Ester Derivatives of Tournefolic Acid B Attenuate N-Methyl-d-aspartate-Mediated Excitotoxicity in Rat Cortical Neurons

Abstract

The effects of tournefolic acid B (TAB) and two ester derivatives, TAB methyl ester (TABM) and TAB ethyl ester (TABE), on N-methyl-D-aspartate (NMDA)-mediated excitotoxicity and the underlying mechanisms were investigated. Treatment with 50 M NMDA elicited neuronal death by 48.7 Ϯ 5.1%, coinciding with the appearance of injured morphology. TABM (50 M) attenuated the NMDA-induced cell death by 60.9 Ϯ 19.7%, and to a lesser extent by TABE. The NMDA-mediated activation of calpain was not affected by TABM and TABE, as determined by the cleavage of ␣-spectrin. NMDA increased the activity of caspases 2, 3, 6, 8, and 9 and reached the maximum after 8-h treatment. TABM and TABE abrogated NMDA-induced activation of caspases 2, 3, 6, and 8 by approximately 80 to 90% and 50 to 60%, respectively, and to a higher extent for caspase 9. TABM and TABE also blocked the NMDA-mediated activation of caspase 12. Furthermore, TABM and TABE eliminated the NMDA-induced accumulation of superoxide anion (O 2 . ). NMDA evoked significant depolarization of mitochondria, whereas TABM elicited a mild decrease of mitochondrial membrane potential as determined by tetramethylrhodamine methyl ester perchlorate. NMDA treatment induced elevation of Ca 2ϩ levels in cytosol, endoplasmic reticulum (ER), and mitochondria. TABM (50 M) significantly diminished the NMDA-induced elevation of Ca 2ϩ levels in mitochondria and ER but not cytosol. Therefore, TABM decreased mitochondrial membrane potential and attenuated the NMDA-mediated Ca 2ϩ -loading in ER and mitochondria. These events subsequently eliminated the accumulation of O 2. and blocked the activation of caspase cascade, thereby conferring their neuroprotective effects on NMDA-mediated excitotoxicity.

NMDA receptor‐mediated excitotoxic neuronal apoptosis in vitro and in vivo occurs in an ER stress and PUMA independent manner

“…A previous study has demonstrated acute increases in ER Ca 2+ levels following NMDA receptor activation (Wang et al. 2006).…”

Neuroprotective and Antineuroinflammatory Effects of Hydroxyl-Functionalized Stilbenes and 2-Arylbenzo[b]furans

“…activated by LPS to produce NO were used to evaluate the antineuroinflammatory effects of the compounds. 25,26 Results of this assay revealed that 13 compounds (5,11,17,20,24,27,28,29,34,37,38,42, and 43) possessed antineuroinflammatory activities and compounds 24, 34, 37, and 38 were the most active (Tables 3 and 4). APP/PS1 mice obtained lower nesting scores and presented less nestlet shredding than did WT mice.…”

“…In previous studies, we demonstrated that TAB and LSA derivatives effectively attenuate neurotoxicity mediated by Aβ, glutamate, NMDA, and 1-methyl-4-phenylpyridinium. Specifically, TAB and LSA achieve this by abrogating calcium overload in mitochondria and retarding the caspase 8-truncated bid–cytochrome c pathway. − Other polyphenols, such as resveratrol (a natural compound with stilbene structure), have also been studied extensively as anti-AD agents because of their antineuroinflammatory properties and ability to inhibit Aβ aggregation by scavenging oxidants. − Therefore, we hypothesize that polyphenolic compounds presenting antioxidant activity could form the basis of novel treatments for AD. However, the TAB molecule comprises a seven-membered ring scaffold (belonging to the dibenzoxazepine class), which makes it difficult to synthesize.…”

Lithospermic acid attenuates 1-methyl-4-phenylpyridine-induced neurotoxicity by blocking neuronal apoptotic and neuroinflammatory pathways

“…The calpain-dependent cleavage of α-spectrin is involved in the death of primary cortical neurons, but not of CATH.a cells. The reason may be due to that CATH.a cells is not a neurite-bearing mature neurons [ 19 , 30 ] and which may explain why LSA fail to protect the primary cortical neurons against MPP + -mediated neuron death. The previous reports suggested that calpain plays a central role in MPP + mediates cell death in spinal cord motoneurons [ 31 ] and cerebellar granule neurons [ 32 ] may supported this speculation.…”

“…The intracellular level of O 2 − . was measured by dihydroethidium assay as described previously [ 19 ]. Treated cells were loaded with 3.2 μM dihydroethidium at 37 °C for 30 min and then observed by a Leica DMIRB fluorescence microscope.…”