Cuprizone Affects Hypothermia-Induced Neuroprotection and Enhanced Neuroblast Differentiation in the Gerbil Hippocampus after Ischemia.

Woosuk Kim,In Koo Hwang,Yeo Sung Yoon,Hyun Jung Kwon,Tae Hyeong Kim,Kyu Ri Hahn,Sung Min Nam,Dae Won Kim,Jong Whi Kim,Jung Hoon Choi,Dae Young Yoo,Hyo Young Jung

doi:10.3390/cells9061438

Abstract

In the present study, we investigated the effects of cuprizone on cell death, glial activation, and neuronal plasticity induced by hypothermia after ischemia in gerbils. Food was supplemented with cuprizone at 0.2% ad libitum for eight weeks. At six weeks after diet feeing, gerbils received transient forebrain ischemia with or without hypothermic preconditioning. Cuprizone treatment for 8 weeks increased the number of astrocytes, microglia, and pro-inflammatory cytokine levels in the hippocampus. In addition, cuprizone treatment significantly decreased the number of proliferating cells and neuroblasts in the dentate gyrus. Brain ischemia caused cell death, disruption of myelin basic proteins, and reactive gliosis in CA1. In addition, ischemia significantly increased pro-inflammatory cytokines and the number of proliferating cells and differentiating neuroblasts in the dentate gyrus. In contrast, hypothermic conditioning attenuated these changes in CA1 and the dentate gyrus. However, cuprizone treatment decreased cell survival induced by hypothermic preconditioning after ischemia and increased the number of reactive microglia and astrocytes in CA1 as well as that of macrophages in the subcallosal zone. These changes occurred because the protective effect of hypothermia in ischemic damage was disrupted by cuprizone administration. Furthermore, cuprizone decreased ischemia-induced proliferating cells and neuroblasts in the dentate gyrus.

Highlights

Cerebral ischemia is a major cause of disability, acute mortality, chronic morbidity, and death worldwide [1]
We investigated the effects of hypothermia on cell proliferation and neuroblast differentiation in the dentate gyrus of gerbils after demyelination induced by cuprizone, which significantly decreases hippocampal neurogenesis in the dentate gyrus, as described in a previous study [25]
There were no significant differences in the number of cresyl violet-positive cells in the hippocampal CA1 region (Figure 2M)

Summary

Introduction

Cerebral ischemia is a major cause of disability, acute mortality, chronic morbidity, and death worldwide [1]. This condition results from the reduction or loss of oxygen supply, and prolonged ischemia may lead to insidious delayed degeneration of specific vulnerable neurons within the affected brain region, such as the hippocampus [2,3,4]. Ischemia followed by reperfusion causes a rapid, transient increase in the production of reactive oxygen species (ROS) [5]. Antioxidants have neuroprotective effects against ischemic damage because they neutralize ROS production and mitochondrial dysfunction [11,12,13,14]

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Conclusion