Neuroprotective Effects of Ginsenoside Rf on Amyloid-ß-Induced Neurotoxicity in vitro and in vivo.

Alzheimer's disease (AD) is a neurodegenerative disease characterized by the deposition of amyloid-ß peptides (Aß). Aß accumulation leads to the formation of neurofibrillary tangles, inflammation, axonal injury, synapse loss, and neuronal apoptosis. Thus, reducing Aß levels should exert a neuroprotective effect against AD. Ginsenoside Rf, an extract from Panax notoginseng, has potent anti-fatigue, anti-nociception, anti-oxidation, and anti-inflammation properties. However, it is unclear whether ginsenoside Rf is effective in the treatment of AD. Here, we reported that ginsenoside Rf could significantly attenuate Aß-induced apoptosis in N2A cells, as reflected by a dramatic increase in mitochondrial membrane potential and decrease in Ca2 + concentration, reactive oxygen species, and active caspase-3 expression. Meanwhile, ginsenoside Rf could alleviate the Aß-induced inflammation reaction, such as the decrease of interferon-gamma (IFN-γ) and active caspase-1 expression and the increase of interleukin-13. Furthermore, we also found that Rf is able to accelerate Aß clearance and subsequently reduces Aß level in N2A cells stably transfected with human Swedish mutant APP695 (N2A-APP). More importantly, daily Rf treatment (20 mg/kg, i.p.) throughout the experiment dramatically improved spatial learning and memory in Aß42-induced mouse model of AD. Taken together, these results indicate that ginsenoside Rf may decrease Aß-induced neurotoxicity and memory decline via anti-inflammatory response during AD development, suggesting that Rf may be a potential therapeutic agent for treating AD.

Vitamin A Deficiency Induces Autistic-Like Behaviors in Rats by Regulating the RARß-CD38-Oxytocin Axis in the Hypothalamus.

SCOPE: Vitamin A (VA) is an essential nutrient for the development of the brain. We previously found that children with autism spectrum disorder (ASD) have a significant rate of VA deficiency (VAD). In the current study, we aim to determine whether VAD is a risk factor for the generation of autistic-like behaviors via the transcription factor retinoic acid receptor beta (RARß)-regulated cluster of differentiation 38 (CD38)-oxytocin (OXT) axis. METHODS AND RESULTS: Gestational VAD or VA supplementation (VAS) rat models are established, and the autistic-like behaviors in the offspring rats are investigated. The different expression levels of RARß and CD38 in hypothalamic tissue and serum retinol and OXT concentration are tested. Primary cultured rat hypothalamic neurons are treated with all-trans retinoic acid (atRA), and recombinant adenoviruses carrying the rat RARß (AdRARß) or RNA interference virus RARß-siRNA (siRARß) are used to infect neurons to change RARß signal. Western blotting, chromatin immunoprecipitation (ChIP), and intracellular Ca2+ detections are used to investigate the primary regulatory mechanism of RARß in the CD38-OXT signaling pathway. We found that gestational VAD increases autistic-like behaviors and decreases the expression levels of hypothalamic RARß and CD38 and serum OXT levels in the offspring. VAS ameliorates these autistic-like behaviors and increases the expression levels of RARß, CD38, and OXT in the gestational VAD pups. In vitro, atRA increases the Ca2+ excitability of neurons, which might further promote the release of OXT. Different CD38 levels are induced in the neurons by infection with different RARß adenoviruses. Furthermore, atRA enhances the binding of RARß to the proximal promoter of CD38, indicating a potential upregulation of CD38 transcriptional activity by RARß. CONCLUSIONS: Gestational VAD might be a risk factor for autistic-like behaviors due to the RARß signal suppression of CD38 expression in the hypothalamus of the offspring, which improves with VAS during the early-life period. The nutritional status during pregnancy and the early-life period is important in rats.

Capsaicin Attenuates Amyloid-ß-Induced Synapse Loss and Cognitive Impairments in Mice.

Alzheimer's disease (AD) is the most common cause of progressive cognitive impairment in the aged. The aggregation of the amyloid ß-protein (Aß) is a hallmark of AD and is linked to synapse loss and cognitive impairment. Capsaicin, a specific agonist of the transient receptor potential vanilloid 1 (TRPV1), has been proven to ameliorate stress-induced AD-like pathological and cognitive impairments, but it is unclear whether TRPV1 activation can affect cognitive and synaptic functions in Aß-induced mouse model of AD. In this study, we investigated the effects of TRPV1 activation on spatial memory and synaptic plasticity in mice treated with Aß. To induce AD-like pathological and cognitive impairments, adult C57Bl/6 mice were microinjected with Aß42 (100 µM, 2.5 µl/mouse, i.c.v.). Two weeks after Aß42 microinjection, spatial learning and memory as well as hippocampal long-term potentiation (LTP) were examined. The results showed that Aß42 microinjection significantly impaired spatial learning and memory in the Morris water maze and novel object recognition tests compared with controls. These behavioral changes were accompanied by synapse loss and impaired LTP in the CA1 area of hippocampus. More importantly, daily capsaicin (1 mg/kg, i.p.) treatment throughout the experiment dramatically improved spatial learning and memory and synaptic function, as reflected by enhanced hippocampal LTP and reduced synapse loss, whereas the TRPV1 antagonist capsazepine (1 mg/kg, i.p.) treatment had no effects on cognitive and synaptic function in Aß42-treated mice. These results indicate that TRPV1 activation by capsaicin rescues cognitive deficit in the Aß42-induced mouse model of AD both structurely and functionally.