Schisantherin A recovers Aβ-induced neurodegeneration with cognitive decline in mice

Highlights

• Schisantherin A (STA) noticeably improved neurodegeneration of Aβ_1–42-treated mice.

• STA significantly attenuated learning and memory impairment of AD model mice.

• STA could restore oxidative stress status and enhance the antioxidant status.

• Successive intracerebroventricular administration was applied to treatment of AD.

Abstract

Schisantherin A (STA) is a main bioactive lignan isolated from Schisandra chinensis (Turcz.) Baill., which has been widely used as a tonic in traditional Chinese medicine for many years. Lots of studies have reported that STA exhibited anti-inflammatory and antioxidant effects. This paper was designed to investigate the effects of STA on cognitive function and neurodegeneration in the mouse control of Alzheimer's disease (AD) induced by Aβ_1–42. It was found that successive intracerebroventricular (ICV) administration of STA (0.01 and 0.1 mg/kg) for 5 days significantly attenuated Aβ_1–42-induced learning and memory impairment as measured by the Y-maze test, shuttle-box test and Morris water maze test. Furthermore, STA at a dose of 0.1 mg/kg restored the activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) as well as the levels of Aβ_1–42, malondialdehyde (MDA) and glutathione (GSH) to some extent in the hippocampus and cerebral cortex. It also noticeably improved the histopathological changes in the hippocampus. The results suggested that STA might protect against cognitive deficits, oxidative stress and neurodegeneration induced by Aβ_1–42, and serve as a potential agent in treatment of AD.

Introduction

Alzheimer's disease (AD) is the most frequent type of neurodegenerative disorder in the elderly brain [1], [2], initially characterized by increased levels of oxidative stress, by reduced levels of acetylcholine [3], and greatly by the extracellular deposits of amyloid beta peptide (Aβ) which leads to the formation of neuritic plaques, and neurofibrillary tangles in vulnerable brain regions [4]. AD interrupts various functions of the brain like memory, intelligence, judgment and learning abilities [5]. It affects millions of people both in developed and developing countries and has become a major medical and social problem all over the world [6]. Furthermore, the number of AD cases in Europe was almost 6 million in 2010, and will reach around 14 million in 2050 [7], and 80% of those individuals may suffer from it [8]. Therefore, an agent can prevent or slow down the progression of AD as necessary.

Although, to date, AD is probably caused by complex interactions, such as genetic, oxidative stress, inflammatory, and environmental factors. Evidences also suggested that the overproduction of Aβ peptides, especially Aβ_1–42, oxidative stress and apoptosis induced by Aβ play a critical role in the progressive of AD [9]. It has been demonstrated that Aβ is directly toxic to cultured neurons and also induces the neurodegenerative of the CA1 region of the hippocampus, and those findings supported the hypothesis that Aβ is involved in the neurodegenerative associated with AD [10], [11], [12]. Moreover, the synthetic Aβ seemed to be responsible for neurotoxic and oxidative events leading to neurodegenerative damage in hippocampal neurons and the cultured cortical neurons [13].

Oxidative stress is the imbalance between prooxidant and antioxidant, and this imbalance produces the reactive oxygen species (ROS). Reactive oxygen species (ROS) are oxygen free radicals which possess one or more unpaired electron(s). The brain consumes oxygen, but is highly vulnerable to oxidative damage [14], [15]. Nearly all individuals who meet clinical criteria for AD have abnormally high ROS, which lead to oxidative damage on proteins, lipids, DNA and RNA [16]. Accumulated evidences suggested that degenerative changes in cholinergic systems are due to oxidative stress, which means the free radicals play an important role in the progression of AD [17]. Lots of clinical studies have reported that not only can oxidative stress initiate production of Aβ in vivo and convert nonaggregated Aβ into aggregated Aβ in vitro, but Aβ can also induce oxidative stress and is itself a source of free radicals [18], [19].

Recently, there are many reports about total lignans and active components from Schisandra chinensis (Turcz.) Baill. ameliorate cognition in rodents with dementia. All of the research studies suggested that major bioactive constituents of S. chinensis were lignans, which belong to the dibenzocyclooctadiene type compound [20], [21], [22]. Schisantherin A (STA Fig. 1), as one of those compounds, was isolated from S. chinensis (Turcz.) Baill. It exhibits several therapeutic properties, including anti-inflammatory effects, antihepatotoxic effects, anticarcinogenic effects, and antioxidant effects [23], [24].

On the basis of the compelling evidences on pathological roles of Aβ in the progress of AD, others have generated partial controls of AD in rodents by intracerebroventricular (ICV) injection of Aβ to induce clinical signs reminiscent, including learning and memory deficits and impairment of the cholinergic system [25], [26]. In the present study we investigated the effect of STA with successive ICV administration of STA on learning and memory deficits in the mouse control induced by Aβ_1–42 with behavioral studies for the first time. In addition, related biochemical parameters of oxidative stress and glutathione (GSH)-dependent antioxidant status in the cerebral cortex and hippocampus of mice were evaluated.