Emerging roles of system antiporter and its inhibition in CNS disorders

Abstract

System is an antiporter belonging to the hetero(di)meric amino acid transporter family. It is located on astrocytes as well as on blood-brain barrier within the CNS. It plays a pivotal role in free radical neutralization as well as neuronal signalling by regulating the glutathione production which occurs via the exchange of intracellular glutamate with extracellular cystine at 1:1 molar ratio. Understandably, it is a vital component responsible for the maintenance of neuronal homeostasis (e.g. redox state). Hence, it could be postulated that any perturbation in system function may contribute, directly or indirectly, to the pathophysiology of a variety of CNS disorders like Alzheimers disease, schizophrenia, drug addiction, depression, multiple sclerosis, hypoglycemic neuronal cell death, glioma, and excitotoxicity, making system a promising target for treating CNS disorders. In recent times, recognizing the potential of this target, variety of inhibitors has been synthesized by modifying commercially available potent inhibitors including sulfasalazine, erastin, and sorafenib. Although, they have demonstrated efficacy, the in-depth data is still lacking to warrant their use for the treatment of aforementioned CNS disorders. In this review, we discuss the in-depth role of system transporter in maintaining normal physiology as well as in the pathophysiology of CNS diseases. Additionally, we have also listed some of the potent inhibitors of system. In conclusion, the critical role of system in multiple CNS disorders and advanced research on its inhibitors have promising future prospects for better management of the CNS ailments.