Protective activity of carnosine and anserine against zinc-induced neurotoxicity: a possible treatment for vascular dementia

Abstract

Carnosine (β-alanyl-L-histidine) is a small dipeptide with numerous beneficial effects, including the maintenance of the acid-base balance, antioxidant properties, chelating agent, anti-crosslinking, and anti-glycation activities. High levels of carnosine and its analogue anserine (1-methyl carnosine) are found in skeletal muscle and the brain. Zinc (Zn)-induced neurotoxicity plays a crucial role in the pathogenesis of vascular dementia (VD), and carnosine inhibits Zn-induced neuronal death. Here, the protective activity of carnosine against Zn-induced neurotoxicity and its molecular mechanisms such as cellular Zn influx and Zn-induced gene expression were investigated using immortalised hypothalamic neurons (GT1-7 cells). Carnosine and anserine protected against Zn-induced neurotoxicity not by preventing increases in intracellular Zn(2+) but by participating in the regulation of the endoplasmic reticulum (ER) stress pathway and the activity-regulated cytoskeletal protein (Arc). Accordingly, carnosine and anserine protected against neurotoxicity induced by ER-stress inducers thapsigargin and tunicamycin. Hence, carnosine and anserine are expected to have future therapeutic potential for VD and other neurodegenerative diseases.

Technological and nutritional properties of ostrich, emu, and rhea meat quality

“…Anserine as a biological dipeptide is present in high concentration in human brain and muscles and plays an important role in protection of the nervous system and skeletal muscles showing high antioxidant activity. Carnosine and anserine are expected to have future therapeutic potential in neurodegenerative diseases (29).…”

Carnosine as a Possible Drug for Zinc-Induced Neurotoxicity and Vascular Dementia

“…As carnosine can chelate Zn 2+ , it is plausible that it binds extracellular Zn 2+ and inhibits Zn 2+ translocation like other chelators. However, our results using a Zn 2+ -sensitive fluorescent dye and RT-PCR indicated that carnosine did not influence [Zn 2+ ] i nor the expression of ZnT-1 [57]. Meanwhile, we demonstrated that carnosine inhibited Zn 2+ -induced upregulation of ER stress-related genes such as GADD34 and CHOP, and attenuated neurodegeneration induced by ER-stressors such as thapsigargin and tunicamycin [57].…”

“…Our DNA microarray analysis demonstrated that Zn 2+ induced a marked upregulation of ER stress-related genes, including CCAAT-enhancer-binding protein homologous protein (CHOP), and growth-arrest and DNA-damage-inducible gene 34 (GADD34) [56,57].…”

“…First, we tested the effects of treatment with various pharmacological agents prior to Zn 2+ treatment of GT1-7 cells and found that neither antagonists nor agonists of excitatory neurotransmitters (D-APV, glutamate, and CNQX), nor those of inhibitory neurotransmitters (bicuculline, muscimol, baclofen, and GABA) influenced the viability of GT1-7 cells. However, several compounds including energy substrates (pyruvate and citrate), metal chelators (o-phenanthroline and deferoxamine), peptides, and amino acids (carnosine, anserine, and histidine) attenuated the Zn 2+ -induced death of GT1-7 cells [53][54][55][56][57] (Figure 1). Furthermore, we investigated the viability of GT1-7 cells with or without other metal ions after exposure to Zn 2+ .…”

“…Next, we analyzed the Zn 2+ -induced genetic changes using DNA microarray analysis and real-time PCR (RT-PCR). After 4 h of exposure to Zn 2+ , various genes including metal-related genes (Zn transporter 1 (ZnT-1), metallothionein 1 (MT1), and metallothionein 2 (MT2)), endoplasmic reticulum (ER) stress-related genes, signal transduction-related genes, and Ca 2+ signaling-related genes were upregulated [56,57]. Moreover, the gene expression after co-exposure to Cu 2+ and Zn 2+ (Cu 2+ + Zn 2+ ) was investigated [59].…”