Effect of electroacupuncture on proBDNF/mBDNF and synaptic plasticity in rats with learning and memory impairment after cerebral ischemia-reperfusion. / ç”µé’ˆå¯¹è„‘ç¼ºè¡€å†çŒæ³¨å­¦ä¹ è®°å¿†éšœç¢å¤§é¼ æµ·é©¬è„‘æºæ€§ç¥žç»è¥å »å› å­è½¬åŒ–å’Œçªè§¦å¯å¡‘æ€§çš„å½±å“.

OBJECTIVES: To observe the effect of electroacupuncture (EA) at "Baihui" (GV20) and "Shenting" (GV24) on the rats' behavior and the transforming precursor of brain-derived neurotrophic factor (proBDNF) into mature brain-derived neurotrophic factor (mBDNF) in the hippocampus of rats with learning and memory impairment induced by cerebral ischemia-reperfusion (IR), so as to explore its mechanisms underlying improvement of learning and memory ability. METHODS: SD rats were randomly divided into blank, sham operation, model, and EA groups, with 6 rats in each group. The model of IR was established by occlusion of the middle cerebral artery. EA (1 Hz/20 Hz) was applied to GV24 and GV20 for 30 min, once daily for 14 days. The neurological function was evaluated according to the Zea Longa's score criteria 24 h after modeling and after intervention. Morris water maze test was used to detect the learning and memory function of the rats. TTC staining was used to evaluate the cerebral infarction volume on the affected side. The protein expression levels of proBDNF, mBDNF, tissue plasminogen activator (tPA), tyrosine kinase receptor B (TrkB) and p75 neurotrophin receptor (p75NTR) in hippocampal tissue were detected by Western blot. RESULTS: Compared with the sham operation group, the neurological function score, the percentage of cerebral infarction volume and the expression levels of proBDNF and p75NTR protein in hippocampus were increased (P<0.01), while the times of crossing the original platform and the total distance in the target quadrant, the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were decreased (P<0.01, P<0.05) in the model group. Compared with the model group, the neurological function score, the percentage of cerebral infarction volume, and the expression levels of proBDNF and p75NTR protein in hippocampus were decreased (P<0.01, P<0.05), while the times of crossing the original platform, the total distance in the target quadrant, and the expression levels of mBDNF, TrkB and tPA protein and the ratio of mBDNF/proBDNF were increased (P<0.05, P<0.01) in the EA group. CONCLUSIONS: EA can alleviate learning and memory impairment in IR rats, which may be related to its function in up-regulating the expression of tPA protein and promoting the transformation of proBDNF to mBDNF, thus improving the synaptic plasticity.

Caffeic acid attenuates memory dysfunction and restores the altered activity of cholinergic, monoaminergic and purinergic in brain of cadmium chloride exposure rats.

OBJECTIVES: This study aims to evaluate the neuroprotective effect of caffeic acid (CAF) against cadmium chloride (CdCl2) in rats via its effect on memory index as well as on altered enzymatic activity in the brain of CdCl2-induced neurotoxicity. METHODS: The experimental rats were divided into seven groups (n=6 rats per group) of healthy rats (group 1), CdCl2 -induced (CD) (3 mg/kg BW) rats (group 2), CD rats + Vitamin C (group 3), CD rats + CAF (10 and 20 mg/kg BW respectively) (group 4 & 5), and healthy rat + CAF (10 and 20 mg/kg BW respectively) (group 6 & 7). Thereafter, CdCl2 and CAF were administered orally to the experimental rats in group 2 to group 5 on daily basis for 14 days. Then, the Y-maze test was performed on the experimental rats to ascertain their memory index. RESULTS: CdCl2 administration significantly altered cognitive function, the activity of cholinesterase, monoamine oxidase, arginase, purinergic enzymes, nitric oxide (NOx), and antioxidant status of Cd rats (untreated) when compared with healthy rats. Thereafter, CD rats treated with vitamin C and CAF (10 and 20 mg/kg BW) respectively exhibited an improved cognitive function, and the observed altered activity of cholinesterase, monoamine oxidase, arginase, purinergic were restored when compared with untreated CD rats. Also, the level of brain NOx and antioxidant status were significantly (p<0.05) enhanced when compared with untreated CD rats. In the same vein, CAF administration offers neuro-protective effect in healthy rats vis-à-vis improved cognitive function, reduction in the activity of some enzymes linked to the progression of cognitive dysfunction, and improved antioxidant status when compared to healthy rats devoid of CAF. CONCLUSIONS: This study demonstrated the neuroprotective effect of CAF against CdCl2 exposure and in healthy rats.

Acteoside ameliorates learning and memory impairment in APP/PS1 transgenic mice by increasing Aß degradation and inhibiting tau hyperphosphorylation.

Alzheimer's disease (AD) is a neurodegenerative disease. Senile plaques and intracellular neurofibrillary tangles are pathological hallmarks of AD. Recent studies have described the improved cognitive and neuroprotective functions of acteoside (AS). This study aimed to investigate whether the improved cognition of AS was mediated by Aß degradation and tau phosphorylation in APP/PS1 mice. The open field, Y maze, and novel object recognition tests were used to assess cognitive behavioral changes. We evaluated the levels of Aß40 and Aß42 in serum, cortex, and hippocampus, and Aß-related scavenging enzymes, phosphorylated GSK3ß and hyperphosphorylated tau in the cortex and hippocampus of APP/PS1 mice by western blotting. Our results revealed that AS treatment ameliorated anxious behaviors, spatial learning, and memory impairment in APP/PS1 mice and significantly reduced Aß deposition in their serum, cortex, and hippocampus. AS significantly increased Aß degradation, inhibited the hyperphosphorylation of tau, and significantly decreased the activity of GSK3ß, which is involved in tau phosphorylation. Altogether, these findings indicated that the beneficial effects of AS on AD-associated anxious behaviors and cognitive impairments could be attributed to promoting Aß degradation and inhibiting tau hyperphosphorylation, which might be partly mediated by GSK3ß.

LPC20K modified from krill oil ameliorates the scopolamine-induced cognitive impairment.

Alzheimer's disease (AD) is characterized by cognitive impairment. It is common in the elderly. Etiologically, dysfunction of cholinergic neurotransmitter system is prominent in AD. However, disease modifying drug for AD is still unavailable. We hypothesized that krill oil and modified krill oil containing 20 % lysophosphatidylcholine-docosahexaenoic acid (LPC-DHA, LPC20K) could play a crucial role in AD by improving cognitive functions measured by several behavioral tests. We found that LPC20K could ameliorate short-term, long-term, spatial, and object recognition memory under cholinergic hypofunction states. To find the underlying mechanism involved in the effect of LPC20K on cognitive function, we investigated changes of signaling molecules using Western blotting. Expression levels of protein kinase C zeta (PKCζ) and postsynaptic density protein 95 (PSD-95), and phosphorylation levels of extracellular signal-regulated kinase (ERK), Ca2+/calmodulin-dependent protein kinase Ⅱ (CaMKⅡ), and cAMP response element-binding protein (CREB) were significantly increased in LPC20K-administered group compared to those in the memory impairment group. Moreover, the expression levels of BDNF were temporally increased especially 6 or 9 h after administration of LPC20K compared with the control group. These results suggest that LPC20K could ameliorate memory impairment caused by hypocholinergic state by enhancing the expression levels of PKCζ and PSD-95, and phosphorylation levels of ERK, CaMKⅡ and CREB and increasing BDNF expression levels. Therefore, LPC20K could be used as a dietary supplement against cognitive impairment observed in diseases such as AD with a hypocholinergic state.

Icariin improves learning and memory function in Aß1-42-induced AD mice through regulation of the BDNF-TrκB signaling pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Epimedium brevicornu Maxim. is a traditional medicinal Chinese herb that is enriched with flavonoids, which have remarkably high medicinal value. Icariin (ICA) is a marker compound isolated from the total flavonoids of Epimedium brevicornu Maxim. It has been shown to improve Neurodegenerative disease, therefore, ICA is probably a potential drug for treating AD. MATERIALS AND METHODS: The 6-8-week-old SPF-class male ICR mice were randomly divided into 8 groups for modeling, and then the mice were administered orally with ICA for 21 days. The behavioral experiments were conducted to evaluate if learning and memory behavior were absent in mice, confirming that infusion of Amyloid ß-protein (Aß)1-42 caused significant memory impairment. The morphological changes and damage of neurons in the mice's brains were observed by HE and Nissl staining. The spinous protrusions (dendritic spines) on neuronal dendrites were investigated by Golgi-Cox staining. The molecular mechanism of ICA was examined by Western Blot. The protein docking of ICA and Donepezil with BDNF were analyzed to determine their interaction. RESULTS: The behavioral experimental results showed that in Aß1-42-induced AD mice, the learning and memory abilities were improved after using ICA. At the same time, the low, medium, and high doses of ICA could reduce the content of Aß1-42 in the hippocampus of AD mice, repair neuronal damage, enhance synaptic plasticity, as well as increase the expression of BDNF, TrκB, CREB, Akt, GAP43, PSD95, and SYN proteins in the hippocampus of mice. However, the effect with high doses of ICA is more pronounced. The high-dose administration of ICA has the best therapeutic effect on AD mice. After administering the inhibitor k252a, the therapeutic effect of ICA was reversed. The macromolecular docking results of ICA and BDNF protein demonstrated a strong interaction of -7.8 kcal/mol, which indicates that ICA plays a therapeutic role in AD mice by regulating the BDNF-TrκB signaling pathway. CONCLUSIONS: The results confirm that ICA can repair neuronal damage, enhance synaptic plasticity, as well as ultimately improve learning and memory impairment through the regulation of the BDNF-TrκB signaling pathway.

Post-operative cognitive dysfunction is exacerbated by high-fat diet via TLR4 and prevented by dietary DHA supplementation.

Post-operative cognitive dysfunction (POCD) is an abrupt decline in neurocognitive function arising shortly after surgery and persisting for weeks to months, increasing the risk of dementia diagnosis. Advanced age, obesity, and comorbidities linked to high-fat diet (HFD) consumption such as diabetes and hypertension have been identified as risk factors for POCD, although underlying mechanisms remain unclear. We have previously shown that surgery alone, or 3-days of HFD can each evoke sufficient neuroinflammation to cause memory deficits in aged, but not young rats. The aim of the present study was to determine if HFD consumption before surgery would potentiate and prolong the subsequent neuroinflammatory response and memory deficits, and if so, to determine the extent to which these effects depend on activation of the innate immune receptor TLR4, which both insults are known to stimulate. Young-adult (3mo) & aged (24mo) male F344xBN F1 rats were fed standard chow or HFD for 3-days immediately before sham surgery or laparotomy. In aged rats, the combination of HFD and surgery caused persistent deficits in contextual memory and cued-fear memory, though it was determined that HFD alone was sufficient to cause the long-lasting cued-fear memory deficits. In young adult rats, HFD + surgery caused only cued-fear memory deficits. Elevated proinflammatory gene expression in the hippocampus of both young and aged rats that received HFD + surgery persisted for at least 3-weeks after surgery. In a separate experiment, rats were administered the TLR4-specific antagonist, LPS-RS, immediately before HFD onset, which ameliorated the HFD + surgery-associated neuroinflammation and memory deficits. Similarly, dietary DHA supplementation for 4 weeks prior to HFD onset blunted the neuroinflammatory response to surgery and prevented development of persistent memory deficits. These results suggest that HFD 1) increases risk of persistent POCD-associated memory impairments following surgery in male rats in 2) a TLR4-dependent manner, which 3) can be targeted by DHA supplementation to mitigate development of persistent POCD.

Neuroprotective Effects of N-methyl-(2S, 4R)-trans-4-hydroxy-L-proline (NMP) against Amyloid-ß-Induced Alzheimer's Disease Mouse Model.

Alzheimer's disease (AD), is a progressive neurodegenerative disorder that involves the deposition of ß-amyloid plaques and the clinical symptoms of confusion, memory loss, and cognitive dysfunction. Despite enormous progress in the field, no curative treatment is available. Therefore, the current study was designed to determine the neuroprotective effects of N-methyl-(2S, 4R)-Trans-4-hydroxy-L-proline (NMP) obtained from Sideroxylon obtusifolium, a Brazilian folk medicine with anti-inflammatory and anti-oxidative properties. Here, for the first time, we explored the neuroprotective role of NMP in the Aß1-42-injected mouse model of AD. After acclimatization, a single intracerebroventricular injection of Aß1-42 (5 µL/5 min/mouse) in C57BL/6N mice induced significant amyloidogenesis, reactive gliosis, oxidative stress, neuroinflammation, and synaptic and memory deficits. However, an intraperitoneal injection of NMP at a dose of (50 mg/kg/day) for three consecutive weeks remarkably decreased beta secretase1 (BACE-1) and Aß, activated the astrocyte and microglia expression level as well as downstream inflammatory mediators such as pNF-ĸB, TNF-α, and IL-1ß. NPM also strongly attenuated oxidative stress, as evaluated by the expression level of NRF2/HO-1, and synaptic failure, by improving the level of both the presynaptic (SNAP-25 and SYN) and postsynaptic (PSD-95 and SNAP-23) regions of the synapses in the cortexes and hippocampi of the Aß1-42-injected mice, contributing to cognitive improvement in AD and improving the behavioral deficits displayed in the Morris water maze and Y-maze. Overall, our data suggest that NMP provides potent multifactorial effects, including the inhibition of amyloid plaques, oxidative stress, neuroinflammation, and cognitive deficits.

Enhanced neuronal activity by suffruticosol A extracted from Paeonia lactiflora via partly BDNF signaling in scopolamine-induced memory-impaired mice.

Neurodegenerative diseases are explained by progressive defects of cognitive function and memory. These defects of cognition and memory dysfunction can be induced by the loss of brain-derived neurotrophic factors (BDNF) signaling. Paeonia lactiflora is a traditionally used medicinal herb in Asian countries and some beneficial effects have been reported, including anti-oxidative, anti-inflammatory, anti-cancer activity, and potential neuroprotective effects recently. In this study, we found that suffruticosol A is a major compound in seeds of Paeonia lactiflora. When treated in a SH-SY5 cell line for measuring cell viability and cell survival, suffruticosol A increased cell viability (at 20 µM) and recovered scopolamine-induced neurodegenerative characteristics in the cells. To further confirm its neural amelioration effects in the animals, suffruticosol A (4 or 15 ng, twice a week) was administered into the third ventricle beside the brain of C57BL/6 mice for one month then the scopolamine was intraperitoneally injected into these mice to induce impairments of cognition and memory before conducting behavioral experiments. Central administration of suffruticosol A into the brain restored the memory and cognition behaviors in mice that received the scopolamine. Consistently, the central treatments of suffruticosol A showed rescued cholinergic deficits and BDNF signaling in the hippocampus of mice. Finally, we measured the long-term potentiation (LTP) in the hippocampal CA3-CA1 synapse to figure out the restoration of the synaptic mechanism of learning and memory. Bath application of suffruticosol A (40 µM) improved LTP impairment induced by scopolamine in hippocampal slices. In conclusion, the central administration of suffruticosol A ameliorated neuronal effects partly through elevated BDNF signaling.

Myricetin improves pathological changes in 3×Tg-AD mice by regulating the mitochondria-NLRP3 inflammasome-microglia channel by targeting P38 MAPK signaling pathway.

BACKGROUND: Alzheimer's disease (AD) represents the common neurodegenerative disease featured by the manifestations of cognitive impairment and memory loss. AD could be alleviated with medication and improving quality of life. Clinical treatment of AD is mainly aimed at improving the cognitive function of patients. Donepezil, memantine and galantamine are commonly used drug. But they could only relieve AD, not cure it. Therefore, new treatment strategies focusing on AD pathogenesis are of great significance and value. Myricetin (Myr) is a natural flavonoid extracted from Myrica rubra. And it shows different bioactivities, such as anti-inflammation, antioxidation as well as central nervous system (CNS) activities. Nonetheless, its associated mechanism in treating AD remains unknown. PURPOSE: Here we focused on investigating Myr's effect on treating AD and exploring if its protection on the nervous system activity was associated with specifically inhibiting P38 MAPK signaling pathway while regulating mitochondria-NLRP3 inflammasome-microglia. STUDY DESIGN AND METHODS: This work utilized triple transgenic mice (3 × Tg-AD) as AD models and Aß25-35 was used to induce BV2 cells to build an in vitro AD model. Behavioristics, pathology and related inflammatory factors were examined. Molecular mechanisms are investigated by western-blot, immunofluorescence staining, CETSA, molecular docking, network pharmacology. RESULTS: According to our findings, Myr could remarkably improve memory loss, spatial learning ability, Aß plaque deposition, neuronal and synaptic damage in 3 × Tg-AD mice through specifically inhibiting P38 MAPK pathway activation while restraining microglial hyperactivation. Furthermore, Myr promoted the transformation of microglial phenotype, restored the mitochondrial fission-fusion balance, facilitated mitochondrial biogenesis, and restrained NLRP3 inflammasome activation and neuroinflammation. For the in-vitro experiments, P38 agonist dehydrocorydaline (DHC) was utilized to confirm the key regulatory role of P38 MAPK signaling pathway on the mitochondria-NLRP3 inflammasome-microglia channel. CONCLUSIONS: Our results revealed the therapeutic efficacy of Myr in experimental AD, and implied that the associated mechanism is possibly associated with inhibiting tmitochondrial dysfunction, activating NLRP3 inflammasome, and neuroinflammation which was mediated by P38 MAPK pathway. Myr is the drug candidate in AD therapy via targeting P38 MAPK pathway.

17ß-oestradiol inhibits ferroptosis in the hippocampus by upregulating DHODH and further improves memory decline after ovariectomy.

Ovariectomy (OVX) conducted before the onset of natural menopause is considered to bringing forward and accelerate the process of ageing-associated neurodegeneration. However, the mechanisms underlying memory decline and other cognitive dysfunctions following OVX are unclear. Given that iron accumulates during ageing and after OVX, we hypothesized that excess iron accumulation in the hippocampus would cause ferroptosis-induced increased neuronal degeneration and death associated with memory decline. In the current study, female rats that underwent OVX showed decreased dihydroorotate dehydrogenase (DHODH) expression and reduced performance in the Morris water maze (MWM). We used primary cultured hippocampal cells to explore the ferroptosis resistance-inducing effect of 17ß-oestradiol (E2). The data supported a vital role of DHODH in neuronal ferroptosis. Specifically, E2 alleviated ferroptosis induced by erastin and ferric ammonium citrate (FAC), which can be blocked by brequinar (BQR). Further in vitro studies showed that E2 reduced lipid peroxidation levels and improved the behavioural performance of OVX rats. Our research interprets OVX-related neurodegeneration with respect to ferroptosis, and both our in vivo and in vitro data show that E2 supplementation exerts beneficial antiferroptotic effects by upregulating DHODH. Our data demonstrate the utility of E2 supplementation after OVX and provide a potential target, DHODH, for which hormone therapy has not been available.

Extract of Aster koraiensis Nakai Leaf Ameliorates Memory Dysfunction via Anti-inflammatory Action.

Aster koraiensis Nakai (AK) leaf reportedly ameliorates health problems, such as diabetes. However, the effects of AK on cognitive dysfunction or memory impairment remain unclear. This study investigated whether AK leaf extract could attenuate cognitive impairment. We found that AK extract reduced the production of nitric oxide (NO), tumour necrosis factor (TNF)-α, phosphorylated-tau (p-tau), and the expression of inflammatory proteins in lipopolysaccharide- or amyloid-ß-treated cells. AK extract exhibited inhibitory activity of control specific binding on N-methyl-D-aspartate (NMDA) receptors. Scopolamine-induced AD models were used chronically in rats and acutely in mice. Relative to negative controls (NC), hippocampal choline acetyltransferase (ChAT) and B-cell lymphoma 2 (Bcl2) activity was increased in rats chronically treated with scopolamine and fed an AK extract-containing diet. In the Y-maze test, spontaneous alterations were increased in the AK extract-fed groups compared to NC. Rats administered AK extract showed increased escape latency in the passive avoidance test. In the hippocampus of rats fed a high-AK extract diet (AKH), the expression of neuroactive ligand-receptor interaction-related genes, including Npy2r, Htr2c, and Rxfp1, was significantly altered. In the Morris water maze assay of mice acutely treated with scopolamine, the swimming times in the target quadrant of AK extract-treated groups increased significantly to the levels of the Donepezil and normal groups. We used Tg6799 Aß-overexpressing 5XFAD transgenic mice to investigate Aß accumulation in animals. In the AD model using 5XFAD, the administration of AK extract decreased amyloid-ß (Aß) accumulation and increased the number of NeuN antibody-reactive cells in the subiculum relative to the control group. In conclusion, AK extract ameliorated memory dysfunction by modulating ChAT activity and Bcl2-related anti-apoptotic pathways, affecting the expression of neuroactive ligand-receptor interaction-related genes and inhibiting Aß accumulation. Therefore, AK extract could be a functional material improving cognition and memory.

The neuroprotective effect of ginsenoside Rb1 on the cerebral cortex changes induced by aluminium chloride in a mouse model of Alzheimer's disease: A histological, immunohistochemical, and biochemical study.

Alzheimer's disease (AD) is one of the most common types of dementia among neurodegenerative disorders characterized by attention deficits and memory loss. Panax ginseng is a traditional Chinese herbal remedy that has been employed for millennia to manage dementia linked with aging and memory impairment. Ginsenoside Rb1 is one of Panax ginseng's most abundant components. The present work evaluated the neuroprotective effects of ginsenoside Rb1 on the cerebral cortex of AlCl3-induced AD in adult male albino mice. Forty male mice were alienated arbitrarily into; control group, ginsenoside Rb1 group (70 mg/kg/day), AlCl3 group (50 mg/kg/day), and ginsenoside Rb1-AlCl3 group that received ginsenoside Rb1 one hour before AlCl3. Oxidative stress parameters, Amyloid ß (Aß) and phosphorylated tau protein, and acetylcholine esterase (AChE) activity were measured. Cerebral cortex sections were evaluated histologically by light microscopic examination and immunohistochemistry. AlCl3-induced memory impairment, Aß and phosphorylated tau protein accumulation, and AChE elevation. Moreover, histopathological alterations in the cerebral cortex were reported in the form of irregular shrunken neurons and the surrounding neuropil showed vacuolation. Some neurons appeared with darkly stained nuclei, others had faintly stained ones. The synaptophysin expression was significantly decreased, while the expression of cleaved caspase-3, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were significantly elevated. It's interesting to note that these changes were attenuated in mice pretreated with ginsenoside Rb1. Collected data indicated that ginsenoside Rb1 showed a potential neuroprotective effect against cerebral cortex changes caused by AlCl3 via suppression of Amyloid ß and phosphorylated tau protein formation, oxidative stress correction, anti-apoptotic effect, and by minimizing gliosis.

Theaflavin-3,3'-digallate ameliorates learning and memory impairments in mice with premature brain aging induced by D-galactose.

Age-related neurodegenerative diseases accompanied by learning and memory deficits are growing in prevalence due to population aging. Cellular oxidative stress is a common pathomechanism in multiple age-related disorders, and various antioxidants have demonstrated therapeutic efficacy in patients or animal models. Many plants and plant extracts possess potent antioxidant activity, but the compounds responsible are frequently unknown. Identification and evaluation of these phytochemicals is necessary for optimal targeted therapy. A recent study identified theaflavin-3,3'-digallate (TFDG) as the most potent among a large series of phytochemical antioxidants. Here we examined if TFDG can mitigate learning and memory impairments in the D-galactose model of age-related neurodegeneration. Experimental mice were injected subcutaneously with D-galactose (120 mg/kg) for 56 days. In treatment groups, different doses of TFDG were administered daily by gavage starting on day 29 of D-galactose injection. Model mice exhibited poor learning and memory in the novel object recognition and Y-maze tests, reduced brain/body mass ratio, increased brain glutamate concentration and acetylcholinesterase activity, decreased brain acetylcholine concentration, and lower choline acetyltransferase, glutaminase, and glutamine synthetase activities. Activities of antioxidant enzymes glutathione peroxidase and superoxide dismutase were also reduced, while the concentration of malondialdehyde, a lipid peroxidation product, was elevated. Further, antioxidant genes Nrf2, Prx2, Gsh-px1, and Sod1 were downregulated in brain. Each one of these changes was dose-dependently reversed by TFDG. TFDG is an effective antioxidant response inducer and neuroprotectant that can restore normal neurotransmitter metabolism and ameliorate learning and memory dysfunction in the D-galactose model of age-related cognitive decline.

Red-light radiation: does it enhance memory by increasing hippocampal LRP-1 and TRPA-1 genes expression?

PURPOSE: Despite the extensive efforts to treat the leading cause of neurodegenerative diseases (ND), a little progress has been reported. Red light might affect ND through many specific mechanisms. The purpose of this investigation is to explore the effect of red light on the expression of low-density lipoprotein receptor-1 (LRP-1) and transient receptor potential ankyrin-1 (TRPA-1) gene in the hippocampus, and the serum melatonin level (SML) of the lipopolysaccharide (LPS)-induced neuro-inflammated rats. MATERIALS AND METHODS: Red-light therapy was implemented using a wavelength 630 nm under different light conditions and the passive avoidance (PA) and Y-Maze tests were employed to assess memory performance. To evaluate the LRP-1 and TRPA-1 genes expression, quantitive real-time polymerase chain reaction was performed. To measure the SML, ELISA was performed before and after the red-light radiation. RESULTS: LPS caused memory impairment in both behavioral tests. Red-light therapy improved PA memory in all light conditions (p < .001). However, in Y-maze, only the red-light radiation during light and dark cycles, improved memory (p < .01 and p < .001, respectively). In addition, red-light radiation caused significant increase in SML (p < .05). The LRP-1 and TRPA-1 genes expression increased significantly during the dark phase in the red light radiated group compared to non-radiated group (p < .001). CONCLUSIONS: Taken together, the results suggest that red-light therapy can reduce the complications of memory impairment in rats. This study has found that red-light therapy demonstrates higher effect during the period of dark phase compared to light phase. No doubt, further experimental studies would help us to establish a greater degree of accuracy on this matter.

Cajanus cajan (L) Millsp. seed extract ameliorates scopolamine-induced amnesia through increase in antioxidant defense mechanisms and cholinergic neurotransmission.

Decline in cholinergic function and oxidative/nitrosative stress play a central role in Alzheimer's disease (AD). Previous quantitative HPLC profiling analysis has revealed the presence of Pinostrobin, formononetin, vitexin and other neuroprotective flavonoids in Cajanus cajan seed extract. This study was designed to investigate the protective action of Cajanus cajan ethanol seed extract (CC) on learning and memory functions using scopolamine mouse model of amnesia. Materials and methods: Adult mice were pretreated with CC (50, 100, or 200mg/kg, p.o) or vehicle (10ml/kg, p.o) for 16 days consecutively. Scopolamine, a competitive muscarinic cholinergic receptor antagonist (1mg/kg, i.p.) was given an hour after CC pretreatment from days 3 to 16.  The mice were subjected to behavioural tests from day 11 (open field test (OFT)/ Y-maze test (YMT) and Morris water maze task (MWM) from days 12-16. Animals were euthanized 1h after behavioral test on day 16 and discrete brain regions isolated for markers of oxidative stress and cholinergic signaling. Molecular docking analysis was undertaken to predict the possible mechanism(s) of CC-induced anti-amnesic action.  pre-administration of CC significantly reversed working memory and learning deficits caused by scopolamine in YMT and MWM tests, respectively. Moreover, CC prevented scopolamine-induced oxidative and nitrosative stress radicals in the hippocampus evidenced in significant increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities with a marked decrease in malondialdehyde (MDA) production, as well as significant inhibition of hippocampal scopolamine-induced increase in acetylcholinesterase activity by CC. The molecular docking analysis showed that out of the 19 compounds, the following had the highest binding affinity; Pinostrobin (-8.7 Kcal/mol), friedeline (-7.5kCal/mol), and lupeol (-8.2 Kcal/mol), respectively, to neuronal muscarinic M1 acetylcholine receptor, α7 nicotinic acetylcholine receptor and amyloid beta peptide binding pockets, which further supports the ability of CC to enhance neuronal cholinergic signaling and possible inhibition of amyloid beta aggregation. This study showed that Cajanus cajan seeds extract improved working memory and learning through enhancement of cholinergic signaling, antioxidant capacity and reduction in amyloidogenesis.

The Potential Neuroprotective Effect of Cyperus esculentus L. Extract in Scopolamine-Induced Cognitive Impairment in Rats: Extensive Biological and Metabolomics Approaches.

The aim of the present study is to investigate the phytochemical composition of tiger nut (TN) (Cyperus esculentus L.) and its neuroprotective potential in scopolamine (Scop)-induced cognitive impairment in rats. The UHPLC-ESI-QTOF-MS analysis enabled the putative annotation of 88 metabolites, such as saccharides, amino acids, organic acids, fatty acids, phenolic compounds and flavonoids. Treatment with TN extract restored Scop-induced learning and memory impairments. In parallel, TN extract succeeded in lowering amyloid beta, ß-secretase protein expression and acetylcholine esterase (AChE) activity in the hippocampus of rats. TN extract decreased malondialdehyde levels, restored antioxidant levels and reduced proinflammatory cytokines as well as the Bax/Bcl2 ratio. Histopathological analysis demonstrated marked neuroprotection in TN-treated groups. In conclusion, the present study reveals that TN extract attenuates Scop-induced memory impairments by diminishing amyloid beta aggregates, as well as its anti-inflammatory, antioxidant, anti-apoptotic and anti-AChE activities.

Acupuncture Interventions for Alzheimer's Disease and Vascular Cognitive Disorders: A Review of Mechanisms.

Cognitive impairment (CI) related to Alzheimer's disease (AD) and vascular cognitive disorders (VCDs) has become a key problem worldwide. Importantly, CI is a neuropsychiatric abnormality mainly characterized by learning and memory impairments. The hippocampus is an important brain region controlling learning and memory. Recent studies have highlighted the effects of acupuncture on memory deficits in AD and VCDs. By reviewing the literature published on this topic in the past five years, the present study intends to summarize the effects of acupuncture on memory impairment in AD and VCDs. Focusing on hippocampal synaptic plasticity, we reviewed the mechanisms underlying the effects of acupuncture on memory impairments through regulation of synaptic proteins, AD characteristic proteins, intestinal microbiota, neuroinflammation, microRNA expression, orexin system, energy metabolism, etc., suggesting that hippocampal synaptic plasticity may be the common as well as the core link underlying the above mechanisms. We also discussed the potential strategies to improve the effect of acupuncture. Additionally, the effects of acupuncture on synaptic plasticity through the regulation of vascular-glia-neuron unit were further discussed.

Brassica rapa L. (Tibetan turnip) prevents sleep-deprivation induced cognitive deficits via the inhibition of neuroinflammation and mitochondrial depolarization.

Brassica rapa L., an edible, feeding and medicinal plant cultivated on the Tibetan plateau with altitudes above 3800 m, has several pharmacological effects. However, its therapeutic effects against memory impairment and central fatigue have yet to be conclusively established. In this study, the Y-maze and Morris water maze tasks revealed that Brassica rapa L. aqueous extract (BE) significantly ameliorated cognitive deficits of sleep deprivation (SD)-treated mice. Moreover, BE treatment partially alleviated SD-induced reductions in the levels of peripheral energy metabolism, and significantly decreased inflammatory factor levels in serum and hippocampus. In addition, BE treatment significantly relieved central fatigue and stabilized the excitability as well as activities of neurons by regulating the levels of hypothalamus tryptophan metabolites and striatum neurotransmitters. The neuroprotective effects of BE were also confirmed using glutamate-treated HT22 cells, whereby BE pretreatment significantly attenuated intracellular ROS production and mitochondrial depolarization via adenosine 5'-monophosphate activated protein kinase/peroxisome proliferators-activated receptors (AMPK/PPAR-γ) signaling pathways. Thus, BE might probably prevent SD-induced learning and memory deficits by inhibiting neuroinflammation and restoring mitochondrial energy metabolism in the hippocampus. These findings imply that BE is a potential complementary therapy for those suffering from deficient sleep or neurometabolic disorders, although this needs verification by prospective clinical studies.

Patchouli alcohol ameliorates the learning and memory impairments in an animal model of Alzheimer's disease via modulating SIRT1.

BACKGROUND: Alzheimer's disease (AD) is one of the most prevalent neurodegenerative diseases. Patchouli alcohol (PA), a major active ingredient isolated from Pogostemonis Herba, exhibits extensive bioactivity in the central nervous system (CNS) and exerts neuroprotective effects. PURPOSE: This study aimed to investigate the anti-AD effects of PA in an animal model of AD and to elucidate the underlying molecular mechanisms. METHODS: The gas chromatography (GC) was used to determine the ability of PA to pass the blood-brain barrier (BBB) in rats after oral administration. The sporadic AD rat model was established by intracerebroventricularly (ICV) injection with streptozotocin (STZ). PA (25 and 50 mg/kg) was given to rat orally once daily for 42 consecutive days. Morris water maze (MWM) test was performed to determine the learning and memory functions of the STZ-induced AD rats. EX527, a silent information regulator 1 (SIRT1) selective inhibitor, was used to investigate the involvement of SIRT1 in the anti-AD effects of PA in rats. RESULTS: PA could penetrate the BBB. MWM test results showed that PA could significantly ameliorate the learning and memory deficits induced by STZ in rats. Meanwhile, PA enhanced the expression of SIRT1, and markedly alleviated the tau pathology by inhibiting the hyperacetylation (at the site of Lys174) and hyperphosphorylation (at the sites of Thr181, Thr205, Ser396 and Ser404) of tau protein. PA also efficiently suppressed the activation of microglia and astrocytes, and the beta-amyloid (Aß) expression and the deacetylation of nuclear factor-kappa B (NF-κB) at Lys 310 (K310) in the STZ-treated AD rats. EX527, a SIRT1 selective inhibitor, could partially abolish the cognitive deficits improving effect of PA and inhibit the down-regulation of acetylated tau and acetylated NF-κB p65, suggesting that PA exhibited neuroprotective effects against AD via upregulating SIRT1. CONCLUSION: This study reported for the first time that PA could penetrate the BBB to exert its protective effects on the brain after a single-dose oral administration. The current experimental findings also amply demonstrated that PA could improve the cognitive and memory impairments in the STZ-induced AD rat model. The underlying mechanisms involve the alleviations of neuroinflammation, tau pathology and Aß deposition via modulating of SIRT1 and NF-κB pathways. All these findings strongly suggest that PA is a promising naturally occurring compound worthy of further development into an anti-AD pharmaceutical.

The effect of electroacupuncture on the expression of Sirt1 and STAT3 in hippocampus and amygdala of vascular dementia rats.

OBJECTIVE: Inflammation has long been considered a key factor in learning and memory impairment in patients with vascular dementia (VaD). Studies have confirmed that electroacupuncture can improve the learning and memory impairment of patients with VaD by reducing inflammation, but the specific mechanism of this effect is still unclear. The aim of this study was to explore the underlying mechanism of electroacupuncture in the treatment of VaD. METHODS: The vascular dementia animal model was established by bilateral occlusion of common carotid arteries, and electroacupuncture treatment was given at Baihui (DU20) and Zusanli (ST36). The morris water maze (MWM) was used to test the spatial learning and memory ability of rats in each group. To evaluate the expression of Sirtuin1 (Sirt1), Signal transducer and activator of transcription 3 (STAT3) and inflammatory cytokine (IL-17) in the hippocampus and amygdala, immunohistochemistry and western blot were performed. RESULTS: The MWM test and Nissl staining results show that electroacupuncture can significantly improve the learning and memory impairment of VaD rats, and can repair damaged neurons. Immunohistochemistry and western blot results showed that electroacupuncture could enhance the expression of sirt1 in VaD rats, on the contrary, the expression of STAT3 and IL-17 was reduced due to electroacupuncture. CONCLUSIONS: The result suggests that electroacupuncture can suppress inflammation through the Sirt1/STAT3 pathway and improve spatial learning and memory in VaD rats.