Abstract
Therapeutic agents to the central nervous system (CNS) need to be efficiently delivered to the target site of action at appropriate therapeutic levels. However, a limited number of effective drugs for the treatment of neurological diseases has been developed thus far. Further, the pharmacological mechanisms by which such therapeutic agents can protect neurons from cell death have not been fully understood. We have previously reported the novel small-molecule compound, 2-[mesityl(methyl)amino]-N-[4-(pyridin-2-yl)-1H-imidazol-2-yl] acetamide trihydrochloride (WN1316), as a unique neuroprotectant against oxidative injury and a highly promising remedy for the treatment of amyotrophic lateral sclerosis (ALS). One of the remarkable characteristics of WN1316 is that its efficacious doses in ALS mouse models are much less than those against oxidative injury in cultured human neuronal cells. It is also noted that the WN1316 cytoprotective activity observed in cultured cells is totally dependent upon the addition of fetal bovine serum in culture medium. These findings led us to postulate some serum factors being tightly linked to the WN1316 efficacy. In this study, we sieved through fetal bovine serum proteins and identified two N-linked glycoproteins, alpha-2-HS-glycoprotein (AHSG) and hemopexin (HPX), requisites to exert the WN1316 cytoprotective activity against oxidative injury in neuronal cells in vitro. Notably, the removal of glycan chains from these molecules did not affect the WN1316 cytoprotective activity. Thus, two glycoproteins, AHSG and HPX, represent a pivotal glycoprotein of the cytoprotective activity for WN1316, showing a concrete evidence for the novel glycan-independent function of serum glycoproteins in neuroprotective drug efficacy.
Highlights
Oxidative stress in the central nervous system (CNS) plays a critical role in the pathogenesis of many acute as well as chronic neurological disorders, such as stroke, Alzheimer’ s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) [1]
We found that fetal bovine serum (FBS) was essential to exhibit the cytoprotective activity of WN1316 in vitro
We investigated whether FBS affected the cytoprotective activity of WN1316 by Anti-oxidative stress-induced neuronal cell death (AOND) assay
Summary
Oxidative stress in the central nervous system (CNS) plays a critical role in the pathogenesis of many acute as well as chronic neurological disorders, such as stroke, Alzheimer’ s disease, Parkinson’s disease, Huntington’s disease, and amyotrophic lateral sclerosis (ALS) [1]. During the course of study, we found that the concentration of WN1316 in the brain after oral administration in wild-type mice was approximately three times higher than that in serum, despite the fact that almost all WN1316 molecules bound to serum proteins [2]. Differences in the efficacy dose of WN1316 between in vitro and in vivo implies the presence of a mechanism by which WN1316 is preferentially enriched in the brain. It has been demonstrated by our preliminary study that fetal bovine serum (FBS) is a requisite for the cytoprotective activity of WN1316 in vitro. These led us to hypothesize that some of serum proteins closely linked to the WN1316-dependent cytoprotective activity
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