2+ concentration, [Ca2+]i and found that [Ca2+]i was increased markedly prior to the morphological changes and cytotoxicity. The downstream pathway of the increased [Ca2+]i was investigated: there was increased production of free radicals, decreased mitochondrial membrane potential, and depleted cellular ATP content. MK801 and suramin effectively suppressed these detrimental effects of β-BuTX. Furthermore, the [3H]MK801 binding was reduced by unlabeled MK801, β-BuTX, and suramin. Thus, activation of N-methyl-D-aspartate (NMDA) receptors appeared to play a crucial role in the cytotoxic effects following βBuTX exposure. In conclusion, the novel finding of this study was that a polypeptide β-BuTX exerted a potent cytotoxic effect through sequential events, including activating NMDA receptors followed by increasing [Ca2+]i, ROS production, and impaired mitochondrial energy metabolism. Suramin, clinically used as a trypanocidal agent, was an effective antagonist against β-BuTX. Data suggest that suramin might have value to detect the possible pathway of certain neuropathological disorders.
AB - We demonstrated that β-bungarotoxin (β-BuTX), a snake presynaptic neurotoxin, exhibited a potent cytotoxic effect on cultured cerebellar granule neurons. The mechanism of action of β-BuTX and the cytoprotective agents against β-BuTX were studied. The neuronal death of cerebellar granule neurons induced by β-BuTX was manifested with apoptosis and necrosis processes as revealed by neurite fragmentation, morphological alterations, and staining apoptotic bodies with the fluorescent dye Hoechst 33258. By means of microspectrofluorimetry and fura-2, we measured intracellular Ca2+ concentration, [Ca2+]i and found that [Ca2+]i was increased markedly prior to the morphological changes and cytotoxicity. The downstream pathway of the increased [Ca2+]i was investigated: there was increased production of free radicals, decreased mitochondrial membrane potential, and depleted cellular ATP content. MK801 and suramin effectively suppressed these detrimental effects of β-BuTX. Furthermore, the [3H]MK801 binding was reduced by unlabeled MK801, β-BuTX, and suramin. Thus, activation of N-methyl-D-aspartate (NMDA) receptors appeared to play a crucial role in the cytotoxic effects following βBuTX exposure. In conclusion, the novel finding of this study was that a polypeptide β-BuTX exerted a potent cytotoxic effect through sequential events, including activating NMDA receptors followed by increasing [Ca2+]i, ROS production, and impaired mitochondrial energy metabolism. Suramin, clinically used as a trypanocidal agent, was an effective antagonist against β-BuTX. Data suggest that suramin might have value to detect the possible pathway of certain neuropathological disorders.
UR - http://www.scopus.com/inward/record.url?scp=0038737155&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0038737155&partnerID=8YFLogxK
U2 - 10.1016/S0041-008X(03)00102-9
DO - 10.1016/S0041-008X(03)00102-9
M3 - Article
C2 - 12758059
AN - SCOPUS:0038737155
VL - 189
SP - 45
EP - 55
JO - Toxicology and Applied Pharmacology
JF - Toxicology and Applied Pharmacology
SN - 0041-008X
IS - 1
ER -