Prophylactic effects of apigenin against hyperglycemia-associated amnesia via activation of the Nrf2/ARE pathway in zebrafish.

The escalating focus on ageing-associated disease has generated substantial interest in the phenomenon of cognitive impairment linked to diabetes. Hyperglycemia exacerbates oxidative stress, contributes to ß-amyloid accumulation, disrupts mitochondrial function, and impairs cognitive function. Existing therapies have certain limitations, and apigenin (AG), a natural plant flavonoid, has piqued interest due to its antioxidant, anti-inflammatory, and anti-hyperglycemic properties. So, we anticipate that AG might be a preventive medicine for hyperglycemia-associated amnesia. To test our hypothesis, naïve zebrafish were trained to acquire memory and pretreated with AG. Streptozotocin (STZ) was administered to mimic hyperglycemia-induced memory dysfunction. Spatial memory was assessed by T-maze and object recognition through visual stimuli. Acetylcholinesterase (AChE) activity, antioxidant enzyme status, and neuroinflammatory genes were measured, and histopathology was performed in the brain to elucidate the neuroprotective mechanism. AG exhibits a prophylactic effect and improves spatial learning and discriminative memory of STZ-induced amnesia in zebrafish under hyperglycemic conditions. AG also reduces blood glucose levels, brain oxidative stress, and AChE activity, enhancing cholinergic neurotransmission. AG prevented neuronal damage by regulating brain antioxidant response elements (ARE), collectively contributing to neuroprotective properties. AG demonstrates a promising effect in alleviating memory dysfunction and mitigating pathological changes via activation of the Nrf2/ARE mechanism. These findings underscore the therapeutic potential of AG in addressing memory dysfunction and neurodegenerative changes associated with hyperglycemia.

Dihydroergotamine Increases Histamine Brain Levels and Improves Memory in a Scopolamine-Induced Amnesia Model.

The beneficial effects of increasing histamine levels on memory have acquired special interest due to their applicability to psychiatric conditions that cause memory impairments. In addition, by employing drug repurposing approaches, it was demonstrated that dihydroergotamine (DHE), an FDA drug approved to treat migraines, inhibits Histamine N Methyl Transferase (HNMT), the enzyme responsible for the inactivation of histamine in the brain. For this reason, in the present work, the effect of DHE on histamine levels in the hippocampus and its effects on memory was evaluated, employing the scopolamine-induced amnesia model, the Novel Object Recognition (NOR) paradigm, and the Morris Water Maze (MWM). Furthermore, the role of histamine 1 receptor (H1R) and histamine 2 receptor (H2R) antagonists in the improvement in memory produced by DHE in the scopolamine-induced amnesia model was evaluated. Results showed that the rats that received DHE (10 mg/kg, i.p.) showed increased histamine levels in the hippocampus after 1 h of administration but not after 5 h. In behavioral assays, it was shown that DHE (1 mg/kg, i.p.) administered 20 min before the training reversed the memory impairment produced by the administration of scopolamine (2 mg/kg, i.p.) immediately after the training in the NOR paradigm and MWM. Additionally, the effects in memory produced by DHE were blocked by pre-treatment with pyrilamine (20 mg/kg, i.p.) administered 30 min before the training in the NOR paradigm and MWM. These findings allow us to demonstrate that DHE improves memory in a scopolamine-induced amnesia model through increasing histamine levels at the hippocampus due to its activity as an HNMT inhibitor.

A comprehensive assessment of the cholinergic-supporting and cognitive-enhancing effects of Rosa damascena Mill. (Damask rose) essential oil on scopolamine-induced amnestic rats.

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative condition characterized by gradual loss of cognitive abilities (dementia) and is a major public health problem. Here, we aimed at investigating the effects of Rosa damascena essential oil (RDEO) on learning and memory functions in a rat model of amnesia induced by scopolamine, as well as on changes in acetylcholinesterase (AChE) activity, M1 muscarinic acetylcholine receptor (mAChR) expression, and brain-derived neurotrophic factor (BDNF) levels in the extracted brain tissues. METHODS: The control, amnesia (scopolamine, 1 mg/kg/i.p.) and treatment (RDEO, 100 µL/kg/p.o. or galantamine, 1.5 mg/kg/i.p.) groups were subjected to Morris water maze and new object recognition tests. AChE activity was assayed by ELISA, and M1 mAChR and BDNF concentration changes were determined by western blotting. Also, using computational tools, human M1 mAChR was modeled in an active conformation, and the major components of RDEO were docked onto this receptor. RESULTS: According to our behavioral tests, RDEO was able to mitigate the learning and memory impairments caused by scopolamine in vivo. Our in vitro assays showed that the observed positive effects correlated well with a decrease in AChE activity and an increase in M1 mAChR and BDNF levels in amnestic rat brains. We also demonstrated in an in silico setting that the major components of RDEO, specifically -citronellol, geraniol, and nerol, could be accommodated favorably within the allosteric binding pocket of active-state human M1 mAChR and anchored here chiefly by hydrogen-bonding and alkyl-π interactions. CONCLUSION: Our findings offer a solid experimental foundation for future RDEO-based medicinal product development for patients suffering from AD.

New curcumin-loaded nanocapsules as a therapeutic alternative in an amnesia model.

This study aimed to investigate the action of two different formulations of curcumin (Cur)-loaded nanocapsules (Nc) (Eudragit [EUD] and poly (ɛ-caprolactone) [PCL]) in an amnesia mice model. We also investigated the formulations' effects on scopolamine-induced (SCO) depressive- and anxiety-like comorbidities, the cholinergic system, oxidative parameters, and inflammatory markers. Male Swiss mice were randomly divided into five groups (n = 8): group I (control), group II (Cur PCL Nc 10 mg/kg), group III (Cur EUD Nc 10 mg/kg), group IV (free Cur 10 mg/kg), and group V (SCO). Treatments with Nc or Cur (free) were performed daily or on alternate days. After 30 min of treatment, the animals received the SCO and were subjected to behavioral tests 30 min later (Barnes maze, open-field, object recognition, elevated plus maze, tail suspension tests, and step-down inhibitory avoidance tasks). The animals were then euthanized and tissue was removed for biochemical assays. Our results demonstrated that Cur treatment (Nc or free) protected against SCO-induced amnesia and depressive-like behavior. The ex vivo assays revealed lower acetylcholinesterase (AChE) and catalase (CAT) activity, reduced thiobarbituric species (TBARS), reactive species (RS), and non-protein thiols (NSPH) levels, and reduced interleukin-6 (IL-6) and tumor necrosis factor (TNF) expression. The treatments did not change hepatic markers in the plasma of mice. After treatments on alternate days, Cur Nc had a more significant effect than the free Cur protocol, implying that Cur may have prolonged action in Nc. This finding supports the concept that it is possible to achieve beneficial effects in nanoformulations, and treatment on alternate days differs from the free Cur protocol regarding anti-amnesic effects in mice.

Suv39h1 Silencing Recovers Memory Decline in Scopolamine-Induced Amnesic Mouse Model.

Histone post-translational modifications play an important role in the regulation of long-term memory and modulation of expression of neuronal immediate early genes (IEGs). The lysine methyltransferase KMT1A/ Suv39h1 (a mammalian ortholog of the Drosophila melanogaster SU (VAR) 3-9) aids in the methylation of histone H3 at lysine 9. We previously reported that age-related memory decline is associated with an increase in Suv39h1 expression in the hippocampus of male mice. The scopolamine-induced amnesic mouse model is a well-known animal model of memory impairment. In the current study, we have made an attempt to find a link between the changes in the H3K9 trimethylation pattern and memory decline during scopolamine-induced amnesia. It was followed by checking the effect of siRNA-mediated silencing of hippocampal Suv39h1 on memory and expression of neuronal IEGs. Scopolamine treatment significantly increased global levels of H3K9me3 and Suv39h1 in the amnesic hippocampus. Suv39h1 silencing in amnesic mice reduced H3K9me3 levels at the neuronal IEGs (Arc and BDNF) promoter, increased the expression of Arc and BDNF in the hippocampus, and improved recognition memory. Thus, these findings suggest that the silencing of Suv39h1 alone or in combination with other epigenetic drugs might be effective for treating memory decline during amnesia.

Impact of antithrombotic therapy on acute and delayed intracranial haemorrhage and evaluation of the need of short-term hospitalisation based on CT findings after mild traumatic brain injury: experience from an oral and maxillofacial surgery unit.

PURPOSE: The primary aim was to compare the prevalence of acute and delayed intracranial haemorrhage (ICH) following mild traumatic brain injury (mTBI) in patients on antithrombotic medication referred to a clinic for oral and plastic maxillofacial surgery. The secondary aim was to evaluate the need for short-term hospitalisation based on initial radiological and clinical findings. METHODS: This was an observational retrospective single-centre study of all patients on antithrombotic medication who were admitted to our department of oral and plastic maxillofacial surgery with mTBI over a 5 year period. Demographic and anamnesis data, injury characteristics, antithrombotic medication, radiological findings, treatment, and outcome were analysed. Patients were divided into the following four groups based on their antithrombotic medication: (1) single antiplatelet users, (2) vitamin K antagonist users, (3) direct oral anticoagulant users, and (4) double antithrombotic users. All patients underwent an emergency cranial CT (CT0) at admission. Based on clinical and radiological evaluation, different treatment protocols were applied. Patients with positive CT0 findings and patients with secondary neurological deterioration received a control CT (CT1) before discharge. Acute and delayed ICH and patient's outcome during hospitalisation were evaluated using descriptive statistical analysis. RESULTS: A total of 696 patients (mean age, 71.6 years) on antithrombotic medication who presented at our department with mTBI were included in the analysis. Most injuries were caused by a ground-level fall (76.9%). Thirty-six patients (5.1%) developed an acute traumatic ICH, and 47 intracerebral lesions were detected by radiology-most of these in patients taking acetylsalicylic acid. No association was detected between ICH and antithrombotic medication (p = 0.4353). In total, 258 (37.1%) patients were admitted for 48 h in-hospital observation. The prevalence of delayed ICH was 0.1%, and the mortality rate was 0.1%. Multivariable analysis identified a Glasgow Coma Scale (GCS) of < 15, loss of consciousness, amnesia, headache, dizziness, and nausea as clinical characteristics significantly associated with an increased risk of acute ICH, whereas age, sex, and trauma mechanism were not associated with ICH prevalence. Of the 39 patients who underwent a control CT1, most had a decreasing or at least constant intracranial lesion; in three patients, intracranial bleeding increased but was not clinically relevant. CONCLUSION: According to our experience, antithrombotic therapy does not increase the rate of ICH after mTBI. A GCS of < 15, loss of consciousness, amnesia, headache, dizziness, and nausea are indicators of higher ICH risk. A second CT scan is more effective in patients with secondary neurological deterioration. Initial CT findings were not clinically relevant and should not indicate in-hospital observation.

The Potent and Selective Histamine H3 Receptor Antagonist E169 Counteracts Cognitive Deficits and Mitigates Disturbances in the PI3K/AKT/GSK-3ß Signaling Pathway in MK801-Induced Amnesia in Mice.

The role of histamine H3 receptors (H3Rs) in memory and the prospective of H3R antagonists in pharmacological control of neurodegenerative disorders, e.g., Alzheimer's disease (AD), is well-accepted. Therefore, the procognitive effects of acute systemic administration of H3R antagonist E169 (2.5-10 mg/kg, i.p.) on MK801-induced amnesia in C57BL/6J mice using the novel object recognition test (NORT) were evaluated. E169 (5 mg) provided a significant memory-improving effect on MK801-induced short- and long-term memory impairments in NORT. The E169 (5 mg)-provided effects were comparable to those observed with the reference phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 and were abrogated with the H3R agonist (R)-α-methylhistamine (RAMH). Additionally, our results demonstrate that E169 ameliorated MK801-induced memory deficits by antagonism of H3Rs and by modulation of the level of disturbance in the expression of PI3K, Akt, and GSK-3ß proteins, signifying that E169 mitigated the Akt-mTOR signaling pathway in the hippocampus of tested mice. Moreover, the results observed revealed that E169 (2.5-10 mg/kg, i.p.) did not alter anxiety levels and locomotor activity of animals in open field tests, demonstrating that performances improved following acute systemic administration with E169 in NORT are unrelated to changes in emotional response or in spontaneous locomotor activity. In summary, these obtained results suggest the potential of H3R antagonists such as E169, with good in silico physicochemical properties and stable retained key interactions in docking studies at H3R, in simultaneously modulating disturbed brain neurotransmitters and the imbalanced Akt-mTOR signaling pathway related to neurodegenerative disorders, e.g., AD.

Polyphenol-enriched Desmodium elegans DC. ameliorate scopolamine-induced amnesia in animal model of Alzheimer's disease: In Vitro, In Vivo and In Silico approaches.

The current study aims to quantify HPLC-DAD polyphenolics in the crude extracts of Desmodium elegans, evaluating its cholinesterase inhibitory, antioxidant, molecular docking and protective effects against scopolamine-induced amnesia in mice. A total of 16 compounds were identified which include gallic acid (239 mg g-1), p-hydroxybenzoic acid (11.2 mg g-1), coumaric acid (10.0 mg g-1), chlorogenic acid (10.88 mg g-1), caffeic acid (13.9 mg g-1), p-coumaroylhexose (41.2 mg g-1), 3-O-caffeoylquinic acid (22.4 mg g-1), 4-O-caffeoylquinic acid (6.16 mg g-1), (+)-catechin (71.34 mg g-1), (-)-catechin (211.79 mg g-1), quercetin-3-O-glucuronide (17.9 mg g-1), kaempferol-7-O-glucuronide (13.2 mg g-1), kaempferol-7-O-rutinoside (53.67 mg g-1), quercetin-3-rutinoside (12.4 mg g-1), isorhamnetin-7-O-glucuronide (17.6 mg g-1) and isorhamnetin-3-O-rutinoside (15.0 mg g-1). In a DPPH free radical scavenging assay, the chloroform fraction showed the highest antioxidant activity, with an IC50 value of 31.43 µg mL-1. In an AChE inhibitory assay, the methanolic and chloroform fractions showed high inhibitory activities causing 89% and 86.5% inhibitions with IC50 values of 62.34 and 47.32 µg mL-1 respectively. In a BChE inhibition assay, the chloroform fraction exhibited 84.36% inhibition with IC50 values of 45.98 µg mL-1. Furthermore, molecular docking studies revealed that quercetin-3-rutinoside and quercetin-3-O-glucuronide fit perfectly in the active sites of AChE and BChE respectively. Overall, the polyphenols identified exhibited good efficacy, which is likely as a result of the compounds' electron-donating hydroxyl groups (-OH) and electron cloud density. The administration of methanolic extract improved cognitive performance and demonstrated anxiolytic behavior among tested animals.

Ameliorative effects of Albizia adianthifolia aqueous extract against pentylenetetrazole-induced epilepsy and associated memory loss in mice: Role of GABAergic, antioxidant defense and anti-inflammatory systems.

Albizia adianthifolia (Schumach.) (Fabaceae) is a medicinal herb used for the treatment of epilepsy and memory impairment. This study aims to investigate the anticonvulsant effects of Albizia adianthifolia aqueous extract against pentylenetetrazole (PTZ)-induced spontaneous convulsions in mice; and determine whether the extract could mitigate memory impairment, oxidative/nitrergic stress, GABA depletion and neuroinflammation. Ultra-high performance liquid chromatography/mass spectrometry analysis was done to identify active compounds from the extract. Mice were injected with PTZ once every 48 h until kindling was developed. Animals received distilled water for the normal group and negative control groups, doses of extract (40, 80, or 160 mg/kg) for the test groups and sodium valproate (300 mg/kg) for the positive control group. Memory was measured using Y maze, novel object recognition (NOR) and open field paradigms, while the oxidative/nitrosative stresses (MDA, GSH, CAT, SOD and NO), GABAergic transmission (GABA, GABA-T and GAD) and neuro-inflammation (TNF-α, IFN-γ, IL- 1ß, and IL-6) were determined. Brain photomicrograph was also studied. Apigenin, murrayanine and safranal were identified in the extract. The extract (80-160 mg/kg) significantly protected mice against seizures and mortality induced by PTZ. The extract significantly increased the spontaneous alternation and the discrimination index in the Y maze and NOR tests, respectively. PTZ kindling induced oxidative/nitrosative stress, GABA depletion, neuroinflammation and neuronal cells death was strongly reversed by the extract. The results suggest that the anticonvulsant activity of Albizia adianthifolia extract is accompanied by its anti-amnesic property, and may be supported by the amelioration of oxidative stress, GABAergic transmission and neuroinflammation.

Memory Enhancing and Neurogenesis Activity of Honey Bee Venom in the Symptoms of Amnesia: Using Rats with Amnesia-like Alzheimer's Disease as a Model.

BACKGROUND/OBJECTIVE: Alzheimer's disease (AD) is mainly characterized by amnesia that affects millions of people worldwide. This study aims to explore the effectiveness capacities of bee venom (BV) for the enhancement of the memory process in a rat model with amnesia-like AD. METHODS: The study protocol contains two successive phases, nootropic and therapeutic, in which two BV doses (D1; 0.25 and D2: 0.5 mg/kg i.p.) were used. In the nootropic phase, treatment groups were compared statistically with a normal group. Meanwhile, in the therapeutic phase, BV was administered to scopolamine (1mg/kg) to induce amnesia-like AD in a rat model in which therapeutic groups were compared with a positive group (donepezil; 1mg/kg i.p.). Behavioral analysis was performed after each phase by Working Memory (WM) and Long-Term Memory (LTM) assessments using radial arm maze (RAM) and passive avoidance tests (PAT). Neurogenic factors; Brain-derived neurotrophic factor (BDNF), and Doublecortin (DCX) were measured in plasma using ELISA and Immunohistochemistry analysis of hippocampal tissues, respectively. RESULTS: During the nootropic phase, treatment groups demonstrated a significant (P < 0.05) reduction in RAM latency times, spatial WM errors, and spatial reference errors compared with the normal group. In addition, the PA test revealed a significant (P < 0.05) enhancement of LTM after 72 hours in both treatment groups; D1 and D2. In the therapeutic phase, treatment groups reflected a significant (P < 0.05) potent enhancement in the memory process compared with the positive group; less spatial WM errors, spatial reference errors, and latency time during the RAM test, and more latency time after 72 hours in the light room. Moreover, results presented a marked increase in the plasma level of BDNF, as well as increased hippocampal DCX-positive data in the sub-granular zone within the D1 and D2 groups compared with the negative group (P < 0.05) in a dose-dependent manner. CONCLUSION: This study revealed that injecting BV enhances and increases the performance of both WM and LTM. Conclusively, BV has a potential nootropic and therapeutic activity that enhances hippocampal growth and plasticity, which in turn improves WM and LTM. Given that this research was conducted using scopolamine-induced amnesia-like AD in rats, it suggests that BV has a potential therapeutic activity for the enhancement of memory in AD patients in a dose-dependent manner but further investigations are needed.

Hesperetin-loaded polymeric nanofibers: assessment of bioavailability and neuroprotective effect.

OBJECTIVE: The purpose of the study is to assess the bioavailability and neuroprotective effect of hesperetin (Hesp)-loaded nanofibers. METHODS: Electrospinning was used to create and characterize polyvinyl pyrrolidone-based Hesp-loaded nanofibers. To evaluate the produced nanofibers, preclinical studies were conducted. The study involved five groups of Wistar rats, and the treatments were administered as follows. Group 1 (control) was given regular saline for 14 d. On the 14th day, Group 2 was given scopolamine. Group 3 was given donepezil for 14 d and then scopolamine on the 14th. Group 4 was given Hesp for 14 d and then scopolamine on the 14th. Group 5 was given Hesp-loaded nanofibers for 14 d, followed by scopolamine on the 14th. On the 14th day, rats' memory was tested using Cook's pole climbing apparatus and the Morris water maze (MWM). On the 15th day, rats from each group were slaughtered, brain tissues were separated, and biochemical and histological analyses were performed. In addition, in vitro dissolution experiments and pharmacokinetic studies were carried out. RESULTS: When compared to the control group, scopolamine-treated rats had considerably longer escape latency times, as well as increased acetylcholinesterase (AChE) activity, lipid peroxidation, degeneration, and inflammation in the hippocampus. These parameters were greatly recovered by donepezil and Hesp-loaded nanofibers that had been pretreated. Because of the greatly improved bioavailability of Hesp, the Hesp-loaded nanofibers significantly protected rats from scopolamine-induced amnesia. CONCLUSIONS: Hesp-loaded nanofibers have an excellent neuroprotective effect against scopolamine-induced amnesia due to enhanced bioavailability.

Therapeutic potential of blackberry extract in the preventing memory deficits and neurochemical alterations in the cerebral cortex, hippocampus and cerebellum of a rat model with amnesia.

The blackberry (Rubus sp.) is a popular fruit that has a high concentration of phenolic compounds. Pharmacological investigations have demonstrated the important biological activities of the blackberry extract, such as neuroprotective actions. This study aimed to evaluate the effects of blackberry extract on memory and neurochemical parameters in rats subjected to scopolamine (SCO)-induced amnesia. Male rats were divided into five groups: I, control (saline); II, SCO; III, SCO + Rubus sp. (100 mg/kg); IV, SCO + Rubus sp. (200 mg/kg); and V, SCO + donepezil (5 mg/kg). Blackberry extract and donepezil were orally administered for 10 days. On day 11, group I received saline, and groups II, III, IV, and V received SCO (1 mg/kg) intraperitoneally after object recognition behavioral training. Twenty-four hours after the training session, animals were subjected to an object recognition test. Finally, the animals were euthanized, and the cerebral cortex, hippocampus, and cerebellum were collected to evaluate the oxidative stress and acetylcholinesterase (AChE) activity. Rubus sp. extract prevented memory impairment induced by SCO in a manner similar to that of donepezil. Additionally, Rubus sp. extract and donepezil prevented the increase in AChE activity induced by SCO in all the evaluated brain structures. SCO induced oxidative damage in the cerebral cortex, hippocampus, and cerebellum, which was prevented by Rubus sp. and donepezil. Our results suggest that the antioxidant and anticholinesterase activities of Rubus sp. are associated with memory improvement; hence, it can potentially be used for the treatment of neurodegenerative diseases.

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.

Anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats.

OBJECTIVE: Alzheimer's disease (AD) is a neurological ailment that causes memory loss and impairments and is linked to a drop-in acetylcholine level. Acetylcholinesterase (AChE) inhibitors are used for the management of AD. In our ongoing research to search for natural AChE inhibitors from medicinal plants, we found that the Acorus calamus possesses memory-enhancing properties. α-Asarone is the major compound isolated from the Acorus calamus and it has neuroprotective action in animal models, nonetheless, its anticholinesterase activity in different brain regions was not fully understood. The purpose of this research was to determine the anti-amnesic and anti-cholinesterase activities of α-asarone against scopolamine-induced memory impairments in rats. MATERIALS AND METHODS: The anti-cholinesterase activity of α-asarone was determined using Ellman's method in different brain areas, such as the cortex, hippocampus, and striatum. In addition, the anti-amnesic effect of α-asarone was also investigated using elevated plus-maze, passive avoidance, and active avoidance tests. RESULTS: The effect of α-asarone on memory impairment against scopolamine-induced (1 mg/kg body weight) amnesia was evaluated. Administration of α-asarone (15 and 30 mg/kg body weight) for 14 days to rats significantly ameliorated the scopolamine-induced memory impairment as measured in the elevated plus-maze, passive avoidance, and avoidance active tests compared to the scopolamine-treated group. In this study, we also show that α-asarone treatment significantly (p<0.05) reduced brain acetylcholinesterase activity in the cortex, hippocampus, and striatum brain regions of amnesic rats. CONCLUSIONS: These results confirmed that α-asarone has anti-amnesic and anti-cholinesterase potential which may be useful for the management of AD.

An aqueous macerate of Ziziphus jujuba reduces long-term spatial memory impairment in D-galactose treated rats: role of anti-inflammatory pathways.

Pharmacological treatments against Alzheimer disease provide only symptomatic relief and are associated with numerous side effects. Previous studies showed that a concoction of Ziziphus jujuba leaves possesses anti-amnesic effects in scopolamine-treated rats. More recently, an aqueous macerate of Z. jujuba leaves has been shown to reduce short-term memory impairment in D-galactose-treated rats. However, no study on the effect of an aqueous macerate of Z. jujuba on long-term memory impairment was performed. Therefore, this study evaluates the effect of an aqueous macerate of Z. jujuba on long-term spatial memory impairment in D-galactose-treated rats. Long-term spatial memory impairment was induced in rats by administering D-galactose (350 mg/kg/day, s.c.), once dailyfor 21 days. On the 22nd day, the integrity of this memory was assessed using the Morris water maze task. Rats that developed memory impairment were treated with tacrine (10 mg/kg, p.o.), or aspirin (20 mg/kg, p.o.), or extract (41.5, 83, and 166 mg/kg, p.o.), once daily, for 14 days. At the end of the treatment, memory impairment was once more assessed using the same paradigm. Animals were then euthanized, and some pro-inflammatory cytokine markers were analyzed in the hippocampus or blood. The extract at all doses significantly reduced the latency to attain the platforming of the water maze test. The extract (83 mg/kg) also increased the time spent in the target quadrant during the retention phase. The extract markedly reduced the concentration of pro-inflammatory cytokine markers in the hippocampus and blood. Together, these results suggest that this aqueous extract Z. jujuba reduces long-term spatial memory impairment. This effect may be mediated in part by its anti-inflammatory activity.

An aqueous extract of Syzygium cumini protects against kainate-induced status epilepticus and amnesia: evidence for antioxidant and anti-inflammatory intervention.

Temporal lobe epilepsy is the most common drug-resistant epilepsy. To cure epilepsy, drugs must target the mechanisms at the origin of seizures. Thus, the present investigation aimed to evaluate the antiepileptic- and anti-amnesic-like effects of an aqueous extract of Syzygium cumini against kainate-induced status epilepticus in mice, and possible mechanisms of action. Mice were divided into 7 groups and treated as follows: normal group or kainate group received po distilled water (10 mL/kg), four test groups received Syzygium cumini (28.8, 72, 144, and 288 mg/kg, po), and the positive control group treated intraperitoneally (ip) with sodium valproate (300 mg/kg). An extra group of normal mice was treated with piracetam (200 mg/kg, po). Treatments were administered 60 min before the induction of status epilepticus with kainate (15 mg/kg, ip), and continued daily throughout behavioral testing. Twenty-four hours after the induction, T-maze and Morris water maze tasks were successively performed. The animals were then sacrificed and some markers of oxidative stress and neuroinflammation were estimated in the hippocampus. The extract significantly prevented status epilepticus and mortality. In the T-maze, the aqueous extract markedly increased the time spent and the number of entries in the discriminated arm. In the Morris water maze, the extract significantly increased the time spent in the target quadrant during the retention phase. Furthermore, the aqueous extract induced a significant reduction of oxidative stress and neuroinflammation. These results suggest that the aqueous extract of Syzygium cumini has antiepileptic- and anti-amnesic-like effects, likely mediated in part by antioxidant and anti-inflammatory activities.

Wheatgrass extract imparts neuroprotective actions against scopolamine-induced amnesia in mice.

The rich and diverse phytoconstituents of wheatgrass have established it as a natural antioxidant and detoxifying agent. The anti-inflammatory potential of wheatgrass has been studied extensively. However, the neuroprotective potential of wheatgrass has not been studied in depth. In this study, we investigated the neuroprotective response of wheatgrass against age-related scopolamine-induced amnesia in mice. Scopolamine is an established anticholinergic drug that demonstrates the behavioural and molecular characteristics of Alzheimer's disease. In the current study, wheatgrass extracts (prepared from 5 and 7 day old plantlets) were administered to scopolamine-induced memory deficit mice. The Morris water maze (MWM) and Y-maze tests demonstrated that wheatgrass treatment improves the behavior and simultaneously enhances the memory of amnesic mice. We further evaluated the expression of neuroinflammation related genes and proteins in the hippocampal region of mice. Wheatgrass significantly upregulated the mRNA and protein expression of neuroprotective markers such as BDNF and CREB in scopolamine-induced mice. Simultaneously, wheatgrass also downregulated the expression of inflammatory markers such as TNF-α and tau genes in these mice. The treatment of scopolamine-induced memory impaired mice with wheatgrass resulted in an elevation in the level of the phosphorylated form of ERK and Akt proteins. Wheatgrass treatment of mice also regulated the phosphorylation of tau protein and simultaneously prevented its aggregation in the hippocampal region of the brain. Overall, this study suggests the therapeutic potential of wheatgrass in the treatment of age-related memory impairment, possibly through the involvement of ERK/Akt-CREB-BDNF pathway and concomitantly ameliorating the tau-related pathogenesis.

Pharmacological mechanism of xanthoangelol underlying Nrf-2/TRPV1 and anti-apoptotic pathway against scopolamine-induced amnesia in mice.

Alzheimer's disease (AD) is a well-known type of age-related dementia. The present study was conducted to investigate the effect of xanthoangelol against memory deficit and neurodegeneration associated with AD. Preliminarily, xanthoangelol produced neuroprotective effect against H2O2-induced HT-22 cells. Furthermore, effect of xanthoangelol against scopolamine-induced amnesia in mice was determined by intraperitoneally (i.p.) administering xanthoangelol (1, 10 and 20 mg/kg), 30 min prior to induction. Mice were administered scopolamine at a concentration of 1 mg/kg; i.p. for the induction of amnesia associated with AD. Xanthoangelol dose dependently reduced the symptoms of Alzheimer's disease as observed by the results obtained from the behavioral analysis performed using Morris water maze and Y-maze test. The immunohistochemical analysis suggested that xanthoangelol significantly improved Keap-1/Nrf-2 signaling pathway. It greatly reduced the effects of oxidative stress and showed improvement in the anti-oxidant enzyme such as GSH, GST, SOD and catalase. Additionally, xanthoangelol decreased the expression of transient receptor potential vanilloid 1 (TRPV-1), a nonselective cation channel, involved in synaptic plasticity and memory. It activated the anti-oxidants and attenuated the apoptotic (Bax/Bcl-2) pathway. Xanthoangelol also significantly attenuated the scopolamine-induced neuroinflammation by the inhibition of interleukin-1 beta (IL-1ß), and tumor necrosis factor-α (TNF-α) levels. The histological analysis, showed a significant reduction in amyloid plaques by xanthoangelol. Therefore, the present study indicated that xanthoangelol has the ability to ameliorate the AD symptoms by attenuating neuroinflammation and neurodegeneration induced by scopolamine.

Danggui-Shaoyao-San Attenuates Cognitive Impairment via the Microbiota-Gut-Brain Axis With Regulation of Lipid Metabolism in Scopolamine-Induced Amnesia.

Danggui-Shaoyao-San (DSS) has a long history of being used as a traditional medicine (TCM) and has been reported to show therapeutic effects in alleviating the symptoms of cognitive impairment. The purpose of this study was to investigate whether DSS treatment attenuates cognitive impairment via the microbiota-gut-brain axis in scopolamine-induced amnesia. In this work, we first performed the Morris water maze (MWM) test and novel object recognition (NOR) test to evaluate the memory function of treated C57BL/6N mice. Then we evaluated 16S rRNA for gut microbiota analysis, as well as assessment of blood-brain barrier function and intestinal barrier function and lipid metabolism analysis on tissues from different groups. We hypothesised that DSS may affect brain function and behavior through the gut-brain axis in a bidirectional interplay with both top-down and bottom-up regulation. Furthermore, in order to confirm whether intestinal flora plays a crucial role in scopolamine-induced amnesia, C57BL/6N mice were treated with fecal microbial transplantation (FMT), and then behavioral tests were performed. The mice's feces were simultaneously evaluated by 16S rRNA analysis. The result supported that the FMT-induced improvement in cognitive function highlights the role of the gut microbiota-brain axis to mediate cognitive function and behavior. Besides theses works, more findings indicated that DSS altered lipid metabolism by activating LXR-PPAR-γ and repaired mucosal barrier dysfunction assessed with a broad range of techniques, which attenuated cognitive impairment via the microbiota-gut-brain axis.

Post-Weaning Treatment with Probiotic Inhibited Stress-Induced Amnesia in Adulthood Rats: The Mediation of GABAergic System and BDNF/c-Fos Signaling Pathways.

The current study aimed to examine the effect of post-weaning treatment with probiotics on memory formation under stress during the adult period in male Wistar rats. Considering GABA is a potential mediator between probiotics and the host, the present study also investigated the involvement of the GABAergic system in the probiotic response. The hippocampal and prefrontal cortical (PFC) expression levels of BDNF and c-Fos were also assessed to show whether the treatments affect the memory-related signaling pathway. Three weeks after birth, the post-weaning rats were fed with probiotic water (PW) or tap water (TW) for 2, 3, 4, or 5 weeks. Exposure to acute stress impaired memory formation in a passive avoidance learning task. Feeding the post-weaning animals with probiotic strains (3, 4, or 5 weeks) inhibited stress-induced amnesia of the adult period. Post-training intracerebroventricular (ICV) microinjection of muscimol improved stress-induced amnesia in the animals fed with TW. ICV microinjection of muscimol inhibited probiotic treatment's significant effect on the stress response in the memory task. The expression levels of BDNF and c-Fos in the PFC and the hippocampus were significantly decreased in the stress animal group. The levels of BDNF and c-Fos were increased in the PW/stress animal group. The muscimol response was compounded with the decreased levels of BDNF and c-Fos in the PFC and the hippocampus. Thus, the GABA-A receptor mechanism may mediate the inhibitory effect of this probiotic mixture on stress-induced amnesia, which may be associated with the PFC and hippocampal BDNF/c-Fos signaling changes.