Salvianolic acid B ameliorates retinal deficits in an early-stage Alzheimer's disease mouse model through downregulating BACE1 and Aß generation.

Alzheimer's disease (AD) is a neurodegenerative disease with subtle onset, early diagnosis remains challenging. Accumulating evidence suggests that the emergence of retinal damage in AD precedes cognitive impairment, and may serve as a critical indicator for early diagnosis and disease progression. Salvianolic acid B (Sal B), a bioactive compound isolated from the traditional Chinese medicinal herb Salvia miltiorrhiza, has been shown promise in treating neurodegenerative diseases, such as AD and Parkinson's disease. In this study we investigated the therapeutic effects of Sal B on retinopathy in early-stage AD. One-month-old transgenic mice carrying five familial AD mutations (5×FAD) were treated with Sal B (20 mg·kg-1·d-1, i.g.) for 3 months. At the end of treatment, retinal function and structure were assessed, cognitive function was evaluated in Morris water maze test. We showed that 4-month-old 5×FAD mice displayed distinct structural and functional deficits in the retinas, which were significantly ameliorated by Sal B treatment. In contrast, untreated, 4-month-old 5×FAD mice did not exhibit cognitive impairment compared to wild-type mice. In SH-SY5Y-APP751 cells, we demonstrated that Sal B (10 µM) significantly decreased BACE1 expression and sorting into the Golgi apparatus, thereby reducing Aß generation by inhibiting the ß-cleavage of APP. Moreover, we found that Sal B effectively attenuated microglial activation and the associated inflammatory cytokine release induced by Aß plaque deposition in the retinas of 5×FAD mice. Taken together, our results demonstrate that functional impairments in the retina occur before cognitive decline, suggesting that the retina is a valuable reference for early diagnosis of AD. Sal B ameliorates retinal deficits by regulating APP processing and Aß generation in early AD, which is a potential therapeutic intervention for early AD treatment.

Berberine attenuates ischemia-reperfusion injury through inhibiting HMGB1 release and NF-κB nuclear translocation.

Inflammatory damage plays an important role in cerebral ischemic pathogenesis and represents a new target for treatment of stroke. Berberine is a natural medicine with multiple beneficial biological activities. In this study, we explored the mechanisms underlying the neuroprotective action of berberine in mice subjected transient middle cerebral artery occlusion (tMCAO). Male mice were administered berberine (25, 50 mg/kg/d, intragastric; i.g.), glycyrrhizin (50 mg/kg/d, intraperitoneal), or berberine (50 mg/kg/d, i.g.) plus glycyrrhizin (50 mg/kg/d, intraperitoneal) for 14 consecutive days before tMCAO. The neurological deficit scores were evaluated at 24 h after tMCAO, and then the mice were killed to obtain the brain samples. We showed that pretreatment with berberine dose-dependently decreased the infarct size, neurological deficits, hispathological changes, brain edema, and inflammatory mediators in serum and ischemic cortical tissue. We revealed that pretreatment with berberine significantly enhanced uptake of 18F-fluorodeoxyglucose of ischemic hemisphere comparing with the vehicle group at 24 h after stroke. Furthermore, pretreatment with berberine dose-dependently suppressed the nuclear-to cytosolic translocation of high-mobility group box1 (HMGB1) protein, the cytosolic-to nuclear translocation of nuclear factor kappa B (NF-κB) and decreased the expression of TLR4 in ischemic cortical tissue. Moreover, co-administration of glycyrrhizin and berberine exerted more potent suppression on the HMGB1/TLR4/NF-κB pathway than berberine or glycyrrhizin administered alone. These results demonstrate that berberine protects the brain from ischemia-reperfusion injury and the mechanism may rely on its anti-inflammatory effects mediated by suppressing the activation of HMGB1/TLR4/NF-κB signaling.