Natural compounds derived from Chinese herbal medicine prevent chemotherapy-induced cognitive impairment : behavioral, biochemical, and neuroimaging approaches

Abstract

Chemotherapy-induced cognitive impairment, often referred to as “chemobrain,” is a common side effect of chemotherapy. The pathogenesis of chemobrain is poorly understood and there is a lack of effective interventions to prevent and treat chemobrain. In this thesis, the twofold objectives were proposed: (1) to determine whether chemobrain is associated with cytokine dysregulation and disruption in neuroplasticity; (2) to evaluate the effects of resveratrol and Ginsenoside Rg1 in preventing chemobrain and whether their therapeutic effects are associated with the modulation of cytokines and protecting neuroplasticity. In Study #1, mice received three intraperitoneal injections of a combination of docetaxel, adriamycin, and cyclophosphamide (DAC) at 2-day intervals. The DAC-treated mice displayed a significantly shorter duration remaining in and fewer entries into the target quadrant of the water maze than the control mice and a pronounced decrease in MEMRI signal intensity in the hippocampal subregions. In vivo transcranial two-photon imaging, DAC markedly eliminated dendritic spines. DAC treatment resulted in significant elevations in the levels of the IL-6 and TNF-α and in significant decreases in the levels of IL-4 and IL-10 in serum and brain tissues. The IL-6 and TNF-α levels showed strong inverse correlations with the duration and number of entries in the target quadrant of the water maze and with the hippocampal MEMRI signal intensity, but also showed striking positive correlations with spine elimination and loss. These results indicate that chemobrain is associated with cytokine dysregulation and disrupted neuroplasticity of the brain. Resveratrol, a natural polyphenol widely existing in fruits and medicinal plants, has nootropic, neuroprotective, and immunomodulatory effects. In Study #2, cotreatment with resveratrol ameliorated DAC-induced cognitive impairment and decreases in prefrontal and hippocampal neuronal activity. Mice co-treated with resveratrol displayed significantly lower levels of TNF-α and IL-6, but markedly higher levels of IL-4 and IL-10 in serum and brain tissues than those co-treated with vehicle. Resveratrol modulated the cytokine-regulating pathway PPAR-γ/NF-κB, and protected against DAC-induced decreases in the expression of the neuroplasticity biomarkers, BDNF, TrkB, amino acid neurotransmitter receptors, and CaMKII. Ginsenoside Rg1 is a bioactive component extracted from ginseng which has multiple pharmacological activities. In Study #3, Rg1 improved the cognitive performance efficiently in the water maze test. DAC treatment induced the decreased prefrontal cortex and hippocampal neural activities, which were reversed by Rg1 in MEMRI scanning. Rg1 also attenuated the neuroplasticity by down-regulating the elimination rate of dendritic spines and modulating the synaptic plasticity related signaling pathways in prefrontal cortex and hippocampus, including amino acid neurotransmitter receptors/ CaMKII and BDNF/ TrkB pathways. Besides, Rg1 blocked the cytokine dysfunction, astrocytes activation and microglia phenotypes from M1 to M2 induced by DAC treatment. The phosphorylation of NF-κB was also partially inhibited by treatment of Rg1 both in vivo and in vitro. In vitro data suggested that neuroinflammation induced by DAC can decrease the synaptic plasticity, whereas Rg1 treatment can completely blocked the neuroplasticity deterioration. Taken together, resveratrol and Rg1 are potential candidates to attenuate cognitive impairment induced by chemotherapy via regulating neuroinflammation and synaptic plasticity in related brain regions.