Brain changes associated with thromboxane receptor antagonist SQ 29,548 treatment in a mouse model

Abstract

The purpose of this study was to characterize behavioral and physiological effects of a selective thromboxane receptor (TP) antagonist, SQ 29,548, in the C57BL/6 mouse model. At six months of age, male mice were given either sham or drug intraperitoneal injections for three days at a dose of 2mg/kg each day. On the day after the final injection mice were subjected to behavioral testing paradigms before brain collection. Left hemisphere hippocampi were collected from all mice for protein analysis via western blot. Right brain hemispheres were fixed and imbedded in gelatin, and serially sectioned. The sections were immunostained using anti-c-Fos antibodies. Prostaglandin analysis was performed from remaining homogenized brain samples, minus the hippocampi. Injection of SQ 29,548 decreased selective brain prostaglandin levels compared to sham controls. This correlated with robust increases in limbic region c-Fos immunoreactivity in the SQ 29,548 injected mice. However, drug treated mice demonstrated no significant changes in relevant hippocampal protein levels compared to sham treatments, as determined by western blots. Surprisingly, injection of SQ 29,548 caused mixed changes in parameters of depression and anxiety-like behavior in the mice. In conclusion, the results indicate that administration of peripheral TP receptor antagonists alters brain levels of prostanoids and influences neuronal activity with only minimal alterations of behavior. Whether the drug affects neurons directly or through a secondary pathway involving endothelium or other tissues remains unclear.

Thromboxane A2 receptor antagonist SQ29548 attenuates SH‑SY5Y neuroblastoma cell impairments induced by oxidative stress

“…TXA2R, which is mainly distributed in platelets, has been suggested to be an important membrane receptor in the coagulation and inflammation processes in humans (6). In recent years, it has been reported that TXA2R also exists in nerve cells (5), and participates in the regulation of a series of physiological processes in peripheral and central nervous cells (5,24,25). Our previous study observed that the mutation of TXA2R affected the coagulation system function and further affected the onset of cI (6).…”

“…SH-SY5Y, a neuron cell line, is widely used in studies investigating neurological disorders (27,28) and oxidative stress in nerve cells (17,28). SQ29548 has been proposed to be a specific, reliable and safe TXA2R antagonist (29), and is broadly utilized in studies on TXA2R (7,25,30,31). H 2 O 2 , as one of main ROS products in cellular oxidative stress (32), is typically used to establish an in vitro oxidative stress cell model (23,33).…”

Cyclooxygenase inhibition attenuates brain angiogenesis and independently decreases mouse survival under hypoxia

“…However, this mechanism is rather convoluted and implicates COX as a source and regulator of a number of vasodilators and vasoconstrictors and their receptors. As part of arachidonic acid cascade, COX activity is required for producing CBF vasoactive PGs such as PGE 2 , PGF 2α , TXA 2 , prostacyclins, and their receptors (Davidge, 2001; Li et al., 1997; Rebel et al., 2015). In addition, COX catabolizes P450 products that also regulate CBF, such as vasodilator epoxyeicosatrienoic acids, and vasoconstrictor 20‐hydroxyeicosatetraenoic acid to produce vasoconstrictor endoperoxides or vasodilator prostanoids (Alkayed et al., 1996; Iliff et al., 2009, 2010; Imig, 2016; Toth et al., 2011; Zhang et al., 2008).…”