Abstract
Polygala tenuifolia Willdenow is a herb known for its therapeutic effects in insomnia, depression, disorientation, and memory impairment. In Alzheimer’s disease (AD) animal model, there has been no report on the effects of memory and cognitive impairment. PSM-04, an extract from the root of P. tenuifolia Willdenow, was developed with improved bioabsorption. The present study aimed to investigate the neuroprotective effects of PSM-04 on AD and reveal the possible molecular mechanism. The neuroprotective effect of PSM-04 in primary cortical neurons treated with L-glutamate, oligomeric Aβ, or H2O2. PSM-04 exhibited significant neuroprotective effects against neurotoxicity induced by L-glutamate or oligomeric Aβ was studied. PSM-04 exhibited significant neuroprotective effects against neurotoxicity induced by L-glutamate or oligomeric Aβ. Oxidative stress induced by ROS was monitored using the DCF-DA assay, and apoptosis was assessed using the TUNEL assay in primary cortical neurons treated with H2O2 or oligomeric Aβ. PSM-04 also decreased oxidative stress induced by H2O2 and apoptotic cell death induced by oligomeric Aβ. We evaluated the therapeutic effect of PSM-04 in 5xFAD (Tg) mice, an animal model for AD. PSM-04 was orally administered to 4-month-old 5xFAD mice for 2 months. To confirm the degree of cognitive impairment, a novel object recognition task was performed. The treatment with PSM-04 significantly alleviated cognitive impairments in Tg mice. In addition, amyloid plaques and gliosis decreased significantly in the brains of PSM-04-administered Tg mice compared with Tg-vehicle mice. Furthermore, the administration of PSM-04 increased the superoxide dismutase-2 (SOD-2) protein level in hippocampal brain tissues. Our results indicated that PSM-04 showed therapeutic effects by alleviating cognitive impairment and decreasing amyloid plaque deposition in Tg mice. Therefore, PSM-04 was considered as a potential pharmacological agent for neuroprotective effects in neurodegenerative diseases, including AD.
Highlights
Alzheimer’s disease (AD) is the most common neurodegenerative disease and constitutes approximately two-thirds of all cases of dementia (Reitz et al, 2011)
Primary cortical neurons pre-treated with PSM-04 or brain-derived neurotrophic factor (BDNF) showed that apoptotic cell death was reduced (20.2 ± 1.19%, p < 0.001; 20.13 ± 1.26%, p < 0.001) compared with the L-glutamate -only treatment (Supplementary Figure S2C)
Primary cortical neurons pre-treated with PSM-04 showed that apoptotic cell death induced by Aβ1−42 peptides (Aβ) was reduced (15.83 ± 1.22%, p < 0.001) compared to that observed with Aβ-only treatment (23.2 ± 1.18%); further, BDNF treatment reduced apoptotic cell death (16.53 ± 1.35%, p < 0.001) (Figure 1D)
Summary
Alzheimer’s disease (AD) is the most common neurodegenerative disease and constitutes approximately two-thirds of all cases of dementia (Reitz et al, 2011). Researches have been conducted to search for novel active extracts or components derived from various natural products which can be used for the treatment of brain diseases (Howes et al, 2003; Houghton and Howes, 2005). These natural products have proven effective with low side effects (Bent, 2008). The roots of P. tenuifolia Willdenow, a natural oriental plant, have been used for memory improvement and for the treatment of insomnia, amnesia, depression, and palpitations with anxiety (Liu et al, 2010). We checked the improvement of cognitive dysfunction and pathological changes in 5xFAD transgenic mice, an animal model for AD
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