Ameliorates Memory Impairment Research Articles

Curcumin-loaded chitosan-alginate-STPP nanoparticles ameliorate memory deficits and reduce glial activation in pentylenetetrazol-induced kindling model of epilepsy

Despite several beneficial effects of curcumin, its medical application has been hampered due to low water solubility. To improve the aqueous solubility of curcumin, it has been loaded on chitosan (CS)-alginate (ALG) - sodium tripolyphosphate (STPP) nanoparticles (NPs). Then, the effect of curcumin NPs on memory improvement and glial activation was investigated in pentylenetetrazol (PTZ)-induced kindling model. Male NMRI mice have received the daily injection of curcumin NPs at dose of 12.5 or 25mg/kg. All interventions were injected intraperitoneally (i.p), 10days before PTZ administration and the injections were continued until 1h before each PTZ injection. Spatial learning and memory was evaluated using Morris water maze test after the 7th PTZ injection. Animals have received 10 injections of PTZ and then, brain tissues were removed for histological evaluation. Nissl staining was used to determine the level of cell death in hippocampus and immunostaining method was performed against NeuN and GFAP/Iba1 for assessment of neuronal density and glial activation respectively. Behavioral results showed that curcumin NPs exhibit anticonvulsant activity and prevent cognitive impairment in fully kindled animals. The level of cell death and glial activation reduced in animals which have received curcumin NPs compared to those received free curcumin. To conclude, these findings suggest that curcumin NPs effectively ameliorate memory impairment and attenuate the level of activated glial cells in a mice model of chronic epilepsy.

(-)-Epigallocatechin-3-gallate ameliorates memory impairment and rescues the abnormal synaptic protein levels in the frontal cortex and hippocampus in a mouse model of Alzheimer's disease.

(-)-Epigallocatechin-3-gallate (EGCG) is the most abundant polyphenolic extract in green tea and it has attracted increasing attention for its multiple bioactive effects. However, the mechanisms by which EGCG exerts its neuroprotective actions in Alzheimer's disease (AD) are presently lacking. In the present study, a sporadic AD transgenic mouse model known as senescence-accelerated mouse prone 8 (SAMP8) was used to investigate whether oral administration of EGCG could improve recognition and memory function through reduction of amyloid β (Aβ) and tau hyperphosphorylation. We also investigated the effects of chronic EGCG treatment on the synaptic dysfunction in the frontal cortex (FC) and the hippocampus (Hip) of AD mice. The results showed that long-term oral consumption of EGCG at a relatively high dose (15 mg/kg) improved memory function in SAMP8 mice in the Y-maze and Morris water maze. The levels of Aβ1-42 and BACE-1 in FC and Hip were significantly reduced by EGCG treatment. EGCG treatment also prevented the hyperphosphorylation of tau and reversed the decreased synaptic protein marker synaptophysin and postsynaptic density protein 95 in FC and Hip of SAMP8 mice. The present study suggests that long-term oral consumption of EGCG ameliorates impairments in spatial learning and memory and rescues the reduction in synaptic proteins observed in an AD mouse model. Thus, EGCG may represent a novel candidate agent for the treatment of neurodegenerative diseases.

Simvastatin ameliorates memory impairment and neurotoxicity in streptozotocin-induced diabetic mice

Diabetes comes with an additional burden of moderate to severe hyperlipidemia, but little is known about the effects of lipid-lowering therapy on diabetic complications such as diabetes-associated cognitive decline. Herein we investigated the effects of statins on memory impairment and neurotoxicity in streptozotocin-induced diabetic mice. Our data indicated that oral administration of simvastatin at 10 or 20mg/kg for 4weeks significantly ameliorated diabetes-associated memory impairment reflected by performance better in the Morris water maze and Y-maze tests. The further study showed that these treatments caused significant increase of peroxisome proliferator-activated receptors gamma and decrease of NF-κB p65 in nucleus of hippocampus and cortex, and ameliorated neuroinflammatory response as evidenced by less Iba-1-positive cells and lower inflammatory mediators including IL-1β, IL-6 and TNF-α as well as suppressed neuronal apoptosis as indicated by decreased TUNEL-positive cells, increased ratio of Bcl-2/Bax and decreased caspase-3 activity in the hippocampus and cortex. Moreover, simvastatin pronouncedly attenuated amyloidogenesis by decreasing amyloid-β, amyloid precursor protein (APP) and beta-site APP cleaving enzyme-1. As expected, treated with simvastatin, the diabetic mice exhibited significant improvement of hyperlipidemia rather than hyperglycemia. Our findings disclosed novel therapeutic potential of simvastatin for the diabetes-associated cognitive impairment.

Inhibitory effect of ethanol extract of Nannochloropsis oceanica on lipopolysaccharide-induced neuroinflammation, oxidative stress, amyloidogenesis and memory impairment.

Oxidative stress and neuroinflammation is implicated in the pathogenesis and development of Alzheimer's disease (AD). Here, we investigated the suppressive possibility of ethanol extract of Nannochloropsis oceanica (N. oceanica) on memory deficiency along with the fundamental mechanisms in lipopolysaccharide (LPS)-treated mice model. Among several extracts of 32 marine microalgae, ethanol extract of N. oceanica showed the most significant inhibitory effect on nitric oxide (NO) generation, NF-κB activity and β-secretase activity in cultured BV-2 cells, neuronal cells and Raw 264.7 cells. Ethanol extract of N. oceanica (50, 100 mg/kg) also ameliorated LPS (250 μg/kg)-induced memory impairment. We also found that ethanol extract of N. oceanica inhibited the LPS-induced expression of iNOS and COX-2. Furthermore, the production of reactive oxygen species (ROS), malondialdehyde (MDA) level as well as glutathione (GSH) level was also decreased by treatment of ethanol extract of N.oceanica. The ethanol extract of N. oceanica also suppresses IκB degradation as well as p50 and p65 translocation into the nucleus in LPS-treated mice brain. Associated with the inhibitory effect on neuroinflammation and oxidative stress, ethanol extract of N. oceanica suppressed Aβ1-42 generation through down-regulation of APP and BACE1 expression in in vivo. These results suggest that ethanol extract of N. oceanica ameliorated memory impairment via anti-inflammatory, anti-oxidant and anti-amyloidogenic mechanisms.

Adrenocorticotropic hormone protects learning and memory function in epileptic Kcna1-null mice

ACTH, a member of the melanocortin family of peptides, is often used in the treatment of the developmental epileptic encephalopathy spectrum disorders including, Ohtahara, West, Lennox Gastaut and Landau-Kleffner Syndromes and electrical status epilepticus of sleep. In these disorders, although ACTH is often successful in controlling the seizures and/or inter-ictal EEG abnormalities, it is unknown whether ACTH possesses other beneficial effects independent of seizure control. We tested whether ACTH can ameliorate the intrinsic impairment of hippocampal-based learning and memory in epileptic Kcna1-null (KO) mice. We found that ACTH − administered in the form of Acthar Gel given i.p. four times daily at a dose of 4 IU/kg (16 IU/kg/day) for 7days – prevented impairment of long-term potentiation (LTP) evoked with high-frequency stimulation in CA1 hippocampus and also restored spatial learning and memory on the Barnes maze test. However, with this treatment regimen, ACTH did not exert a significant effect on the frequency of spontaneous recurrent seizures. Together, our findings indicate that ACTH can ameliorate memory impairment in epileptic Kcna1-null mice separate from seizure control, and suggest that this widely used peptide may exert direct nootropic effects in the epileptic brain.

Effect of hachimijiogan on memory impairment induced by beta‐amyloid combined with cerebral ischemia in rats

ABSTRACTAimAlzheimer's disease (AD) is a chronic neurodegenerative condition most often found in older people. Cerebrovascular disease is commonly found in patients with AD. Hachimijiogan (HJG) is a herbal medicine commonly used to treat age‐related disease. The aim of this study was therefore to investigate whether HJG could improve memory impairment in rats treated with amyloid‐β protein (Aβ) and cerebral ischemia (Aβ + CI).MethodsRats were prepared by a combination of intracerebroventricular Aβ injection and transient cerebral ischemia. Spatial memory was evaluated on water maze and eight‐arm radial maze tasks. HJG (1000 mg/kg/day) or donepezil (DPZ; 10 mg/kg/day) was given orally once per day for 7 days before behavioral task assessment.Results HJG reduced the increased time to reach the platform position in Aβ + CI rats in the water maze task as well as DPZ did. Additionally, HJG reduced the increase in errors in Aβ + CI rats in the eight‐arm radial maze task as well as DPZ did.Conclusion HJG ameliorated memory impairment in Aβ + CI rats, indicating that it may be useful for treating AD.

Mechanisms of histamine ameliorating memory impairment induced by pentylenetetrazole-kindling epilepsy in rats

Objective: To investigate the effects of neuronal histamine on spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and to explore its mechanisms. Methods: A subconvulsive dose of pentylenetetrazole (35 mg/kg) was intraperitoneally injected in rats every 48 h to induce chemical kindling until fully kindled. Morris water maze was used to measure the spatial memory acquisition of the rats one week after fully pentylenetetrazole-kindled, and the histamine contents in different brain areas were measured spectrofluorometrically. Different dosages of hitidine (the precursor of histamine), pyrilamine (H1 receptor antagonist), and zolantidine (H2 receptor antagonist) were intraperitoneally injected, and their effects on spatial memory acquisition of the rats were observed. Results: Compared with control group, escape latencies were significantly prolonged on Morris water maze training day 2 and day 3 in pentylenetetrazole-kindling epilepsy rats (all P<0.05); and the histamine contents in hippocampus, thalamus and hypothalamus were decreased significantly (all P<0.05). Escape latencies were markedly shortened on day 3 by intraperitoneally injected with histidine 500 mg/kg, and on day 2 and day 3 by intraperitoneally injected with histidine 1000 mg/kg in pentylenetetrazole-kindling epilepsy rats (all P<0.05). The protection of histidine was reversed by zolantidine (10 and 20 mg/kg), but not by pyrilamine. Conclusion: Neuronal histamine can improve the spatial memory acquisition impairment in rats with pentylenetetrazole-kindling epilepsy, and the activation of H2 receptors is possibly involved in the protective effects of histamine.

Dietary Quercetin Ameliorates Memory Impairment in a Murine Model of Alzheimer’s Disease with Obesity and Diabetes, Suppressing ATF4 Expression

Background: While type 2 diabetes is a known risk factor for Alzheimer’s disease (AD), the underlying mechanism of this relationship remains unclear. In a previous study, we demonstrated that brain expression of activating transcription factor 4 (ATF4) is increased in aged (12- month-old) amyloid-β precursor protein (APP) 23 mice (APP) and in the young (3-month-old) offspring of APP mice crossed with obese and diabetic db/db mice (APP;db/db). On this premise, we examined the relationship between ATF4 expression and memory in APP;db/db mice. Methods and Findings: We demonstrate that ATF4 expression at 6-9 months of age was higher in the brains of APP;db/db mice than that in the brains of non-obese APP mice. Both APP and APP;db/db mice learned to discriminate contextual and auditory cues in contextual and auditory fear conditioning. However, novel object recognition (NOR) memory was impaired in APP;db/db mice, but was unaffected in APP mice. Five weeks of dietary supplementation with quercetin, which is a polyhydroxylated flavonoid, ameliorated NOR memory deficits in APP;db/db mice in association with suppressed ATF4 expression in the brain. Conclusion: These results indicate that dietary quercetin suppresses the obesity-induced ATF4 expression in the brain. Therefore, control of the integrated stress response (ISR) with biologically active compounds that reduce ATF4, such as quercetin, may be valuable for the treatment of memory impairments in early-stage AD, and particularly in cases with comorbid obesity and/or diabetes.

Anticonvulsant effect of piperine ameliorates memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy.

The primary active component of black pepper is piperine, which is purified and used to treat epilepsy, achieving higher efficiency when purified. The present study was conducted to evaluate whether the anticonvulsant effect of piperine ameliorates pilocarpine-induced epilepsy, and to investigate the mechanism underlying these effects. Epilepsy was induced in Sprague Dawley rats using pilocarpine. Pilocarpine-induced epilepsy in the rats was treated with 40 mg/kg piperine for 45 consecutive days. Status epilepticus and a Morris water maze test were used to analyze the anticonvulsant effects of piperine in the epileptic rats. Inflammation and oxidative stress were then measured using commercially-available kits following piperine treatment. Lastly, the activity of caspase-3 and the protein expression levels of B-cell lymphoma 2 (Bcl-2) and Bcl-2-associated X protein (Bax) were evaluated using commercially-available kits and western blot analysis, respectively. The results demonstrated that treatment with piperine was able to reduce the status epilepticus and prevented memory impairment following pilocarpine-induced epilepsy in rats. The anticonvulsant effects of piperine decreased inflammation and oxidative stress following pilocarpine-induced epilepsy in rats. The upregulated activity of caspase-3 and expression levels of Bax/Bcl-2 were suppressed following treatment with piperine in the rats with pilocarpine-induced epilepsy. These results suggest that the anticonvulsant effects of piperine ameliorate memory impairment, inflammation and oxidative stress in a rat model of pilocarpine-induced epilepsy.

Boosting weakened synapses to treat Alzheimer's disease.

This paper highlights a recent report by Roy and colleagues showing that boosting plasticity in synapses activated during initial memory encoding ameliorates memory impairments found in the early stages of the familial version of Alzheimer's disease. Our goal was to describe the main features of the report and evaluate the approach and implications of the work.

Dendropanax morbifera Léveille extract ameliorates memory impairments and inflammatory responses in the hippocampus of streptozotocin-induced type 1 diabetic rats

In this study, we investigated the effect of Dendropanax morbifera stem extract (DMS) on streptozotocin (STZ)-induced type 1 diabetic rats. The effect of DMS on memory function was assessed using the Morris water maze test. In addition, we investigated its effect on the microglial activation and subsequent release of pro-inflammatory cytokines such as tumor necrosis factor-α (TNF-α) and interleukin (IL)-1β in the hippocampus. Seven-week-old Wistar rats were exposed to 65 mg/kg STZ by intraperitoneal injection and 100 mg/kg of DMS was administered orally for 30 days. The administration of STZ significantly increased escape latency compared to the control group on all experimental days. Administration of DMS to STZ-treated rats significantly reduced the escape latency. Blood glucose levels significantly increased, while leptin levels significantly decreased in the STZ-treated rats compared to the control group. The administration of DMS to STZ-treated rats significantly ameliorated these changes in the levels of blood glucose and leptin. In addition, administration of DMS significantly increased the serum insulin levels in the STZ-treated rats, not in the control rats. Similarly, STZ treatment increased the morphological changes with hypertrophy of cytoplasm and processes in the hippocampal CA1 region, and significantly increased the levels of pro-inflammatory cytokines such as TNF-α and IL-1β levels in serum and hippocampal homogenates. Administration of DMS to STZ-treated rats significantly reduced the STZ-induced microglial activation and subsequent increase of TNF-α and IL-1β levels in the serum and hippocampal homogenates. These results indicate that DMS could prevent STZ-induced memory impairment by modulating the inflammatory responses in the hippocampus.

Biflorin Ameliorates Memory Impairments Induced by Cholinergic Blockade in Mice.

To examine the effect of biflorin, a component of Syzygium aromaticum, on memory deficit, we introduced a scopolamine-induced cognitive deficit mouse model. A single administration of biflorin increased latency time in the passive avoidance task, ameliorated alternation behavior in the Y-maze, and increased exploration time in the Morris water maze task, indicating the improvement of cognitive behaviors against cholinergic dysfunction. The biflorin-induced reverse of latency in the scopolamine-treated group was attenuated by MK-801, an NMDA receptor antagonist. Biflorin also enhanced cognitive function in a naïve mouse model. To understand the mechanism of biflorin for memory amelioration, we performed Western blot. Biflorin increased the activation of protein kinase C-ζ and its downstream signaling molecules in the hippocampus. These results suggest that biflorin ameliorates drug-induced memory impairment by modulation of protein kinase C-ζ signaling in mice, implying that biflorin could function as a possible therapeutic agent for the treatment of cognitive problems.

Fructus Corni Officinalis water extract Ameliorates Memory Impairment and Beta amyloid (Aβ) clearance by LRP-1 Expression in the Hippocampus of a Rat model of Alzheimer’s Disease

This study evaluated the effects of Fructus Corni Officinalis water extract (FCE) on congnitive impairment and Aβ clearance induced by beta amyloid Aβ (1-42) injection in the hippocampus of rat. Aβ (1-42) was injected into the hippocampus using a Hamilton syringe and micropump (5 ㎍/5 ㎕, 1 ㎕/min, each hippocampus bilaterally). FCE was administered orally once a day (100, 250, 500 ㎎/㎏) for 4 weeks after the Aβ (1-42) injection. The acquisition of learning and retention of memory were tested using the Morris water maze. Aβ accumulation and Aβ clearance in the hippocampus were observed using immunostaining. Aβ (1-42) level in plasma was confirmed using enzyme-linked immunosorbent assay (ELISA). FCE significantly shortened the escape latencies during acquisition training trials. FCE significantly increased the number of target heading to the platform site and significantly shortened the time for the 1 st targetheadingduringtheretentiontesttrial.FCEsignificantlyattenuatedtheAβ accumulation in the hippocampus produced by Aβ (1-42) injection. FCE significantly increased LRP-1 expression around vessels in the hippocampus and Aβ (1-42) levels in plasma. The results suggest that FCE improved cognitive impairment by ameliorate Aβ clearance and Aβ accumulation in the hippocampus. FCE may be a beneficial herbal formulation in treating cognitive impairment including Alzheimer’s disease.

Anthocyanin-Loaded PEG-Gold Nanoparticles Enhanced the Neuroprotection of Anthocyanins in an Aβ1-42 Mouse Model of Alzheimer's Disease.

Nanomedicine is an emerging research area. In this study, we investigated the neuroprotective efficacy of anthocyanin-loaded polyethylene glycol-gold nanoparticles (PEG-AuNPs) for enhancing the neuroprotective efficacy of anthocyanins in an amyloid beta (Aβ)1-42 mouse model of Alzheimer's disease. We observed that both anthocyanin-loaded PEG-AuNPs and anthocyanins treatment (12μg/g/day for 14days) ameliorated memory impairments in the Aβ1-42-injected mice. However, the anthocyanin-loaded PEG-AuNPs were more effective than free anthocyanins. Anthocyanin-loaded PEG-AuNPs protected pre- and post-synaptic proteins from Aβ1-42-induced synaptic dysfunction. Interestingly, the anthocyanin-loaded PEG-AuNPs also regulated the p-PI3K/p-Akt/p-GSK3β pathway and, as a result, prevented the hyperphosphorylation of tau protein at serines 413 and 404 in the Aβ1-42-injected mice. Western blot results of cytochrome c, Bax/Bcl2, caspases and poly (ADP-ribose) polymerase-1 expression levels, and immunohistochemical Nissl and Fluoro-Jade B staining also indicated that the anthocyanin-loaded PEG-AuNPs inhibited apoptosis and neurodegeneration in the Aβ1-42-injected mice. Our results suggest that the conjugation of dietary polyphenolic compounds with gold nanoparticles, such as anthocyanin-loaded PEG-AuNPs, is a novel approach that may represent an important and promising nanomedicine strategy to prevent age-associated neurodegenerative diseases.

Guarana (Paullinia cupana) ameliorates memory impairment and modulates acetylcholinesterase activity in Poloxamer-407-induced hyperlipidemia in rat brain

Hyperlipidemia is a risk factor for the development of cognitive dysfunction and atherosclerosis. Natural compounds have recently received special attention in relation to the treatment of disease due to their low cost and wide margin of safety. Thus, the aim of this study was to determine the possible preventive effect of guarana powder (Paullinia cupana) on memory impairment and acetylcholinesterase (AChE) activity in the brain structures of rats with Poloxamer-407-induced hyperlipidemia. Adult male Wistar rats were pretreated with guarana (12.5, 25 and 50mg/kg/day) and caffeine (0.2mg/kg/day) by gavage for a period of 30days. Simvastatin (0.04mg/kg) was administered as a comparative standard. Acute hyperlipidemia was induced with intraperitoneal injections of 500mg/kg of Poloxamer-407. Memory tests and evaluations of anxiety were performed. The cortex, cerebellum, hippocampus, hypothalamus and striatum were separated to assess acetylcholinesterase activity. Our results revealed that guarana powder was able to reduce the levels of TC and LDL-C in a manner similar to simvastatin. Guarana powder also partially reduced the liver damage caused by hyperlipidemia. Guarana was able to prevent changes in the activity of AChE and improve memory impairment due to hyperlipidemia. Guarana powder may therefore be a source of promising phytochemicals that can be used as adjuvant therapy in the management of hyperlipidemia and cognitive disorders.

CysLT1R downregulation reverses intracerebroventricular streptozotocin-induced memory impairment via modulation of neuroinflammation in mice

Our previous studies showed that cysteinyl leukotrienes receptor 1 (CysLT1R) is upregulated in amyloid-β (Aβ)-induced neurotoxicity and that administration of CysLT1R antagonists such as pranlukast or montelukast can ameliorate memory impairment in mice. In the current study, we sought to explore the role of CysLT1R in intracerebroventricular streptozotocin (STZ-ICV)-induced mouse model of memory impairment and neuroinflammation through shRNA-mediated knockdown of CysLT1R and also its pharmacological blockade by pranlukast. ICR mice were infused with STZ (3.0mg/kg) by a single bilateral stereotaxic ICV microinjection followed by administration of CysLT1R-shRNA (intra-hippocampal) or pranlukast (intragastric, IG). After 21days, a set of behavioral and biochemical tests were performed in order to assess the degree of memory impairment and neuroinflammation in mice. STZ-infused mice spent less time in the target quadrant of Morris water maze test and took more time to find the shock-free arm in modified Y-maze test, which were rescued in the CysLT1R-knockdowned or pranlukast-treated mice. STZ-induced memory impairment was also accompanied by an elevated level of hippocampal CysLT1R, microglial activation, increased IL-1β, and TNF-α. Such elevation of these factors was found to be mediated through the classical NF-κB pathway and administration of CysLT1R-shRNA or pranlukast for 21days reversed all these parameters, suggesting a role of CysLT1R in STZ-induced memory deficit and neuroinflammation.

Amelioration of scopolamine-induced amnesia by phosphatidylserine and curcumin in the day-old chick.

In the one-trial taste-avoidance task in day-old chicks, acetylcholine receptor activation has been shown to be important for memory formation. Injection of scopolamine produces amnesia, which appears to be very similar in type to that of Alzheimer's disease, which is correlated with low levels of acetylcholine in the brain. Traditional pharmacological treatments of Alzheimer's disease, such as cholinesterase inhibitors and glutamate receptor blockers, improve memory and delay the onset of impairments in memory compared with placebo controls. These agents also ameliorate scopolamine-induced amnesia in the day-old chick trained on the one-trial taste-avoidance task. The present experiments examined the ability of two less traditional treatments for Alzheimer's disease, phosphatidylserine and curcumin, to ameliorate scopolamine-induced amnesia in day-old chicks. The results showed that 37.9 mmol/l phosphatidylserine and 2.7 mmol/l curcumin significantly improved retention in chicks administered scopolamine, whereas lower doses were not effective. Scopolamine did not produce state-dependent learning, indicating that this paradigm in day-old chicks might be a useful one to study the effects of possible Alzheimer's treatments. In addition, chicks administered curcumin or phosphatidylserine showed little avoidance of a bead associated with water reward, indicating that these drugs did not produce response inhibition. The current results extend the findings that some nontraditional memory enhancers can ameliorate memory impairment and support the hypothesis that these treatments might be of benefit in the treatment of Alzheimer's disease.

Enhanced Cognitive Effects of Demethoxycurcumin, a Natural Derivative of Curcumin on Scopolamine-Induced Memory Impairment in Mice

In the present study, we examined the ameliorating effects of demethoxycurcumin (DMC) on memory impairment induced by scopolamine using passive avoidance and Morris water maze tests in mice. Moreover, to determine the neurobiological effects underlying the ameliorating effects of the DMC, choline acetyltransferase (ChAT) immunoreactivity was evaluated in mice exposed to scopolamine. Our results demonstrated that chronic oral administration (28 days) of DMC (10 mg/kg) improved scopolamine-induced learning impairment in the passive avoidance task and memory impairment in the Morris water maze. Moreover, Choline acetyltransferase (ChAT) activity in the DMC-treated group was significantly increased to 33.03% compared with the control group. Our present finding suggests that DMC ameliorates memory impairments induced by scopolamine treatment through reversing the reduction of hippocampal ChAT expression in mice.

Ferulic acid ameliorates memory impairment in d-galactose-induced aging mouse model

Ferulic acid (FA) acts as a powerful antioxidant against various age-related diseases. To investigate the effect and underlying mechanism of FA against d-galactose(d-gal)-induced memory deficit, mice were injected with d-gal to induce memory impairment and simultaneously treated with FA and donepezil. The behavioral results revealed that chronic FA treatment reversed d-gal-induced memory impairment. Further, FA treatment inhibited d-gal-induced AChE activity and oxidative stress via increase of superoxide dismutase activity and reduced glutathione content, as well as decrease of malondialdehyde and nitric oxide levels. We also observed that FA significantly inhibits inflammation in the brain through reduction of NF-κB and IL-1β by enzyme-linked immunosorbent assay. Additionally, FA treatment significantly reduces the caspase-3 level in the hippocampus of d-gal-treated mice. Hematoxylin and eosin and Nissl staining showed that FA prevents neurodegeneration induced by d-gal. These findings showed that FA inhibits d-gal-induced AChE activity, oxidative stress, neuroinflammation and neurodegeneration, and consequently ameliorates memory impairment.

Electroacupuncture ameliorates memory impairments by enhancing oligodendrocyte regeneration in a mouse model of prolonged cerebral hypoperfusion

We modeled prolonged cerebral hypoperfusion in mice using bilateral common carotid artery stenosis (BCAS) and electroacupuncture (EA) stimulation was applied at two acupoints, Baihui (GV20) and Dazhui (GV14). In behavioral tests of memory, BCAS produced impairments in spatial and short-term memory in mice that were attenuated by therapeutic EA stimulation. Therapeutic use of EA in BCAS also enhanced oligodendrocyte (OL) differentiation from oligodendrocyte precursor cells (OPCs), in association with white matter improvements in the corpus callosum (CC). In PCR analyses of growth factor gene expression, significant positive changes in 3 genes were observed following EA stimulation in BCAS, and here we highlight alterations in neurotrophin-4/5 (NT4/5). We confirmed EA-mediated positive changes in the expression of NT4/5 and its receptor, tyrosine receptor kinase B (TrkB). Treatment of naïve and BCAS + EA animals with a selective TrkB antagonist, ANA-12, produced losses of myelin and cognitive function that were ameliorated by EA therapy. Moreover, following BCAS we observed an EA-dependent increase in phospho-activated CREB (a downstream mediator of NT4/5-TrkB signaling) in OPCs and OLs of the CC. Our results suggest that EA stimulation promotes the recovery of memory function following white matter injury via a mechanism that promotes oligodendrocyte regeneration and involves NT4/5-TrkB signaling.