Optimal Formula of Angelica sinensis Ameliorates Memory Deficits in ß-amyloid Protein-induced Alzheimer's Disease Rat Model.

OBJECTIVE: Angelica (A.) sinensis is used as a traditional medical herb for the treatment of neurodegeneration, aging, and inflammation in Asia. A. sinensis optimal formula (AOF) is the best combination in A. sinensis that has been screened to rescue the cognitive ability in ß-amyloid peptide (Aß25-35)-treated Alzheimer's disease (AD) rats. The objective of this study was to investigate the effect of AOF on the learning and memory of AD rats as well as to explore the underlying mechanisms. METHODS: Male Wistar rats were infused with Aß25-35 for AD model induction or saline (negative control). Five groups of AD rats were fed on AOF at 20, 40, or 80 mL/kg every day, donepezil at 0.9 mg/kg every day (positive control), or an equal volume of water (AD model) intragastrically once a day for 4 weeks, while the negative control rats were fed on water. The Morris water maze test was used to evaluate the cognitive function of the rats. The Aß accumulation, cholinergic levels, and antioxidative ability were detected by ELISA. Additionally, the candidate mechanism was determined by gene sequencing and quantitative real-time polymerase chain reaction. RESULTS: The results showed that AOF administration significantly ameliorated Aß25-35-induced memory impairment. AOF decreased the levels of amyloid-ß precursor protein and Aß in the hippocampus, rescued the cholinergic levels, increased the activity of superoxide dismutase, and decreased the malondialdehyde level. In addition, AOF inhibited the expression of IL1b, Mpo, and Prkcg in the hippocampus. CONCLUSION: These experimental findings illustrate that AOF prevents the decrease in cognitive function and Aß deposits in Aß25-35-treated rats via modulating neuroinflammation and oxidative stress, thus highlighting a potential therapeutic avenue to promote the co-administration of formulas that act on different nodes to maximize beneficial effects and minimize negative side effects.

1-Methylnicotinamide attenuates lipopolysaccharide-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis.

Alzheimer's disease (AD) is a neurodegenerative disease that affects cognition and behavior. The neuroinflammatory response in the brain is an important pathological characteristic in AD. In this study, we investigated the neuroprotective effects of 1-Methylnicotinamide (MNA), known as the main metabolite of nicotinamide, on reducing lipopolysaccharide (LPS)-induced cognitive deficits via targeting neuroinflammation and neuronal apoptosis. We found that the mice treated with LPS exhibited cognitive deficits in the novel object recognition, Morris water maze and Y-maze avoidance tests. However, intragastric administration of MNA (100 or 200 mg/kg) for 3 weeks significantly attenuated LPS-induced cognitive deficits in mice. Importantly, MNA treatment suppressed the protein expression of nuclear factor-kappa B p65 (NF-κB p65), pro-inflammatory cytokines (TNF-α, IL-6) and decreased the activation of microglia and astrocytes in the hippocampus and frontal cortex of LPS-induced mice. In addition, MNA treatment suppressed neuronal apoptosis by reducing the number of TUNEL-positive cells, caspase-3 activation and increasing the level of Bcl-2/Bax ratio in the hippocampus and frontal cortex. These findings indicate that MNA could be a potential neuroprotective drug in neurodegenerative diseases such as AD.

Trans-cinnamaldehyde improves memory impairment by blocking microglial activation through the destabilization of iNOS mRNA in mice challenged with lipopolysaccharide.

Microglia activation and neuroinflammation are critically involved in pathogenesis of neurodegenerative disorders. Patients with neurodegenerative disorders often suffer memory impairment and currently there is no effective treatment for inflammation-led memory impairment. Trans-cinnamaldehyde (TCA) isolated from medicinal herb Cinnamomum cassia has been shown to exhibit anti-inflammatory capability. However, the potential of TCA to be used to improve memory impairment under neuroinflammation has not been explored. Primary microglia stimulated by lipopolysaccharide (LPS) were used to evaluate the potential anti-neuroinflammatory effects of TCA by examining the production of nitric oxide (NO), expression of inducible nitric oxide synthase (iNOS), pro-inflammatory cytokines, and activation of MAPKs. A mouse model of LPS-induced memory impairment was established to assess the neuroprotective effects of TCA against memory deficit and synaptic plasticity inhibition by both behavioral tests and electrophysiological recordings. TCA pretreatment decreased LPS-induced morphological changes, NO production and IL-1ß release in primary microglia. Decreased NO production was due to the accelerated degradation of iNOS mRNA in LPS-stimulated microglia through TCA's inhibitory effect on MEK1/2-ERK1/2 signaling pathway. TCA was able to reduce the levels of iNOS and phosphorylated ERK1/2 in hippocampus of mice challenged with LPS. Most importantly, TCA significantly lessened memory deficit and improved synaptic plasticity in LPS-challenged mice. This study demonstrates that TCA suppressed microglial activation by destabilizing iNOS mRNA, which leads to improved memory impairment in mice suffering neuroinflammation.

The anti-aging effects of LW-AFC via correcting immune dysfunctions in senescence accelerated mouse resistant 1 (SAMR1) strain.

Although there were considerable advances in the anti-aging medical field, it is short of therapeutic drug for anti-aging. Mounting evidence indicates that the immunosenescence is the key physiopathological mechanism of aging. This study showed the treatment of LW-AFC, an herbal medicine, decreased the grading score of senescence, increased weight, prolonged average life span and ameliorated spatial memory impairment in 12- and 24-month-old senescence accelerated mouse resistant 1 (SAMR1) strain. And these anti-aging effects of LW-AFC were more excellent than melatonin. The administration of LW-AFC enhanced ConA- and LPS-induced splenocyte proliferation in aged SAMR1 mice. The treatment of LW-AFC not only reversed the decreased the proportions of helper T cells, suppressor T cells and B cells, the increased regulatory T cells in the peripheral blood of old SAMR1 mice, but also could modulate the abnormal secretion of IL-1ß, IL-2, IL-6, IL-17, IL-23, GM-CSF, IFN-γ, TNF-α, TNF-ß, RANTES, eotaxin, MCP-1, IL-4, IL-5, IL-10 and G-CSF. These data indicated that LW-AFC reversed the immunosenescence status by restoring immunodeficiency and decreasing chronic inflammation and suggested LW-AFC may be an effective anti-aging agent.

ASIA or Shoenfeld's syndrome--an autoimmune syndrome induced by adjuvants.

Recently, reports have suggested grouping different autoimmune conditions that are triggered by external stimuli as a single syndrome called autoimmune syndrome induced by adjuvants (ASIA). This syndrome is characterized by the appearance of myalgia, myositis, muscle weakness, arthralgia, arthritis, chronic fatigue, sleep disturbances, cognitive impairment and memory loss, and the possible emergence of a demyelinating autoimmune disease caused by systemic exposure after vaccines and adjuvants. As there are no markers for ASIA, the authors intend to present ASIA, or Shoenfeld's syndrome, as an autoimmune syndrome induced by adjuvants.

[Effect of electroacupuncture on ethology and cytokines of hippocampus in rats with dysmnesy].

OBJECTIVE: To observe the effect of electroacupuncture (EA) on learning and memory impairment and cytokines of hippocampus in aging rats induced by D-galactose for exploring its underlying mechanism in the treatment of dysmnesy. METHODS: A total of 27 SD rats were randomly divided into control group (n = 9), model group (n = 8) and EA group (n = 10). Dysmnesy model was induced by intraperitoneal injection of D-galactose. EA (3 Hz, continuous waves, 1 mA) was applied to "Baihui" (GV 20) and "Zusanli" (ST 36) for 20 min every time and on alternate days, continuously for 21 days. Morris water maze tests were conducted to detect the rat's escape latency, percentage of swimming distance in the original platform quadrant and the total distance (SD/TD) and the percentage of swimming time in the platform quadrant after removal of the platform (spatial probe test) which were used for assessing the animals' learning and memory ability. The contents of IL-1beta, IL-6 and TNF-alpha in the hippocampus tissue were assayed by radioimmunoassay. RESULTS: Location navigation test showed that the escape latencies on the 2nd day and the 3rd day in model group were significantly longer than those of control group (P < 0.05), and the percents of SD/TD and swimming time in the platform quadrant were significantly lower than those of control group (P < 0.05, P < 0.01). In comparison with model group, the escape latency of EA group on the 3rd day was significantly shorter (P < 0.05), and the percent of SD/TD in the platform quadrant of EA group was significantly longer (P < 0.01). Compared with control group, IL-1beta and TNF-alpha contents in the hippocampus increased significantly in model group (P < 0.05, P < 0.01), while IL-6 content in model group decreased significantly (P < 0.01). In comparison with model group, the levels of IL-1beta and TNF-alpha in EA group decreased significantly (P < 0.05). CONCLUSION: EA can improve the learning-memory ability in dysmnesy rats, which may be closely associated with its effects in regulating the levels of cytokines in the hippocampus.

Improving effects of SSF on memory deficits and pathological changes of neural and immunological systems in senescent mice.

AIM: To study the effects of SSF, an effective part isolated from Scutellaria baicalensis George, on memory impairments and the pathological changes of neural and immunological systems in senescent mice induced by chronic galactose. METHODS: Senescent performance in mice was induced by consecutive administration of D-galactose (120 mg/kg, ip) for 47 d. The behavioral tests of mice used water maze task. The neural and immunological changes were assessed by alterations of cerebral cortex morphology and immune tissue index. The improving effects of SSF (50, 100, and 200 mg/kg, ig, 47 d) on above changes in the senescent mice were detected. Piracetam (PIR) was as reference drug. RESULTS: D-Galactose (120 mg/kg, ip, 47 d) resulted in an increase in the latencies to find the terminal platform and the number of errors entering non-exits in water maze, neuropathological changes and immune tissue index (spleen index) deducted in mice as compared with saline treated group. Both PIR (200 mg/kg, ig, 47 d) and SSF (50, 100, and 200 mg/kg, ig, 47 d) could significantly reverse the increased latencies and number of errors and improve the pathological alterations of neural and immunological systems. CONCLUSION: SSF could ameliorate the cognitive deficits and pathological alterations of neuron and immune systems in senescent mice induced by chronic galactose.

Thymectomy-induced deterioration of learning and memory.

Age-associated immunodeficiency and cognitive deterioration are two predominant features of the aging process, but the mutual influences between them are not clear yet. Research on the neuroendocrine immunomodulation (NIM) network indicate reciprocal interactions between the neuroendocrine and the immune systems mediated by neurotransmitters, neuropeptides, hormones and cytokines, which form an integrated network to maintain normal physiological functions of the body. An imbalance in the NIM network is believed to accelerate the aging process, in which the thymus plays an important role. We recently discovered that thymectomy in mice not only reduces the immune response, but also deteriorates learning performances. Cytokines such as interleukin-1, interleukin-6 and tumor necrosis factor, and corticosterone affect the induction of hippocampal long-term potentiation, a synaptic model of memory. Clinical studies have demonstrated that Alzheimer's patients show disordered immune function in addition to cognitive deficit, and the brain lesions of Alzheimer's patients may be associated with abnormal immune reactions occurring in the brain. With these findings, it is speculated that the disordered immune function may induce an imbalance in the NIM network, which consequently influences central cognitive function.