Reversal of homocysteine-induced neurotoxicity in rat hippocampal neurons by astaxanthin: evidences for mitochondrial dysfunction and signaling crosstalk

Xian-Jun Wang,Cun-Dong Fan,Wang Chen,Da-Chen Tian,Xiao-Ting Fu,Ya-Jun Hou,Xiao-Yan Fu,Mei-Hong Wang,Jin-Kui Ma

doi:10.1038/s41420-018-0114-x

Abstract

Elevated plasma level of homocysteine (Hcy) represents an independent risk for neurological diseases, and induction of oxidative damage is considered as one of the most important pathomechanisms. Astaxanthin (ATX) exhibits strong antioxidant activity in kinds of experimental models. However, the potential of ATX against Hcy-induced neurotoxicity has not been well explored yet. Herein, the neuroprotective effect of ATX against Hcy-induced neurotoxicity in rat hippocampal neurons was examined, and the underlying mechanism was evaluated. The results showed that ATX pre-treatment completely reversed Hcy-induced neurotoxicity through inhibiting cell apoptosis in rat primary hippocampal neurons. The mechanical investigation revealed that ATX effectively blocked Hcy-induced mitochondrial dysfunction by regulating Bcl-2 family and opening of mitochondrial permeability transition pore (MPTP). ATX pre-treatment also attenuated Hcy-induced oxidative damage via inhibiting the release of intracellular reactive oxide species (ROS) and superoxide anion through regulating MPTP opening. Moreover, normalization of MAPKs and PI3K/AKT pathways also contributed to ATX-mediated protective effects. Taken together, these results above suggested that ATX has the potential to reverse Hcy-induced neurotoxicity and apoptosis by inhibiting mitochondrial dysfunction, ROS-mediated oxidative damage and regulation of MAKPs and AKT pathways, which validated the strategy of using ATX could be a highly effective way in combating Hcy-mediated neurological disorders.

Highlights

Homocysteinemia (Hcy) has been well demonstrated as an independent risk for human neurological diseases, including cerebrovascular diseases, neurodegenerative (ROS)-mediated oxidative damage can damage neurons, induce neural apoptosis or/and necrosis, and inhibition of reactive oxide species (ROS)-mediated oxidative damage has been accepted as an effective strategy in clinic[7,8]
These results suggested that ATX has the potential to reverse Hcy-induced neuronal toxicity in rat primary hippocampal neurons
Combined treatment of CsA and ATX achieved enhanced improvement of Δψm and neural viability, indicating that ATX can act as a natural inhibitor of mitochondrial permeability transition pore (MPTP) to regulate mitochondriamediated apoptosis. These results clearly suggested that ATX has the potential to block Hcyinduced mitochondrial dysfunction through regulating Bcl-2 family and MPTP opening

Summary

Introduction

Homocysteinemia (Hcy) has been well demonstrated as an independent risk for human neurological diseases, including cerebrovascular diseases, neurodegenerative (ROS)-mediated oxidative damage can damage neurons, induce neural apoptosis or/and necrosis, and inhibition of ROS-mediated oxidative damage has been accepted as an effective strategy in clinic[7,8]. Hcy-induced oxidative damage and underlying mechanism remain elusive. It is reported that ATX could cross the brain-blood barrier (BBB) and show novel neuroprotective effects against neural damage involving anti-oxidation, anti-inflammation, and antiapoptosis[12,13,14]. Our previous study revealed that ATX significantly inhibited ROS-mediated oxidative damage and apoptosis in human myocardial cells in vitro and in vivo[15]. Little information about ATXmediated neuroprotective effect against Hcy-induced neural toxicity is available, and the underlying mechanism remains to be explored

Methods

Results

Conclusion