Background: Cinnamomum cassia bark is the outer skin of an evergreen tall tree belonging to the family Lauraceae containing several active components such as essential oils (cinnamic aldehyde and cinnamyl aldehyde), tannin, mucus and carbohydrate. They have various biological functions including anti-oxidant, anti-microbial, anti-inflammation, anti-diabetic and anti-tumor activity. Previously, we have reported that anti-cancer effect of cinnamon extracts is associated with modulation of angiogenesis and effector function of CD8⁺ T cells. In this study, we further identified that anti-tumor effect of cinnamon extracts is also link with enhanced pro-apoptotic activity by inhibiting the activities NFκB and AP1 in mouse melanoma model. Methods: Water soluble cinnamon extract was obtained and quality of cinnamon extract was evaluated by HPLC (High Performance Liquid Chromatography) analysis. In this study, we tested anti-tumor activity and elucidated action mechanism of cinnamon extract using various types of tumor cell lines including lymphoma, melanoma, cervix cancer and colorectal cancer in vitro and in vivo mouse melanoma model. Results: Cinnamon extract strongly inhibited tumor cell proliferation in vitro and induced active cell death of tumor cells by up-regulating pro-apoptotic molecules while inhibiting NFκB and AP1 activity and their target genes such as Bcl-2, BcL-xL and survivin. Oral administration of cinnamon extract in melanoma transplantation model significantly inhibited tumor growth with the same mechanism of action observed in vitro. Conclusion: Our study suggests that anti-tumor effect of cinnamon extracts is directly linked with enhanced pro-apoptotic activity and inhibition of NFκB and AP1 activities and their target genes in vitro and in vivo mouse melanoma model. Hence, further elucidation of active components of cinnamon extract could lead to development of potent anti-tumor agent or complementary and alternative medicine for the treatment of diverse cancers.

The receptor for advanced glycation end products (RAGE) has been reported to have a pivotal role in the pathogenesis of Alzheimer’s disease (AD). This study investigated RAGE levels in the hippocampus and cortex of a triple transgenic mouse model of AD (3xTg-AD) using western blotting and immunohistochemical double-labeling to assess cellular localization. Analysis of western blots showed that there were no differences in the hippocampal and cortical RAGE levels in 10-month-old adult 3xTg-AD mice, but significant increases in RAGE expression were found in the 22- to 24-month-old aged 3xTg-AD mice compared with those of age-matched controls. RAGE-positive immunoreactivity was observed primarily in neurons of aged 3xTg-AD mice with very little labeling in non-neuronal cells, with the notable exception of RAGE presence in astrocytes in the hippocampal area CA1. In addition, RAGE signals were co-localized with the intracellular amyloid precursor protein (APP)/amyloid beta (Aβ) but not with the extracellular APP/Aβ. In aged 3xTg-AD mice, expression of human tau was observed in the hippocampal area CA1 and co-localized with RAGE signals. The increased presence of RAGE in the 3xTg-AD animal model showing critical aspects of AD neuropathology indicates that RAGE may contribute to cellular dysfunction in the AD brain.

Ginkgo biloba extract (GBE)-a widely used nutraceutical-is reported to have diverse functions, including positive effects on memory and vasodilatory properties. Although numerous studies have assessed the neuroprotective properties of GBE in ischemia, only a few studies have investigated the neuro-pharmacological mechanisms of action of GBE in chronic cerebral hypoperfusion (CCH). In the present study, we sought to determine the effects of GBE on CCH-induced neuroinflammation and cholinergic dysfunction in a rat model of bilateral common carotid artery occlusion (BCCAo). Chronic BCCAo was induced in adult male Wistar rats to reflect the CCH conditions. On day 21 after BCCAo, the animals were treated orally with saline or GBE (5, 10, 20, and 40mg/kg) daily for 42 days. After the final treatment, brain tissues were isolated for the immunohistochemical analysis of glial markers and choline acetyltransferase (ChAT), as well as for the western blot analysis of proinflammatory cytokines, toll-like receptor (TLR)-related pathway, receptor for advanced glycation end products (RAGE), angiotensin-II (Ang-II), and phosphorylated mitogen-activated protein kinases (MAPKs). BCCAo increased glial proliferation in the hippocampus and white matter, whereas proliferation was significantly attenuated by GBE treatment. GBE also attenuated the BCCAo-related increases in the hippocampal expression of proinflammatory cytokines (TNF-α, IL-1β, and IL-6), TLR4, myeloid differentiation primary response gene 88, RAGE, Ang-II, and phosphorylated MAPKs (ERK, p38, and JNK). Furthermore, GBE treatment restored the ChAT expression in the basal forebrain following BCCAo. These findings suggest that GBE has specific neuroprotective effects that may be useful for the treatment of CCH. The pharmacological mechanism of GBE partly involves the modulation of inflammatory mediators and the cholinergic system.

Terminalia chebula Retz. (Combretaceae) is a traditional herbal medicine that is widely used in the treatment of diabetes, immunodeficiency diseases, and stomach ulcer in Asia. However, the anti-amnesic effect of T. chebula has not yet been investigated. The present study was designed to determine whether T. chebula extract (TCE) alleviates amnesia induced by scopolamine in mice. We also investigated possible mechanisms associated with cholinergic system and anti-oxidant effects. TCE (100 or 200 mg/kg) was orally administered to mice for fourteen days (days 1–14), and scopolamine was intraperitoneally injected to induce memory impairment for seven days (days 8–14). Learning and memory status were evaluated using the Morris water maze. Hippocampal levels of acetylcholine (ACh), acetylcholinesterase (AChE) and choline acetyltransferase (ChAT) were measured ex vivo. Levels of reactive oxygen species (ROS), nitric oxide (NO), and malondialdehyde (MDA) in the hippocampus were also examined. In the Morris water maze task, TCE treatment reversed scopolamine-induced learning and memory deficits in acquisition and retention. TCE reduced hippocampal AChE activities and increased ChAT and ACh levels in the scopolamine-induced model. Moreover, TCE treatment suppressed scopolamine-induced oxidative damage by ameliorating the increased levels of ROS, NO, and MDA. These findings suggest that TCE exerts potent anti-amnesic effects via cholinergic modulation and anti-oxidant activity, thus providing evidence for its potential as a cognitive enhancer for amnesia.

Fructus mume (F. mume) has been used as a traditional medicine for many years in Asian countries. The present study was designed to determine the effect of a 70% ethanol extract of F. mume on white matter and hippocampal damage induced by chronic cerebral hypoperfusion. Permanent bilateral common carotid artery occlusion (BCCAo) was performed on male Wistar rats to induce chronic cerebral hypoperfusion. Daily oral administration of F. mume (200 mg/kg) was initiated 21 days after BCCAo and continued for 42 days. The experimental groups in this study were divided into three groups: a sham-operated group, a BCCAo group, and a BCCAo group that was administered with the F. mume extract. The activation of glial cells, including microglia and astrocytes, and the levels of myelin basic protein (MBP), inflammatory mediators, Toll-like receptor 4 (TLR4), myeloid differentiation factor 88 (MyD88), and p38 mitogen-activated protein kinase (MAPK) phosphorylation were measured in brains from rats subjected to chronic BCCAo. Our results revealed that F. mume alleviates the reduction in MBP expression caused by chronic BCCAo in the white matter and the hippocampus and significantly attenuates microglial and astrocytic activation induced by chronic BCCAo in the optic tract of white matter. In addition, F. mume treatment reduced the increased expression of cyclooxygenase-2 (COX-2), interleukin-1β (IL-1β) and interleukin-6 (IL-6), as well as the activation of TLR4/MyD88 and p38 MAPK signaling, in the hippocampus of rats subjected to chronic BCCAo. Taken together, our findings demonstrate that brain injury induced by chronic BCCAo is ameliorated by the anti-inflammatory effects of F. mume via inhibition of MBP degradation, microglial and astrocytic activation, increased inflammatory mediator expression, and activated intracellular signalings, including TLR4 and p38 MAPK, implying that F. mume is potentially an effective therapeutics for the treatment of vascular dementia.

Neuroinflammation plays a key role in the initiation and progression of neurodegeneration in Alzheimer’s disease (AD). Chronic neuroinflammation results in diminished synaptic plasticity and loss of GluN1 N-methyl-D-aspartate (NMDA) receptors in the hippocampus, leading to the cognitive deficits that are the most common symptoms of AD. Therefore, it is suggested that chronic inflammation may alter expression levels of GluN2A and GluN2B subunits of NMDA receptors and associated intracellular signalling. Chronic neuroinflammation was induced by chronic infusion of lipopolysaccharide (LPS) into the fourth ventricle in Fischer-344 rats. The status of hippocampus-dependent memory was evaluated in control rats and rats chronically infused with LPS. Microglial activation in the hippocampus was examined using immunohistochemical staining. Western blot analysis was used to measure membrane levels of GluN2A and GluN2B subunits of NMDA receptors and mitogen-activated protein kinase (MAPK) in the hippocampi of these rats, and immunofluorescent double labeling was used to assess the cellular location of MAPK. Microglial activation was observed in the hippocampi of rats that showed memory impairments with chronic LPS infusion. Chronic LPS infusion reduced the levels of GluN2A and GluN2B and increased the levels of phosphorylated MAPKs in the hippocampus. MAPK-positive immunoreactivity was observed mostly in the neurons and also in non-neuronal cells. Reductions in GluN2A and GluN2B subunits of NMDA receptors coupled with altered MAPK signaling, in response to inflammatory stimuli may be related to the cognitive deficits observed in AD.