Abstract
The beneficial value of the stems of Schisandra chinensis (SSC) in neurological diseases is unclear. We examined whether SSC aqueous extract (SSCE) alleviates striatal toxicity in a 3-nitropropionic acid (3-NPA)-induced mouse model of Huntington's disease (HD). SSCE (75, 150, or 300 mg/kg/day, p.o.) was given daily before or after 3-NPA treatment. Pre- and onset-treatment with SSCE displayed a significant protective effect and pretreatment was more effective as assessed by neurological scores and survival rate. These effects were related to reductions in mean lesion area, cell death, succinate dehydrogenase activity, microglial activation, and protein expression of inflammatory factors including interleukin (IL)−1β, IL-6, tumor necrosis factor-alpha, inducible nitric oxide synthase, and cyclooxygenase-2 in the striatum after 3-NPA treatment. Pretreatment with SSCE stimulated the nuclear factor erythroid 2-related factor 2 pathway and inhibited phosphorylation of the mitogen-activated protein kinase and nuclear factor-kappa B signaling pathways in the striatum after 3-NPA treatment. The gomisin A and schizandrin components of SSCE significantly reduced the neurological impairment and lethality induced by 3-NPA treatment. These results indicate for the first time that SSCE may effectively prevent 3-NPA-induced striatal toxicity during a wide therapeutic time window through anti-oxidative and anti-inflammatory activities. SSCE has potential value in preventive and therapeutic strategies for HD-like symptoms.
Highlights
Huntington’s disease (HD) is an inherited neurological disorder caused by abnormal expansion of a CAG repeat within exon 1 of the huntingtin (Htt) gene, located on chromosome 4 (Damiano et al, 2010; Ross and Tabrizi, 2011)
The survival rate at the end of the experiment was increased by 81.3% (13/16), 81.3% (13/16), and 75% (12/16), respectively, in the 3-nitropropionic acid (3-NPA) + SSC aqueous extract (SSCE) 75, 150, and 300 mg/kg/day SSCE groups, respectively, as compared to the 3-NPA group (50.0%, 8/16) (Figure 2G)
The present findings demonstrate that SSCE has a neuroprotective effect against 3-NPA-induced striatal toxicity through anti-apoptotic, anti-inflammatory, and anti-oxidant activities that are related to the activation Nuclear factor erythroid 2-related factor 2 (Nrf2) pathway and the inhibition of the mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB) pathways
Summary
Huntington’s disease (HD) is an inherited neurological disorder caused by abnormal expansion of a CAG (cytosineadenine-guanine) repeat within exon 1 of the huntingtin (Htt) gene, located on chromosome 4 (Damiano et al, 2010; Ross and Tabrizi, 2011). Nuclear factor erythroid 2-related factor 2 (Nrf2), an important regulator of the antioxidative cellular response, interacts with antioxidant response element (ARE), and has a variety of cytoprotective roles against oxidative stress, apoptosis, and inflammation in the nervous system (Copple, 2012; Joshi and Johnson, 2012; Suzuki et al, 2013). The Nrf signaling pathway is involved in the suppression of mitogen-activated protein kinases (MAPKs) and nuclear factor-κB (NF-κB), associated with inflammatory effects (Juge et al, 2007). The pathways are activated by pro-inflammatory cytokines, neurotrophic factors, neurotransmitters, neural injury, seizure activity, and proteins implicated in neurodegenerative disorders, including HD (Harper and Wilkie, 2003; Memet, 2006), and are upregulated by treatment with 3-nitropropionic acid (3-NPA) or kainate in the striatum, which mimics the pathology caused by mutant Htt (Sugino et al, 2000; Khoshnan et al, 2004). More studies are needed to fully identify the role of the Nrf and MAPKs/NF-κB pathways, it is reasonable to suggest that pharmacological modulation of these pathways may provide a new therapeutic target in HD
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