SYM 2081 Exerts Neuroprotective Effect Modulating Anti-Apoptosis in the Hypoxic-Ischemic Brain Injury of Neonatal Rats

Objective: SYM 2081 ((2S,4R)-4-methylglutamic acid), an agonist and functional antagonist of the kainite receptor, has shown a neuroprotective effect in neurodegenerative diseases in adults but little is known concerning perinatal hypoxic-ischemic encephalopathy. This study is designed to evaluate whether SYM 2081 has preventive mechanisms via anti-apoptosis to gain further insight into neuroprotective roles of SYM 2081. Methods: In an in vivo animal model, the left carotid artery was ligated in 7-day-old Sprague-Dawley rat pups. The pups were divided into six groups: normoxia (N), hypoxia (8% O2, 92% N2) (H), H with shamoperation, H with operation (HO), HO treated with vehicle and HO treated with SYM 2081. In an in vitro model, the cultured embryonic cortical neuronal cells were divided into three groups: normoxia (95% air, 5% CO2), hypoxia (94% N2, 5% CO2) (Hc), and Hc treated with SYM 2081 before a hypoxic insult. Apoptosis was assessed using western blots and real-time polymerase chain reaction with Bcl-2, Bax, and caspase-3 antibodies and mRNAs. Results: In both in vitro and in vivo studies, Bcl-2 expression increased, whereas expressions of Bax, caspase-3, and the ratio of Bax/Bcl-2 were reduced with SYM 2081 treatment resulting in improved cell survival. Conclusion: This study showed that SYM 2081 exerts a neuroprotective effect against hypoxic-ischemic injury through modulating apoptotic signaling pathways.