Buqi Huoxue Tongnao prescription protects against chronic cerebral hypoperfusion via regulating PI3K/AKT and LXRα/CYP7A1 signaling pathways.

BACKGROUND: Chronic cerebral hypoperfusion (CCH) has been confirmed as one of the pathogenesis underlying vascular cognitive impairment. A series of pathological changes, including inflammation, oxidative stress, and apoptosis, are involved in this pathophysiology and contribute to cognitive impairment and neuropathological alterations. The traditional Chinese medicine (TCM) of Buqi Huoxue Tongnao (BQHXTN) prescription possesses a remarkable clinical efficacy for treating patients with CCH, but still lacks a scientific foundation for its pharmacological mechanisms. PURPOSE: To investigate the role and underlying mechanism of the effects of BQHXTN on CCH both in vitro and in vivo. METHODS: In this study, we established a two-vessel occlusion (2-VO) induced CCH model in Sprague-Dawley rats, an oxygen-glucose deprivation model in BV2 cells, and a steatosis cell model in L02 cells to reveal the underlying mechanisms of BQHXTN by behavioral test, histopathological analysis and the detection of pro-inflammatory cytokine, apoptotic factors and reactive oxide species. Donepezil hydrochloride and Buyang Huanwu decoction were used as positive drugs. RESULTS: Compared with the 2-VO group, BQHXTN treatment at three doses significantly enhanced the memory and learning abilities in the Y-maze and novel object recognition tests. The hematoxylin-eosin staining indicated that BQHXTN protected against hippocampal injury induced by CCH. Of note, in both in vivo and in vitro experiments, BQHXTN prominently inhibited the production of IL-1ß, TNF-α, cleaved-caspase 3, and iNOS by regulating the PI3K/AKT pathway, consequently exerting anti-inflammatory, anti-apoptotic, and antioxidant effects. Moreover, it provided the first initial evidence that BQHXTN treatment mitigated dyslipidemia by increasing the LXRα/CYP7A1 expression, thereby delaying the neuropathological process. CONCLUSION: In summary, these findings firstly revealed the pharmacodynamics and mechanism of BQHXTN, that is, BQHXTN could alleviate cognitive impairment, neuropathological alterations and dyslipidemia in CCH rats by activating PI3K/AKT and LXRα/CYP7A1 signaling pathways, as well as providing a TCM treatment strategy for CCH.

Modified Erchen decoction ameliorates cognitive dysfunction in vascular dementia rats via inhibiting JAK2/STAT3 and JNK/BAX signaling pathways.

BACKGROUND: Vascular dementia (VaD) is one of the most common clinical syndromes of progressive neurocognitive dysfunction with uncertain mechanisms. Modified Erchen decoction (MECD), developed from "Erchen decoction (ECD)" recorded in "Taiping Huimin Heji Jufang", showed a good effect in the treatment of VaD. However, its therapeutic mechanism is still unclear. PURPOSE: This study aimed to elucidate the multi-target mechanisms of MECD against VaD in vivo and in vitro. METHODS: VaD model was established by two-vessel obstruction (2-VO) in Sprague-Dawley rats. Six groups, including the control, 2-VO operation, MECD treatment (2.5, 5.0 and 10.0 g kg-1 d-1), donepezil hydrochloride (positive control, 0.45 g kg-1 d-1) were designed in the whole experiment. After oral administration for 4 weeks, the effects of MECD were verified by behavioral experiments, histological observation, and biochemical index analysis. The chemical profiling of MECD was performed by UHPLC-Orbitrap Fusion-HRMS, and a "compound-target-pathway" multivariate network was constructed to validate and elucidate its pharmacological mechanisms. RESULTS: Compared with 2-VO group, MECD treatment significantly alleviated anxiety and improved spatial memory in VaD rats according to the open field test (OFT) and Y-maze test. A significant increase in neuron number was observed from hematoxylin and eosin (H&E) stained images in cornu ammonis 1 (CA1) of the hippocampal region after MECD treatment. On the one hand, MECD reduced the plasma levels of triglyceride (TG), low-density lipoprotein (LDL), malondialdehyde (MDA), and amyloid-beta 42 (Aß42), and inhibited mRNA expression of interleukin-1 beta (Il-1ß) and Il-6 in the hippocampus. On the other hand, superoxide dismutase (SOD) and total antioxidant capacity (T-AOC) were significantly increased after treatment with MECD. Moreover, MECD reduced the mRNA expression and protein expression of janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), c-Jun N-terminal kinase (JNK), and BCL2-associated X (BAX) in the brain of 2-VO rats. Furthermore, 71 compounds were identified from the extract of MECD. Among them, liquiritin and isochlorogenic acid C gave inhibiting effects on the mRNA expression of Jnk. In addition, liquiritin and hesperetin were conformed with the inhibition of Jak2 transcription level in vitro experiments. CONCLUSION: MECD has demonstrated a significant amelioration effect on cognitive dysfunction in VaD rats via JAK2/STAT3 and JNK/BAX signaling pathways, which represents an innovative insight into the "activate blood and eliminate phlegm" theory.

Comparison of the chronic unpredictable mild stress and the maternal separation in mice postpartum depression modeling.

Postpartum depression (PPD) is a serious mental health concern of new mothers worldwide. In view of the particularity of puerpera, the research on pathogenesis and drug development of PPD are highly dependent on animal models. Although both maternal separation (MS) and chronic unpredictable mild stress (CUMS) modeling approaches have been used in PPD studies, the characteristics of the two rodent models have not been compared to explain which is more advantageous in PPD research. In this study, we applied 21-day MS and CUMS paradigms to induce mouse model of PPD and compared their differences in behavior, physiology and gut microbiota. As a result, the two models exhibited significant increases of immobility time in forced swim test (FST) and tail suspension test (TST), whereas sucrose preference index and pup weight were significantly decreased. Both displayed depression-like behaviors, and CUMS was more obvious, which demonstrated by the lower levels of 5-hydroxytryptamine (5-HT) and higher hypothalamic-pituitary-adrenal (HPA) axis related mRNA expression (corticotropin releasing hormone, corticotropin releasing hormone receptor 1) in CMUS group than that in MS group. The gut microbiota in MS and CUMS groups were significantly different in terms of the relative abundances of Bacteroidetes, Firmicutes, Proteobacteria. In conclusion, MS model and CUMS model have different performance in behavior and physiology. The CUMS model showed more obvious parameter changes, which may be more suitable for PPD induced by various social environmental factors.