Mechanism of Neural Regeneration Induced by Natural Product LY01 in the 5×FAD Mouse Model of Alzheimer's Disease.

Background: A sharp decline in neural regeneration in patients with Alzheimer's disease (AD) exacerbates the decline of cognition and memory. It is of great significance to screen for innovative drugs that promote endogenous neural regeneration. Cytisine N-methylene-(5,7,4'-trihydroxy)-isoflavone (LY01) is a new compound isolated from the Chinese herbal medicine Sophora alopecuroides with both isoflavone and alkaloid characteristic structures. Its pharmacological effects are worth studying. Objective: This study was designed to determine whether LY01 delays the cognitive and memory decline in the early stage of AD and whether this effect of LY01 is related to promoting neural regeneration. Methods: Eight-week-old 5×Familial Alzheimer's Disease (5×FAD) mice were used as disease models of early AD. Three doses of LY01 administered in two courses (2 and 5 weeks) of treatment were tested. Cognition, memory, and anxiety-like behaviors in mice were evaluated by the Morris water maze, fear conditioning, and open field experiments. Regeneration of neurons in the mouse hippocampus was observed using immunofluorescence staining. The effect of LY01 on cell regeneration was also demonstrated using a series of tests on primary cultured neurons, astrocytes, and neural stem cells (NSCs). In addition, flow cytometry and transcriptome sequencing were carried out to preliminarily explored the mechanisms. Results: We found that LY01 reduced the decline of cognition and memory in the early stage of 5×FAD mice. This effect was related to the proliferation of astrocytes, the proliferation and migration of NSCs, and increases in the number of new cells and neural precursor cells in the dentate gyrus area of 5×FAD mice. This phenomenon could be observed both in 2-week-old female and 5-week-old male LY01-treated 5×FAD mice. The neuronal regeneration induced by LY01 was related to the regulation of the extracellular matrix and associated receptors, and effects on the S phase of the cell cycle. Conclusion: LY01 increases the proliferation of NSCs and astrocytes and the number of neural precursor cells in the hippocampus, resulting in neural regeneration in 5×FAD mice by acting on the extracellular matrix and associated receptors and regulating the S phase of the cell cycle. This provides a new idea for the early intervention and treatment of AD.

Astragaloside IV protects against diabetic nephropathy via activating eNOS in streptozotocin diabetes-induced rats.

BACKGROUND: Astragaloside IV (AS-IV) was reported to play a role in improving diabetic nephropathy (DN), however, the underlying mechanisms still remain unclear. The aim of the present study is to investigate whether AS-IV ameliorates DN via the regulation of endothelial nitric oxide synthase (eNOS). METHODS: DN model was induced in Sprague-Dawley (SD) male rats by intraperitoneal injection of 65 mg/kg streptozotocin (STZ). Rats in the AS-IV treatment group were orally gavaged with 5 mg/kg/day or 10 mg/kg/day AS-IV for eight consecutive weeks. Body weight, blood glucose, blood urea nitrogen (BUN), Serum creatinine (Scr), proteinuria and Glycosylated hemoglobin (HbA1c) levels were measured. Hematoxylin-Eosin (HE) and Periodic Acid-Schiff (PAS) staining were used to detect the renal pathology. The apoptosis status of glomerular cells was measured by TUNEL assay. The phosphorylation and acetylation of eNOS were detected by western blot. The effects of AS-IV on high-glucose (HG)-induced apoptosis and eNOS activity were also investigated in human renal glomerular endothelial cells (HRGECs) in vitro. RESULTS: Treatment with AS-IV apparently reduced DN symptoms in diabetic rats, as evidenced by reduced BUN, Scr, proteinuria, HbA1c levels and expanding mesangial matrix. AS-IV treatment also promoted the synthesis of nitric oxide (NO) in serum and renal tissues and ameliorated the phosphorylation of eNOS at Ser 1177 with decreased eNOS acetylation. Moreover, HG-induced dysfunction of HRGECs including increased cell permeability and apoptosis, impaired eNOS phosphorylation at Ser 1177, and decreased NO production, were all reversed by AS-IV treatment. CONCLUSIONS: These novel findings suggest that AS-IV ameliorates functional abnormalities of DN through inhibiting acetylation of eNOS and activating its phosphorylation at Ser 1177. AS-IV could be served as a potential therapeutic drug for DN.

Low dose of caffeine enhances the efficacy of antidepressants in major depressive disorder and the underlying neural substrates.

SCOPE: Caffeine is one of the most frequently used psychoactive substances ingested mainly via beverage or food products. Major depressive disorder is a serious and devastating psychiatric disorder. Emerging evidence indicates that caffeine enhances the antidepressant-like activity of common antidepressant drugs in rodents. However, whether joint administration of low dose of caffeine enhances the antidepressant actions in depressed patients remains unclear. METHODS AND RESULTS: A total of 95 male inpatients were assigned to three groups and were asked to take either caffeine (60, 120 mg) or placebo (soymilk powder) daily for 4 wk on the basis of their current antidepressant medications. Results showed that chronic supplementation with low dose of caffeine (60 mg) produced rapid antidepressant action by reduction of depressive scores. Furthermore, low dose of caffeine improved cognitive performance in depressed patients. However, caffeine did not affect sleep as measured by overnight polysomnography. Moreover, chronic caffeine consumption elicited inhibition of hypothalamic-pituitary-adrenal axis activation by normalization of salivary cortisol induced by Trier social stress test. CONCLUSIONS: These findings indicated the potential benefits of further implications of supplementary administration of caffeine to reverse the development of depression and enhance the outcome of antidepressants treatment in major depressive disorder.