TAT-HSA-α-MSH fusion protein with extended half-life inhibits tumor necrosis factor-α in brain inflammation of mice

Meizhu Wang, Dejuan Zhi, Haiqing Wang, Yi Ru, Hui Ren, Na Wang, Yiyao Liu, Yang Li, Hongyu Li

Neuroinflammation constitutes a principal process involved in the progression of various central nervous system (CNS) disorders, including Parkinson's disease, Alzheimer's disease, ischemic stroke, and traumatic brain injury. The safety and efficacy of potential neuroprotective therapeutic agents is controversial and limited. Alpha-melanocyte-stimulating hormone (α-MSH) as a tridecapeptide derived from pro-opiomelanocortin displays potent anti-inflammatory and protective effects with a wide therapeutic window in brain damage. However, it is difficult to deliver effective concentrations of α-MSH into brain tissue via nondirect application. Besides, the half-life of the tridecapeptide is only a few minutes. In the present study, we generated a novel TAT-HSA-α-MSH by genetically fusing α-MSH with N-terminus 11-amino acid protein transduction domain of the human immunodeficiency virus Tat protein (TAT) and human serum albumin (HSA), which showed favorable pharmacokinetic properties and can effectively cross the blood brain barrier (BBB). The findings showed that TAT-HSA-α-MSH significantly inhibits NF-κB activation in human glioma cells A172 and tumor necrosis factor-α (TNF-α) production in experimental brain inflammation. These results indicate that TAT-HSA-α-MSH may be a potential therapeutic agent for treating neuroinflammation which plays a fundamental role in CNS disorders.