This study shows that ginseng total saponins can significantly improve the learning and memory, resist the changes in the morphology of synapse in hippocampus, increase the expression levels of synaptic-related proteins SYP and PSD95 and up-regulate the NR2B-CaMKII signal in hippocampus of rats with exhaustive exercise-induced fatigue in a dose-dependent manner.
Appropriate exercise is an important part of a healthy life style because of its beneficial effects on brain functions. However, excessively intense exercise that results in fatigue can induce brain dysfunction(Baker, et al., 2004). High-intensity treadmill running impairs the spatial memory ability of mice (Sun, et al., 2017). The Morris water maze test is a method of testing spatial learning and memory. In this study, according to behavioral test results, rats have weaker spatial learning and memory after 7 days of exhaustive exercise, which is consistent with previous studies (Wang, et al., 2019 ; Ma, et al., 2018). Ginseng total saponins treatment significantly improved the learning and memory of rats with exhaustive exercise-induced fatigue. The most potent effects were observed at the dose of 200 mg/kg of ginseng total saponins.
The hippocampus is one of the key brain regions for learning and memory. Synapses are the structural basis of functional connections between neurons. Learning and memory are closely related to synapses of the hippocampus (Kempf, et al., 2016). Learning disabilities may not only be caused by neural regeneration, neurodevelopmental abnormalities, neuron migration, and neuronal apoptosis, but also by synapses (Lunardi, et al., 2010). Intense exercise can cause synapse plasticity damage in the hippocampus (Ding, et al., 2015). High- intensity treadmill exercise can impair synaptic functional plasticity in the hippocampus (Sun, et al., 2017). Exercise-induced fatigue could make the PSD thickness thinner and the width of the synaptic cleft wider in the striatum synapses (Hou, et al., 2017). In this study, we found that ginseng total saponins could resist the decrease of the number and PSD thickness of synapses and the increase of the width of synaptic cleft of synapses in the CA1 region of hippocampus of rats with exhaustive exercise-induced fatigue. It is suggested that the effects of ginseng total saponins on improving the learning and memory of rats were related to protecting from the damage of hippocampal synapses caused by exhaustive exercise-induced fatigue.
Intense exercise significantly reduced the protein expression levels of SYP in the hippocampus of rats (Ding, et al., 2014). High-intensity training significantly reduced the expression of protein and mRNA of PSD95 in hippocampus of rats (Ren, et al., 2017). In this study, we found the level of the protein expression of SYP and PSD95 significantly decreased after 7 days of exhaustive exercise. Reduced the levels of synaptic protein markers (PSD95, SYN) were coincided with the decrease of the number and PSD thickness of synapses (Pan, et al., 2016). We also found that ginseng total saponins could resisted the decrease of the protein expression levels of SYP and PSD95 in hippocampus of rats with exhaustive exercise-induced fatigue in a dose-dependent manner. The most potent effects were observed at the dose of 200 mg/kg of ginseng total saponins. It is suggested that ginseng total saponins could improve their learning and memory through increasing the protein expression levels of SYP and PSD95 in the hippocampus of rats with exhaustive exercise-induced fatigue.
The enhanced presynaptic glutamate release and downregulated postsynaptic NR function lead to the impaired corticostriatal plasticity in mice with exercise-induced fatigue (Ma, et al., 2018). High-intensity platform training decreased the the protein expression levels of NR1 and NR2A and NR2B in hippocampus of rats (Ren,et al., 2017). Our previous research showed that the level of NR1 and NR2B mRNA expression in hippocampus of rats decreased after exercise-induced fatigue (Zhu, et al., 2006). In this study, we found that ginseng total saponins could not only resist the decrease of the protein expression levels of NR2B and CAMKII, but also significantly increase the phosphorylation levels of NR2B, CAMKII in hippocampus of rats with exhaustive exercise-induced fatigue. The phosphorylation status of NR is an important factor that reflects the activation status of NR (Sanderson, et al., 2016). CaMKII is a key protein kinase in neural plasticity and memory (Zalcman, et al., 2018). CaMKII directly binds to the NR subunits NR1 and NR2B (Leonard, et al., 1999). CaMKII can be activated by calcium influx through NR (Nicoll & Schulman, 2023). When exhaustive exercise-induced fatigue inhibited the expression and phosphorylation levels of NR2B, it inhibited the phosphorylation of CaMKII which leads to the memory decline. Furthermore, inhibition of this signalling pathway also reduces the expression of PSD95 and SYN (Iyaswamy, et al., 2018), which damaged the neurons. So resistance to the inhibition of NR2B-CaMKII signal caused by exhaustive exercise-induced fatigue may be an important mechanism for ginseng total saponins to improve learning and memory of rats with exhaustive exercise-induced fatigue.
Ginseng is used as an important nootropic herb for many years in traditional Chinese medicine (Gao,et al., 2018). Ginseng saponin is the main active ingredient of ginseng. Promoting learning and memory is one of the main pharmacological effects of ginseng saponin (Wang, et al., 2014). The researches have demonstated that total ginsenoside from ginseng root can improve the learning and memory impairment of rats induced by hindlimb suspension through inhibiting body inflammation and regulating HPA axis imbalance (Bao et al., 2021). Ginsenoside Rg1 alleviates learning and memory impairments and Aβ disposition through inhibiting NLRP1 inflammasome and autophagy dysfunction in APP/PS1 mice (Li et al, 2023). This study clearly demonstrate that ginseng total saponins from ginseng stem leaf can also significantly improve the impairment of learning and memory of rats with exhaustive exercise-induced fatigue. This effect was associated with ginseng total saponins protecting from the damage of hippocampal synapses, increasing the expression levels of SYP and PSD95 and up-regulating NR2B-CaMKII signalling pathway in the hippocampus of rats with exhaustive exercise-induced fatigue. Ginseng total saponins from ginseng stem leaf has no obvious effects on learning and memory in normal rats, which is inconsistent with the literature (Yang, et al., 1994).