Elsevier

Brain Research

Volume 1328, 30 April 2010, Pages 152-161
Brain Research

Research Report
Hydrogen-rich saline improves memory function in a rat model of amyloid-beta-induced Alzheimer's disease by reduction of oxidative stress

https://doi.org/10.1016/j.brainres.2010.02.046 Get rights and content

Abstract

This study is to examine if hydrogen-rich saline reduced amyloid β (Aβ) induced neural inflammation, and learning and memory deficits in a rat model. S-D male rats (n = 84, 280–330 g) were divided into three groups, sham-operated, Aβ1-42 injected and Aβ1-42 plus hydrogen-rich saline-treated animals. Hydrogen-rich saline (5 ml/kg, i.p., daily) was injected for 14 days after intracerebroventricular injection of Aβ1-42. The levels of MDA, IL-6 and TNF-α were assessed by biochemical and ELISA analysis. Morris Water Maze and open field task were used to assess the memory dysfunction and motor dysfunction, respectively. LTP were used to detect the electrophysiology changes, HNE and GFAP immunohistochemistry were used to assess the oxidative stress and glial cell activation. After Aβ1-42 injection, the levels of MDA, IL-6, and TNF-α were increased in brain tissues and hydrogen-rich saline treatment suppressed MDA, IL-6, and TNF-α concentration. Hydrogen-rich saline treatment improved Morris Water Maze and enhanced LTP in hippocampus blocked by Aβ1-42. Furthermore, hydrogen-rich saline treatment also decreased the immunoreactivitiy of HNE and GFAP in hippocampus induced by Aβ1-42. In conclusion, hydrogen-rich saline prevented Aβ-induced neuroinflammation and oxidative stress, which may contribute to the improvement of memory dysfunction in this rat model.

Introduction

Alzheimer's disease (AD) is the most common cause of progressive dementia in the elderly population. It has been estimated that about 5% of the population older than 65 years is affected by Alzheimer's disease. There is an enormous medical need for the development of novel therapeutic strategies that target the underlying pathogenic mechanisms in AD. The proposed pathogenic mechanisms for AD generally include loss of cholinergic function, oxidative stress, amyloid cascade, inflammatory mediators, steroid hormone deficiencies, and excitotoxicity (Shah et al., 2008). Among them the amyloid cascade hypothesis is well accepted which suggesting a central role of Aβ in the pathogenesis. It has been shown that accumulation of β-amyloid (in particular of the Aβ1-42 peptide) in the brain initiates a cascade of events that ultimately leads to neuronal dysfunction, neurodegeneration and dementia (Klafki et al., 2006).

Molecular hydrogen (H2) is a special free radical scavenger which uniquely reduces hydroxyl radicals (radical dotOH), but not superoxide (O2−•), hydrogen peroxide (H2O2), or nitric oxide (NO•) (Buxton et al., 1998, Ohsawa et al., 2007). There are several recent studies reported that molecular hydrogen reduced oxidative stress and its associated disorders. Molecular hydrogen in the form of gas or H2-saturated saline reduced the cerebral infarction (Ohsawa et al., 2007) and decreased apoptosis in neonatal hypoxic brain injury in rats (Cai et al., 2008, Cai et al., 2009). Molecular hydrogen dissolved in drinking water similarly attenuated sclerotic lesions (Ohsawa et al., 2008) and prevented cisplatin-induced nephrotoxicity in mice (Nakashima-Kamimura et al., 2009). To date, most of these studies have been focused on the ischemic and reperfusion injury and the potential effect of hydrogen in AD has not been tested. We hypothesize that hydrogen may attenuate AD by reduction of oxidative stress. We tested this hypothesis by using an intracerebroventricular (i.c.v.) injection of Aβ rat model. The role of MDA, TNF-α, IL-6, LTP, HNE and GFAP in Aβ-induced early impairment of learning and memory were assessed by giving hydrogen-rich saline.

Section snippets

Hydrogen saline improved learning and memory

The escape latency was recorded at 8 days after Aβ1-42 injection. In training trials, the escape latency time on the last training day (the fifth day) was 10.64 ± 8.62 s in sham group, 30.10 ± 20.93 s in Aβ1-42 plus physiological saline group, and 18.14 ± 16.16 s in Aβ1-42 plus hydrogen-rich saline group. Among them, the escape latency time is significantly different between sham and Aβ1-42 plus physiological saline groups (p < 0.05), but not between sham and Aβ1-42 plus hydrogen-rich saline groups (p = 

Discussion

In the present study, we analyzed the mechanisms of action of hydrogen saline in a rat model of i.c.v. injection of Aβ1-42. A single i.c.v. injection of a nanomolar dose of Aβ1-42 effectively impaired learning and memory behavior in rats. Furthermore, this behavioral abnormality was accompanied by increases in hippocampal GFAP/HNE immunoreactivity and high level of inflammation cytokine in brain tissue, which all have been reported existed in clinical AD patients. The major findings of the

Animals and drug treatment

Male Sprague–Dawley rats (Experimental Animal Center of China Medical University, Shengyang, China), maintained at an ambient temperature of 22–24 °C under a 12 h:12 h light:dark cycle, were used in this experiment. Animals were divided into three groups (n = 28 each group): (1) sham-operated plus physiological saline treatment; (2) Aβ1-42 (2.2 nmol/10 µl) i.c.v. (intracerebroventricularly) injection plus physiological saline treatment; and (3) Aβ1-42 (2.2 nmol/10 µl) i.c.v. injection plus hydrogen-rich

Acknowledgments

We thank Qiang SUN, En-zhi YAN and Jing YANG for technical assistance. This study was supported by the National Nature Science Foundation of China Grants 30471927 and 30971199.

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