.png){kind=icon}
.png){kind=icon}
Return
Novel Probucol Analogue, 4,4′-Diselanediylbis (2,6-Di-tert-Butylphenol), Prevents Oxidative Glutamate Neurotoxicity In Vitro and Confers Neuroprotection in a Rodent Model of Ischemic Stroke
.png){kind=icon}
PRE
AI
DOI：10.1021/acschemneuro.3c00138.png)
.png){kind=icon}
Original request for help.png){kind=icon}
Share.png){kind=icon}
Save
Abstract
En 中文
Oxidative glutamate toxicity is regardedas one of the injuriousmechanisms associated with ischemic stroke, which represents a majorhealth problem and requires improved pharmacological treatments. Wedesigned and synthesized two new probucol analogues [2,6-di-tert-butyl-4-selenocyanatophenol ( C1 ) and 4,4 & PRIME;-diselanediylbis (2,6-di-tert-butylphenol) ( C2 )] and investigatedtheir effects against glutamate-induced neuronal oxidative toxicity in vitro in cultured HT22 cells, compared with their parentalcompound (probucol). In addition, C2 , which exhibited the lowest toxicity, was investigated in an in vivo rodent model of ischemic stroke. Glutamate causedconcentration- and time-dependent cytotoxicity in HT22 neuronal cells,which was preceded by increased levels of oxidants and depletion ofthe antioxidant glutathione. The analogues ( C1 and C2 ), but not probucol,significantly decreased the levels of oxidants (including mitochondrialsuperoxide anion and lipid reactive oxygen species (ROS)) and protectedagainst glutamate-induced cytotoxicity. In the in vivo model of ischemic stroke, which was based on central injectionsof the vasoconstrictor agent endothelin-1 (800 pmol/site), C2 (20 or 50 mg/kg/day, intraperitoneally,for 4 consecutive days after stroke) displayed significant beneficialeffects against ischemic injury in vivo, improvingrats' motor-related behavioral skills and decreasing stroke-relatedstriatal gliosis. This is the first study to design, synthesize, andpresent a probucol analogue ( C2 ) with in vivo beneficial effects against ischemic stroke. Thisnovel compound, which was able to mitigate glutamate-induced oxidativetoxicity in vitro, represents a promising neuroprotectivedrug.
Keywords:
probucol analogues
ischemic stroke
oxidativeglutamate toxicity
endothelin-1
neuroprotection
Journal
IF:
3.9
Papers:
4.5K
Citations:
1.3W
Organization
View more organizations