Scopolamine-induced Cognitive Impairment Research Articles

Protective effects of isofraxidin against scopolamine-induced cognitive and memory impairments in mice involve modulation of the BDNF-CREB-ERK signaling pathway.

Isofraxidin is a coumarin compound mainly isolated from several traditional and functional edible plants beneficial for neurodegenerative diseases, including Sarcandra glabra and Apium graveolens, and Siberian Ginseng. This study aimed to assess effects of isofraxidin against memory impairments and cognition deficits in a scopolamine-induced mouse model. Animals were randomly divided into 6 groups, control, vehicle, donepezil (10mg/kg, p.o.), and isofraxidin (3, 10, and 30mg/kg, p.o.). Isofraxidin or donepezil was administered for 44 days, once per day. The scopolamine insults (1mg/kg, i.p.) was given from the 21st day, once per day. Morris water maze test and Y-maze test were used for the behavioral test. After that, brain samples were collected for analysis. Firstly, isofraxidin significantly improved scopolamine-induced behavioral impairments and cognition deficits in Morris water maze and Y-maze test. Then, isofraxidin facilitated cholinergic activity via inhibiting acetylcholinesterase (AChE) activity. Besides, isofraxidin decreased lipid peroxidation level but enhanced levels of glutathione, glutathione peroxidase, and superoxide dismutase. Moreover, isofraxidin suppressed the expression of inflammatory mediators and cytokines. Further investigations showed that isofraxidin up-regulated expression of brain-derived neurotrophic factor (BDNF), and promoted phosphorylation of tropomyosin-related kinase B (TrkB), cyclic AMP-response element-binding protein (CREB), and extracellular signal-regulated kinase (ERK). These results suggested that isofraxidin ameliorated scopolamine-induced cognitive and memory impairments, possibly through regulating AChE activity, suppressing oxidative stress and inflammatory response, and modulating BDNF-CREB-ERK pathways.

Discovery of carbamate-based N-salicyloyl tryptamine derivatives as novel pleiotropic agents for the treatment of Alzheimer's disease

In this work, based on the potential anti-AD molecule previously studied by our group, we continue to introduce different substituents at different positions to improve both drug-like properties and on target activities. 33 N-salicyloyl tryptamine-carbamate hybrids were designed, synthesized and evaluated as cholinesterase inhibitors. H327 was the most potent BChE inhibitor (eqBChE IC50 = 0.057 ± 0.005 μM), and showed threefold improved inhibitory potency than the positive drug rivastigmine (eqBChE IC50 = 0.19 ± 0.001 μM). In addition, H327 as a pseudo-irreversible BChE inhibitor was endowed with neuroprotective, antioxidative and anti-neuroinflammatory properties. Cytotoxicity and acute toxicity tests confirmed the safety of compound H327. The pharmacokinetics study showed that compound H327 had a longer T1/2 time and higher bioavailability than the lead compound 1 g. Compound H327 was able to cross the blood–brain barrier (BBB) in vivo. Moreover, the behavioral tests showed that compound H327 could significantly improve scopolamine-induced cognitive impairment in vivo. Overall, these results demonstrated that compound H327 is a promising multi-target agent for the treatment of AD.

Anti-Alzheimer's and Antioxidant Activity of Ethanolic Seed Extract of Sapindus emarginatus Vahl on Scopolamine-Induced Cognitive Impairment in Mice

Background: Alzheimer's disease (AD) is a common nerve problem that leads to memory loss, particularly in the elderly. A shortage of acetylcholine in the brain, as well as oxidative stress, induces Alzheimer's disease. Currently, limited drugs are available to treat Alzheimer's disease because continuous use of these medications causes several side effects. Hence, we need high efficacious drugs to treat Alzheimer's disease with fewer side effects. Sapindus emarginatus Vahl or soap nut is a member of the Sapindaceae family. It's been used traditionally as an antiepileptic, antipruritic, antifertility, antiemetic, and anti-inflammatory agent. It is cheap, widely available, and reported to counteract chronic diseases linked to oxidative stress, such as ulcers and dyslipidemia. Objective: The purpose of this study was to determine the anti-Alzheimer and antioxidant properties of ethanolic seed extract of Sapindus emarginatus (ESSE) against scopolamine-induced amnesia. Methods: The total flavonoid level of the ESSE was estimated by a UV-visible spectrophotometer. The scopolamine (1 mg/kg/PO) was administered as a single intraperitoneal injection on the seventh day for induction of dementia in mice. The ESSE (250 and 500 mg/kg/PO) and donepezil (2.5 mg/kg/PO) was administered orally for 7 days. The neurobehavioral tests such as an elevated plus maze, radial arm maze, and Y-maze tests were undertaken for estimation of behavioral trials. The brain homogenate was used for the estimation of acetylcholine, acetylcholinesterase, and oxidative cell injury markers such as MDA, LH, SOD, CAT, and GSH. Results: The total flavonoid content of the extract was 0.47 mg of QE/g. Scopolamine degraded memory, as well as caused alterations in acetylcholine, acetylcholinesterase, and elevated oxidative stress in the brain. Pretreatment with ESSE reduced scopolamine-induced behavioral, neurochemical, and oxidative stress markers. Conclusion: The ESSE has an anti-amnesic impact, making it an attractive option for targeting multiple events as a possible technique to slow cognitive impairment.

Petroselinum crispum extract ameliorates scopolamine-induced cognitive dysfunction: role on apoptosis, inflammation and oxidative stress

This study was designed to investigate whether Petroselinum crispum (PC) extract has protective effects on the brain in the scopolamine-induced Alzheimer’s disease (AD) rat model. The rats were divided into; control, scopolamine (1 mg/kg, i.p.), galantamine (1.5 mg/kg, i.p.) and PC extract (2 g/kg, p.o.)-treated scopolamine groups. On day 14, the novel object recognition test (NORT) and Morris water maze test (MWMT) were performed and then the rats were sacrificed. Scopolamine-induced cognitive impairments observed in the NORT and MWMT, significantly improved with PC extract and galantamine treatments. Scopolamine reduced M1 receptor expression, Bcl-2/Bax ratio, and glutathione levels in the hippocampus and frontal cortex, while malondialdehyde levels, caspase-3/9 expressions, and acetylcholinesterase (AChE) activity were found to be increased. On the other hand, PC and galantamine treatments reversed these changes. In conclusion, PC extract has shown an ameliorative effect on the spatial and recognition memory, M1 receptor expression, apoptosis, oxidative stress, and increased AChE activity. Thus, it was concluded that PC could prevent AD-like conditions and can be used as a functional food. However, since animal models do not completely mimic those of humans, based on the data obtained in this study, the importance of PC on human AD should be demonstrated in future studies.

Insights of Valacyclovir in Treatment of Alzheimer's Disease: Computational Docking Studies and Scopolamine Rat Model.

Alzheimer's Disease (AD) impairs memory and cognitive functions in the geriatric population and is characterized by intracellular deposition of neurofibrillary tangles, extracellular deposition of amyloid plaques, and neuronal degeneration. Literature suggests that latent viral infections in the brain act as prions and promote neurodegeneration. Memantine possesses both anti-viral and N-methyl-D-aspartate (NMDA) receptor antagonistic activity. This research was designed to evaluate the efficacy of antiviral agents, especially valacyclovir, a prodrug of acyclovir in ameliorating the pathology of AD based on the presumption that anti-viral agents targeting the Herpes Simplex Virus (HSV) can have a protective effect on neurodegenerative diseases like Alzheimer's disease. Thus, we evaluated acyclovir's potential activity by in-silico computational docking studies against acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and beta-secretase 1 (BACE-1). These findings were further evaluated by in-vivo scopolamine-induced cognitive impairment in rats. Two doses of valacyclovir, a prodrug of acyclovir (100 mg/kg and 150 mg/kg orally) were tested. Genetic Optimisation for Ligand Docking scores and fitness scores of acyclovir were comparable to donepezil. Valacyclovir improved neurobehavioral markers. It inhibited AChE and BuChE (p<0.001) enzymes. It also possessed disease-modifying efficacy as it decreased the levels of BACE-1 (p<0.001), amyloid beta 1-42 (p<0.001), amyloid beta 1-40 (p<0.001), phosphorylatedtau (p<0.001), neprilysin (p<0.01), and insulin-degrading enzyme. It ameliorated neuroinflammation through decreased levels of tumour necrosis factor α (p<0.001), nuclear factor-kappa B (p<0.001), interleukin 6 (p<0.001), interleukin 1 beta (p<0.001), and interferon-gamma (p<0.001). It also maintained synaptic plasticity and consolidated memory. Histopathology showed that valacyclovir could restore cellular density and also preserve the dentate gyrus. Valacyclovir showed comparable activity to donepezil and thus can be further researched for the treatment of Alzheimer's disease.

Influence of Faradarmani Consciousness Field (CF) on Spatial Memory and Passive Avoidance Behavior of Scopolamine Model of Alzheimer Disease in Male Wistar Rats

In another study titled “Influence of Faradarmani Consciousness Field (CF) on Spatial Memory and Passive Avoidance Behavior of Scopolamine Model of Alzheimer Disease in Male Wistar Rats,” (Authors: Mohammad Ali Taheri, Sara Torabi, Noushin Nabavi, Farid Semsarha), we evaluated the influence of Faradarmani CF on scopolamine-induced memory impairments in male Wistar rats. The passive avoidance and Morris water maze (MWM) tests were conducted to evaluate memory function in scopolamine-induced rats. The results of passive avoidance and MWM tests showed a significant decrease in spatial memory and cognitive function in scopolamine groups, whereas Faradarmani CF improved scopolamine-induced cognitive impairment. In conclusion, this experiment suggests that Faradarmani CF, as a non-material/non-energetic Field, can be a safe and suitable way to treat or prevent learning and memory disorders. *Corresponding Author: Farid Semsarha Ph.D., Institute of Biochemistry and Biophysics (IBB), University of Tehran, P.O. Box: 13145-1384, Tehran, Iran. Email: Semsarha@alumni.ut.ac.ir. Pending Review.

Neuroprotective Potential of Guiera senegalensis (Combretaceae) Leaf Hydroethanolic Extract against Cholinergic System Dysfunctions and Oxidative Stress in Scopolamine-Induced Cognitive Impairment in Zebrafish (Danio rerio).

Guiera senegalensis JF Gmel. (Combretaceae) (GS) is a plant used in traditional medicine in West Africa for the treatment of several diseases, such as epilepsy and depression. However, its potential benefits in improving scopolamine (Sco)-induced memory impairment and brain oxidative stress in zebrafish have been investigated. In the present study, zebrafish (Danio rerio) were treated with GS (1, 4, and 8 μg/L) for 19 days as well as Sco (100 µM) 30 min before behavioral tests. Behavioral performance was assessed by the Y-maze test and novel object recognition test (NOR), whereas anxiety response was evaluated in the novel tank diving test (NTT). Subsequently, high-performance liquid chromatography (HPLC) was used to evaluate the GS chemical composition. Sco promoted oxidative stress and acetylcholinesterase (AChE) activity. Moreover, both oxidative stress parameters and AChE activity were ameliorated by GS treatment. Accordingly, the present findings further provided the potential use of GS as a natural, alternative treatment against cognitive disorders associated to Alzheimer’s disease (AD).

Development of 5-hydroxyl-1-azabenzanthrone derivatives as dual binding site and selective acetylcholinesterase inhibitors

A series of novel 5-hydroxyl-1-azabenzanthrone derivatives were designed, synthesized and evaluated as dual binding site acetylcholinesterase inhibitors for the treatment of Alzheimer's disease (AD). The most effective Compound 16 showed selective inhibition of acetylcholinesterase (eeAChE IC50 = 0.045 μM; eeBuChE IC50 = 19.68 μM; SI = 437.33). Most of the compounds showed cytoprotective effects on PC12 cells damaged by hydrogen peroxide, which might be related to their antioxidant activity. Further experiments confirmed that 16 exhibited anti-apoptotic effects at low concentrations and reduced the relative level of ROS generation in PC12 cells. The expression level of proteins related to antioxidant stress pathway in PC12 cells was relatively increased after administrated with 16, which may be beneficial to delay the progression of the disease. Moreover, 16 was evaluated to be safe in vivo and in vitro, and showed good overall pharmacokinetic performance and high bioavailability (Foral = 55.5%). Besides, 16 showed comparable performance in ameliorating the scopolamine-induced cognition impairment to donepezil. In addition, in vitro BBB permeability experiments confirmed that 16 had high BBB permeability.

Chinese Herbal Extracts Exert Neuroprotective Effect in Alzheimer's Disease Mouse Through the Dopaminergic Synapse/Apoptosis Signaling Pathway.

Background: Alzheimer’s disease (AD) as an age-related, irreversible neurodegenerative disease, characterized by cognitive dysfunction, has become progressively serious with a global rise in life expectancy. As the failure of drug elaboration, considerable research effort has been devoted to developing therapeutic strategies for treating AD. TCM is gaining attention as a potential treatment for AD. Gastrodia elata Blume, Polygala tenuifolia Willd., Cistanche deserticola Ma, Rehmannia lutinosa (Gaertn.)DC., Acorus gramineus Aiton, and Curcuma longa L. (GPCRAC) are all well-known Chinese herbs with neuroprotective benefits and are widely used in traditional Chinese decoction for AD therapy. However, the efficacy and further mechanisms of GPCRAC extracts in AD experimental models are still unclear. The purpose of this study was to investigate the synergistic protective efficacy of GPCRAC extracts (composed of extracts from these six Chinese medicines), and the protein targets mediated by GPCRAC extracts in treating AD. Methods: Scopolamine-induced cognitive impairment mouse model was established to determine the neuroprotective effects of GPCRAC extracts in vivo, as shown by behavioral tests and cerebral cholinergic function assays. To identify the potential molecular mechanism of GPCRAC extracts against AD, label-free quantitative proteomics coupled with tandem mass spectrometry (LC-MS/MS) were performed. The integrated bioinformatics analysis was applied to screen the core differentially expressed proteins in vital canonical pathways. Critical altered proteins were validated by qPCR and Western blotting. Results: Administration of GPCRAC extracts significantly recovered scopolamine-induced cognitive impairment, as evidenced by the improved learning and memory ability, increased Ach content and ChAT activity, as well as decreased AchE activity in the hippocampus of mice. In total, 390 proteins with fold-change>1.2 or <0.83 and p < 0.05 were identified as significant differentially expressed proteins, of which 110 were significantly up-regulated and 25 were significantly down-regulated between control and model group. By mapping the significantly regulated proteins, we identified five hub proteins: PPP2CA, Gsk3β, PP3CC, PRKACA, and BCL-2 that were associated with dopaminergic synapse and apoptosis signaling pathway, respectively. Western blotting and QPCR demonstrate that the expression levels of these core proteins could be significantly improved by the administration of GPCRAC extracts. These pathways and some of the identified proteins are implicated in AD pathogenesis. Conclusion: Administration of GPCRAC extracts was effective on alleviating scopolamine-induced cognitive impairment, which might be through modulation of dopaminergic synapse and apoptosis signaling pathway. Consequently, our quantitative proteome data obtained from scopolamine-treated model mice successfully characterized AD-related biological alterations and proposed novel protein biomarkers for AD.

Sea Cucumber-Derived Peptide Attenuates Scopolamine-Induced Cognitive Impairment by Preventing Hippocampal Cholinergic Dysfunction and Neuronal Cell Death.

The incidence of neurodegenerative diseases related to cognitive decline and memory loss is on the rise as the global elderly population increases. In this study, we evaluated the effect of the sea cucumber-derived peptide Phe-Tyr-Asp-Trp-Pro-Lys (FYDWPK) on scopolamine-induced neurotoxicity in an animal model. The Morris water maze, passive avoidance apparatus, and shuttle box test were used to assess learning and memory abilities. In behavioral tests, FYDWPK effectively alleviated learning and memory impairment. FYDWPK also alleviated cholinergic dysfunction in mice with dementia. Furthermore, FYDWPK significantly improved oxidative imbalance by increasing superoxide dismutase activity and decreasing malondialdehyde levels (P < 0.05). The pathological results showed that FYDWPK alleviated neuronal loss, blurred caryotheca, and pyknotic nuclei in the hippocampus, and a high dose of FYDWPK had the best effect. In conclusion, FYDWPK alleviated cognitive and memory impairments by regulating oxidative imbalance, reducing cholinergic dysfunction, and relieving pathological alterations.

&amp;lt;i&amp;gt;Khaya grandifololia&amp;lt;/i&amp;gt; Improves Cognition and Prevents Scopolamine-Induced Impairment of Brain Functions by Activating the Cholinergic and Antioxidant Systems in Rats

Alzheimer’s disease (AD) is a multifactorial, progressive neurodegenerative disorder with dementia and persistent impairment of cognitive functions as the main clinical characteristics. Although signs of progress are being made in developing AD therapy, there is no effective drug capable of stopping and/or slowing down the progression of the disease. We have previously indicated in an in vitro setting of AD that <i>Khaya grandifololia</i> (KG) crude extract possesses antioxidant, anti-inflammatory, and neuroprotective activities. In the current work, we have evaluated the activity of KG hydroethanolic (KG-HE) extract in preventing cognitive impairment and promoting memory improvement in vivo. Results from behavioral tests indicated a significant improvement in memory performance and a delay in depression-like behavior upon treatment of rats with KG-HE extract (5, 25, and 50 mg/kg) or donepezil (1 mg/kg) as standard. Because scopolamine (1 mg/kg) impaired cognitive performance in the tail suspension test, Morris Water Maze test, and Novelty Suppressed Feeding Test, KG-HE extract (5, 25, and 50 mg/kg) or donepezil (1 mg/kg) treatment prevented scopolamine-induced performance impairment. Moreover, both KG-HE extract (5, 25, and 50 mg/kg) and donepezil (1 mg/kg) prevented the scopolamine-induced cognitive impairment by inhibiting the acetylcholinesterase activity. In addition, the brain parameters of stress oxidation (SOD, CAT, and GSH) reduced by scopolamine treatment were regulated by the administration of KG-HE extract or the standard drug donepezil. An increase in the MDA level and the phosphatase activity both in the serum and brain due to scopolamine treatment was restored by the administration of KG-HE extract or donepezil. Taken together, these results suggest that KG-HE extract improves cognition and relieves the scopolamine-induced cognitive impairment via activation of the cholinergic and anti-oxidation systems in rats.

Improvement of cognitive deficit of curcumin on scopolamine-induced Alzheimer's disease models.

Background:It has been suggested that curcumin may be useful in diseases with cognitive dysfunction because it slows the progression and leads to the improvement of cognitive functions. In this study, the protective effects of curcumin on scopolamine-induced rat models of cognitive impairment were evaluated.Methods:21 male Wistar Albino rats, 1 year old, 200±25 grams, were included in the study. They were divided into three groups (n: 7 in each group); the untreated control group, scopolamine group, and the group treated with curcumin and then exposed to scopolamine. Animals were evaluated for behavioral tasks with the Morris Water Maze test. Interleukin-6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), total oxidative status (TOS), and total antioxidative status (TAS) were measured in hippocampal tissues. CRP levels were measured in serum specimens.Results:We found that the length to reach the platform was the highest in the scopolamine group, and the lowest in the curcumin group (p<0.001). Time to reach the platform was the longest in the scopolamine group, and the shortest in the curcumin group (P=0.002). The length to reach the platform was the highest in the scopolamine group, and the lowest in the control group in the probe test (p<0.001). IL-6 levels were higher in the scopolamine group than the curcumin group (P=0.017) and the control group (P=0.005).Conclusion:We revealed that curcumin provides a protective effect on scopolamine-induced cognitive impairment mimicking Alzheimer's disease. The use of curcumin for the protection of cognition in individuals at risk of developing AD may be considered.

Tilapia Head Protein Hydrolysate Attenuates Scopolamine-Induced Cognitive Impairment through the Gut-Brain Axis in Mice.

The destruction of the homeostasis in the gut-brain axis can lead to cognitive impairment and memory decline. Dietary intervention with bioactive peptides from aquatic products is an innovative strategy to prevent cognitive deficits. The present study aimed to determine the neuroprotective effect of tilapia head protein hydrolysate (THPH) on scopolamine-induced cognitive impairment in mice, and to further explore its mechanism through the microbiota–gut-brain axis. The results showed that THPH administration significantly improved the cognitive behavior of mice, and normalized the cholinergic system and oxidative stress system of the mice brain. The histopathological observation showed that THPH administration significantly reduced the pathological damage of hippocampal neurons, increased the number of mature neurons marked by NeuN and delayed the activation of astrocytes in the hippocampus of mice. In addition, THPH administration maintained the stability of cholinergic system, alleviated oxidative stress and further improved the cognitive impairment by reshaping the gut microbiota structure of scopolamine-induced mice and alleviating the disorder of lipid metabolism and amino acid metabolism in serum. In conclusion, our research shows that THPH supplementation is a nutritional strategy to alleviate cognitive impairment through the gut-brain axis.

Agomelatine Reverses Scopolamine-Induced Learning and Memory Impairment in Adult Rats

Objective: The antidepressant agomelatine agent is a melatonin receptor (MT1 and MT2) agonist and a serotonin receptor (5-HT2C) antagonist. Increasing evidence shows that agomelatine has neuroprotective and neuromodulatory effects. In this study, the potential effects of agomelatine in rats with scopolamine-induced cognitive impairment were investigated.Materials and Methods: Adult male rats were administered scopolamine (1 mg/kg) and agomelatine (40 mg/kg) for 21 days. After drug administration, rats were subjected to new object recognition (NOR) and Morris water maze (MWM) tests in order to evaluate cognitive behaviors. In addition, brain-derived neurotrophic factor (BDNF) and acetylcholine (ACh) levels in the hippocampus and prefrontal cortex were evaluated.Results: Scopolamine significantly decreased both spatial memory and discrimination index (p&amp;lt;0.05). Agomelatine treatment increased spatial memory performance and exploration time, but did not affect the discrimination index (P&amp;gt;0.05). In addition, agomelatine significantly increased BDNF levels in both hippocampus and prefrontal cortex compared to the scopolamine group (p&amp;lt;0.05, p&amp;lt;0.01, respectively). On the other hand, there was no statistically significant difference between the ACh levels of the groups (p&amp;gt;0.05).Conclusion: Taken together, these results demonstrated that agomelatine plays a important role in alleviating scopolamine-induced memory impairment. Therefore, we suggest that agomelatine may be a potential agent in the prevention of cognitive impairment.

원감, 수수 및 누에번데기 추출물로 조제된 조성물의 인지기능 개선 효과

Dementia including Alzheimer’s disease, is a severe neurodegenerative disorder characterized by progressive cognitive deficits as major symptom. The compositions (BBGS171) including extracts from root of Wongam (a Glycyrriza cultivar), seed of Sorghum bicolor (L.) pupae of Moench and Bombyx mori L. was selected based on preliminary experiments on the ability to improve cognition function in vitro. BBGS171 showed inhibitory activity on cholinesterases, such as acetylcholinesterase (AChE) and butyrylcholinesterase (BuchE) and inhibited nitric oxide (NO) production in lipopolysaccharide (LPS)-treated BV2 cells (a microglial cell line). The Y-maze test and passive avoidance test (PAT) were used to evaluate the behavior of an animal model of scopolamine-induced cognitive impairment. Rats administered BBGS171 (EM, extract mixture) in the diet showed better spontaneous alteration and escape latency than those of control rats. Levels of hippocampal choline acetyltransferase (ChAT) and serum acetylcholine (ACh) were significantly higher in the BBGS171 diet group than in the control group. Expression levels of brain-derived neurotrophic factor (BDNF) and extracellular signal-regulated kinase (ERK) 1/2 in the hippocampus of the BBGS171 diet group were also higher than those of control group. These results suggest that BBGS171 (EM) could ameliorate cognition impairment and showed potential as a useful functional material.

Chalcone-Derived Nrf2 Activator Protects Cognitive Function via Maintaining Neuronal Redox Status.

NF-E2-related factor 2 (Nrf2), the key transcription regulator of phase II enzymes, has been considered beneficial for neuronal protection. We previously designed a novel chalcone analog, 1-(2,3,4-trimethoxyphenyl)-2-(3,4,5-trimethoxyphenyl)-acrylketone (Tak), that could specifically activate Nrf2 in vitro. Here, we report that Tak confers significant hippocampal neuronal protection both in vitro and in vivo. Treatment with Tak has no significant toxicity on cultured neuronal cells. Instead, Tak increases cellular ATP production by increasing mitochondrial function and decreases the levels of reactive oxygen species by activating Nrf2-mediated phase II enzyme expression. Tak pretreatment prevents glutamate-induced excitotoxic neuronal death accompanied by suppressed mitochondrial respiration, increased superoxide production, and activation of apoptosis. Further investigation indicates that the protective effect of Tak is mediated by the Akt signaling pathway. Meanwhile, Tak administration in mice can sufficiently abrogate scopolamine-induced cognitive impairment via decreasing hippocampal oxidative stress. In addition, consistent benefits are also observed in an energy stress mouse model under a high-fat diet, as the administration of Tak remarkably increases Akt signaling-mediated antioxidative enzyme expression and prevents hippocampal neuronal apoptosis without significant effect on the mouse metabolic status. Overall, our study demonstrates that Tak protects cognitive function by Akt-mediated Nrf2 activation to maintain redox status both vivo and in vitro, suggesting that Tak is a promising pharmacological candidate for the treatment of oxidative neuronal diseases.

A standardized black pepper seed extract containing β-caryophyllene improves cognitive function in scopolamine-induced amnesia model mice via regulation of brain-derived neurotrophic factor and MAPK proteins.

β-caryophyllene (BCP), a natural sesquiterpene present in plants, is a selective agonist of cannabinoid receptor type-2 (CB2) of the endocannabinoid system. In this study, we have prepared an extract from Piper nigrum (black pepper) seeds using supercritical fluid extraction, standardized to contain 30% BCP (ViphyllinTM ). The beneficial effects of prophylactic treatment with Viphyllin on cognitive functions were demonstrated in Scopolamine-induced dementia model mice. Male Swiss albino mice (25-30g) were administered with Viphyllin (50mg and 100mg/kg body weight p.o.) or donepezil (1.60mg/kg) for 14days. Subsequently, cognitive deficits were induced by treating the animals intraperitoneally with Scopolamine (0.75mg/kg). The cognitive behavior of mice was evaluated using a novel object recognition test (NORT) and Morris water maze (MWM) test. The brain homogenates were studied for biochemical parameters including cholinesterase activities and antioxidant status. Western blot analysis was performed to investigate the mechanism of action. Viphyllin dose dependently improved the recognition and spatial memory and cholinergic functions in Scop-treated mice. The extract was found protective against Scop-induced oxidative damage and histopathologic changes in the brain. At 100mg/kg Viphyllin markedly reduced the proBDNF/mBDNF ratio (p<.05) and augmented the TrkB expression (p<.01). Viphyllin (100mg/kg) was found to be neuroprotective by reducing the Scop-induced upregulation of p-JNK and p-p38 MAPK proteins, Bax/Bcl-2 ratio, and caspase activation in the brain. Viphyllin also exerted anti-inflammatory effects by downregulating Cox-2, TNF-α, and NOS-2 in Scop-induced mice (p<.05). To summarize, our data encourage Viphyllin as a functional ingredient/dietary supplement for brain health and cognition. PRACTICAL APPLICATIONS: Black pepper is a culinary spice having several medicinal attributes. Essential oils in the seeds of the plant give aroma and flavor to it. Here we have prepared an extract from the seeds of black pepper using supercritical fluid extraction, characterized for the presence of β-caryophyllene (not <30%). This research work further validates the neuroprotective mechanism of the extract in Scopolamine-induced cognitive impairment model mice. The findings from this study strongly suggest the beneficial neuroactive properties of black pepper seed extract having the presence of BCP, a CB2 receptor agonist. It can thus be used potentially as a functional food ingredient for cognition and brain function.

The protective effect of Centella asiatica and its constituent, araliadiol on neuronal cell damage and cognitive impairment

Alzheimer's disease (AD) is characterized by progressive cognitive decline, and the number of affected individuals has increased worldwide. However, there are no effective treatments for AD. Therefore, it is important to prevent the onset of dementia. Oxidative stress and endoplasmic reticulum (ER) stress are increased in the brains of AD patients, and are postulated to induce neuronal cell death and cognitive dysfunction. In this study, Centella asiatica, a traditional Indian medicinal herb, were fractionated and compared for their protective effects against glutamate and tunicamycin damage. Araliadiol was identified as a component from the fraction with the highest activity. Further, murine hippocampal cells (HT22) were damaged by glutamate, an oxidative stress inducer. C. asiatica and araliadiol suppressed cell death and reactive oxygen species production. HT22 cells were also injured by tunicamycin, an ER stress inducer. C. asiatica and araliadiol prevented cell death by mainly inhibiting PERK phosphorylation; additionally, C. asiatica also suppressed the expression levels of GRP94 and BiP. In Y-maze test, oral administration of araliadiol (10 mg/kg/day) for 7 days ameliorated the arm alternation ratio in mice with scopolamine-induced cognitive impairment. These results suggest that C. asiatica and its active component, araliadiol, have neuroprotective effects, which may prevent cognitive dysfunction.

Novel cannabidiol-carbamate hybrids as selective BuChE inhibitors: Docking-based fragment reassembly for the development of potential therapeutic agents against Alzheimer's disease.

Cannabidiol (CBD) and rivastigmine have been launched as drugs for treating dementia and cholinesterases (ChEs) are ideal drug targets. This study focused on developing novel ChE inhibitors as drug leads against dementia through molecular modeling and fragment reassembly approaches. A potent carbamate fragment binding to active site gorge of BuChE was found via a docking-based structural splicing approach, thus, 17 novel compounds were designed by structural reassembly. Compound C16 was identified as a highly selective potent BuChE inhibitor (IC50=5.3nM, SI>4000), superior to CBD (IC50=0.67μM). C16 possessed BBB penetrating ability, benign safety, neuroprotection, antioxidant and pseudo-irreversible BuChE inhibition (Kd=13nM, k2=0.26 min-1), showing good drug-like properties. Invivo studies confirmed that C16 significantly ameliorated the scopolamine-induced cognition impairment, almost entirely recovered the Aβ1-42 (icv)-impaired cognitive function to the normal level, showed better behavioral performance than donepezil and good anti-amyloidogenic effect. Hence, the potential BuChE inhibitor C16 can be developed as a promising disease-modifying treatment of AD.

Butea superba Roxb. Extract Ameliorates Scopolamine-Induced Cognitive and Memory Impairment in Aged Male Rats.

Butea superba Roxb. (B. superba) is a herb that has been used for rejuvenation, to improve sexual performance, or to prevent erectile dysfunction function. Alzheimer's disease (AD) is a chronic neurodegenerative disorder that is the main cause of progressive dementia. This study aimed to investigate the amelioration for cognitive and memory dysfunction of B. superba ethanolic extract (BSE), a possible mechanism of action, and its toxicity. The results from the Y-maze test, novel object recognition test, and passive avoidance test exhibited that the administration of BSE at 50 mg/kg (BSL) and 200 mg/kg (BSH) could ameliorate scopolamine-induced cognitive impairment in all behavior testing. Moreover, BSE could prevent the cognitive deficit in a dose-dependent manner in a passive avoidance test. Furthermore, BSE inhibited acetylcholinesterase's (AChE) ex vivo activity in the cerebral cortex and hippocampus. Also, the in vitro and ex vivo antioxidative effects of BSE revealed that BSE had free radical scavenging activities in both DPPH and FRAP assay. Furthermore, male rats treated with BSE at 200 mg/kg/day for two weeks could significantly increase serum testosterone compared with control (P < 0.05). The GC-MS analysis and previous studies revealed that BSE contained propanoic acid, 3,3′-thiobis-, didodecyl ester, oleic acid, gamma-sitosterol, and stigmasterol which may play an important role in cognitive and memory impairment prevention. The toxicity test of BSE in rats at 50 and 200 mg/kg/day for two weeks showed that relative organ weight, serum creatinine, ALT, ALP, and CBC levels of both treated groups were not significantly different compared to the CON (P > 0.05). These results suggest that BSE may not be toxic to the vital organ and blood. In conclusion, BSE has the potential to be developed as a health supplement product or medicine for AD prevention and treatment.