Memory Enhancing Properties Research Articles

Protopine promotes the proteasomal degradation of pathological tau in Alzheimer's disease models via HDAC6 inhibition

BackgroundCollective evidences have indicated that intracellular accumulation of hyperphosphorylated tau forms neurofibrillary tangles in the brain, which impairs memory, cognition and affects social activities in Alzheimer's disease (AD). PurposeTo investigate the tau-reducing, and memory-enhancing properties of protopine (PRO), a natural alkaloid isolated from Chinese herbal medicine Corydalis yanhusuo (Yanhusuo in Chinese). Study designBy using Histone deacetylase 6 (HDAC6) profiling and immunoprecipitation assays, we assessed that PRO mediated the heat shock protein 90 (HSP90) chaperonic activities for the degradation of pathological tau in AD cell culture models. To study the efficacy of PRO in vivo, we employed 3xTg-AD and P301S tau mice models. MethodsLiquid chromatography/quadrupole time-of-flight mass spectrometry was used to analyze the pharmacokinetic profile of PRO. Seven-month-old 3xTg-AD mice and 1.5-month-old P301S mice were administered PRO (1 and 2.5 mg/kg) orally every day. Morris water maze, contextual fear conditioning and rotarod assays were applied for studying memory functions. Sarkosyl differential centrifugation was used to analyze soluble and insoluble tau. Immunohistochemical analysis were performed to determine tau deposits in AD mice's brain sections. Molecular docking, binding affinity studies and primary cell culture studies were performed to demonstrate the mechanism of action of PRO in silico and in vitro. ResultsOur pharmacokinetic profiling demonstrated that PRO significantly entered the brain at a concentration of 289.47 ng/g, and specifically attenuated tau pathology, improved learning and memory functions in both 3xTg-AD and P301S mice. Docking, binding affinity studies, and fluorometric assays demonstrated that PRO directly bound to the catalytic domain 1 (CD1) of HDAC6 and down-regulated its activity. In primary cortical neurons, PRO enhanced acetylation of α-tubulin, indicating HDAC6 inhibition. Meanwhile, PRO promoted the ubiquitination of tau and recruited heat shock protein 70 (HSP70) and heat shock cognate complex 71 (HSC70) for the degradation of pathological tau via the ubiquitin-proteasomal system (UPS). ConclusionWe identified PRO as a natural HDAC6 inhibitor that attenuated tau pathology and improved memory dysfunctions in AD mice. The findings from this study provides a strong justification for future clinical development of plant-derived protopine as a novel agent for the treatment of tau-related neurodegenerative diseases.

Loganin substantially ameliorates molecular deficits, pathologies and cognitive impairment in a mouse model of Alzheimer's disease.

Alzheimer’s disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis, is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased Aβ deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the Aβ-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTauS396 and pTauS262) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.

Ameliorative Potential of Glycyrrhiza glabra Extracts on Memory Impairments in Stress Triggered Rats

Background: Glycyrrhiza glabra Linn. (Family: Fabaceae) is known to be a very useful medicinal plant in the Traditional Medicinal Systems since centuries. With ethnopharmacological values, it is a well-reported plant for its anti-inflammatory, antioxidant, anxiolytic, expectorant and antidepressant activities. Objective: Although the plant has been described to possess memory enhancing activity, the present study focused on examining the comparative effect of Glycyrrhiza glabra extracts viz. flavonoid rich (GGFE) and glycyrrhizin rich (GGGE) in stress-triggered rats and providing future research insights on this herbal drug, for which no scientific justification has been reported till now. Methods: Male Wister rats divided into 7 different groups (n= 6 per group) were given chronic foot-shock stress for 21 successive days with scheduled administration of the extracts (50 and 100 mg/kg) and standard drug (10 mg/kg) for 28 days. Elevated Plus Maze, Rectangular Maze, Morris Water Maze, and Locomotor activity were performed to test behavioral alteration and learning ability of stressed rats. Further, rats were sacrificed to assay acetylcholinesterase activity and antioxidant activity in brain samples for their mechanistic role in learning and memory. Results: Extracts of Glycyrrhiza glabra indicated a significant alteration in stress-induced learning and memory deficiency in behavioral parameters studied. These extracts also modulated significant changes in acetylcholinesterase and antioxidant enzyme activity to improve the learning and memory of stressed rats. Conclusions: Both the extracts of Glycyrrhiza glabra (GGFE and GGGE) were found to exert memory enhancing property in stress-triggered rats. Moreover, the comparative results confirmed that the high potential of GGGE in comparison to GGFE might be due to the rich glycyrrhizin content present in GGGE responsible for acetylcholinesterase and antioxidant enzyme modulatory activities. Therefore, GGGE could be used as a promising lead for further mechanistic and molecular studies for defining the role of glycyrrhizin in Glycyrrhiza glabra.

The modulatory role of prime identified compounds in Geophila repens in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease via attenuation of cholinesterase, β-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation

Ethnopharmacological relevanceGeophila repens (L.) I.M. Johnst (Rubiaceae) is a small perennial creeper native to India, China, and other countries in Southeast Asia. The hot decoction of leaves is used orally for memory enhancing by the local folk of Andhra Pradesh, India. The ethnomedicinal claim of G. repens as memory enhancer was initially studied by the authors. Results demonstrated the important antioxidant and anticholinesterase activities of isolated molecule Pentylcurcumene and bioactive hydroalcohol extract of leaves of G. repens (GRHA). Aim of the studyBased on the previous findings, additional research is needed to examine the efficacy of GRHA for memory enhancing properties. We therefore investigated the modulatory role of prime identified compounds in GRHA in mitigating scopolamine-induced neurotoxicity in experimental rats of Alzheimer's disease (AD) via attenuation of cholinesterase, β-secretase, MAPt levels and inhibition of oxidative stress imparts inflammation. MethodsScopolamine (3 mg/kg) induced experimental rats of AD were treated with GRHA (300, 400 mg/kg) for 14 days. During the experimental period, elevated T-maze and locomotion-activity were performed to assess learning and memory efficacy of GRHA. At the end of the experiment, biochemical, neurochemical, neuroinflammation and histopathological observation of brain cortex were examined. GC-MS/MS analysis reported 31 compounds, among them 8 bioactive compounds possess antioxidant, neuroinflammation, neuroprotective activities, and were considered for docking analysis towards cholinesterase, β-secretase activities in AD. ResultsGRHA 400 significantly improved learning and memory impairment with the improvement of oxidative stress (MDA, SOD, GSH, CAT), DNA damage (8-OHdG), neurochemical (AChE, BuChE, BACE1, BACE2, MAPt), neuroinflammation (IL-6, TNF-α) markers in neurotoxic rats. Docking studies of 8 compounds demonstrated negative binding energies for cholinesterase and β-secretase indicating high affinity for target enzymes in AD. Test results were corroborated by the improvement of cellular tissue architecture of brain cortex in AD rats. ConclusionSynergistic action of genistin, quercetin-3-D-galactoside, 9,12,15-octadecatrienoic-acid methyl-ester, phytol, retinal, stigmasterol, n-hexadecanoic acid, β-sitosterol in GRHA restores memory-deficits via attenuation of cholinesterase, β-secretase, MAPt level and inhibition of oxidative-stress imparts inflammation in AD.

Enhanced recombinant expression and purification of human IRAP for biochemical and crystallography studies

Insulin-regulated aminopeptidase (IRAP) in humans is a membrane bound enzyme that has multiple functions. It was first described as a companion protein of the insulin-responsive glucose transporter, Glut4, in specialized vesicles. The protein has subsequently been shown to be identical to the oxytocinase/aminopeptidase or the angiotensin IV (Ang IV) receptor (AT4 receptor). Some AT4 ligand peptides, such as Ang IV and LVV-hemorphin-7, have been shown to act as IRAP inhibitors that exert memory-enhancing properties. As such IRAP has been a target for developing cognitive enhancers. To facilitate detailed mechanistic studies of IRAP catalysis and inhibition, and to pave the way for biophysical and structural studies of IRAP in complex with peptide inhibitors, we report here an optimized expression and purification system using High Five insect cells. We also report biochemical characterizations of the purified recombinant IRAP with a standard aminopeptidase substrate and an optimized IRAP peptide inhibitor with a Ki of 98 nM.

HPLC-MS/MS-Mediated Analysis of the Pharmacokinetics, Bioavailability, and Tissue Distribution of Schisandrol B in Rats.

Schisandrol B, a lignan isolated from dried Schisandra chinensis fruits, has been shown to exhibit hepatoprotective, cardioprotective, renoprotective, and memory-enhancing properties. This study sought to design a sensitive and efficient HPLC-MS/MS approach to measuring Schisandrol B levels in rat plasma and tissues in order to assess the pharmacokinetics, oral bioavailability, and tissue distributions of this compound in vivo. For this analysis, bifendate was chosen as an internal standard (IS). A liquid-liquid extraction (LLE) approach was employed for the preparation of samples that were subsequently separated with an Agilent ZORBAX Eclipse XDB-C18 (4.6 × 150 mm, 5 μm) column with an isocratic mobile phase consisting of methanol and water containing 5 mM ammonium acetate and 0.1% formic acid (90 : 10, v/v). A linear calibration curve was obtained over the 5–2000 ng/mL and 1–1000 ng/mL ranges for plasma samples and tissue homogenates, respectively. This established method was then successfully applied to investigate the pharmacokinetics, oral bioavailability, and tissue distributions of Schisandrol B in Sprague-Dawley (SD) rats that were intravenously administered 2 mg/kg of Schisandrol B monomer, intragastrically administered Schisandrol B monomer (10 mg/kg), or intragastrically administered 6 mL/kg SCE (equivalent to 15 mg/kg Schisandrol B monomer). The oral absolute bioavailability of Schisandrol B following intragastric Schisandrol B monomer and SCE administration was approximately 18.73% and 68.12%, respectively. Tissue distribution studies revealed that Schisandrol B was distributed throughout several tested tissues, with particular accumulation in the liver and kidneys. Our data represent a valuable foundation for future studies of the pharmacologic and biological characteristics of Schisandrol B.

Madecassoside encapsulated in alginate chitosan nanoparticles exerts anti-excitotoxicity effects in pilocarpine-induced seizure

Madecassoside (MAD), a pentacyclic triterpenoid saponin, and its source herb Centella asiatica are best known for their memory enhancing and neuroprotective properties. The effects of MAD- and similar secondary metabolite-encapsulated nanoparticles on brain are least explored. Henceforth, we have developed MAD encapsulated alginate chitosan nanoparticles (MACNPs), and their therapeutic potential is studied against pilocarpine (PC) rodent seizure model. MACNPs were synthesized by ionic-gelation polyelectrolyte technique and characterized by DLS, SEM, TEM and XRD. MAD encapsulation and release profile of MACNPs were studied in vitro. MACNPs distribution in mice brain tissues was also evaluated by SEM and TEM. MACNPs offered a negative zeta potential, considerable hydrodynamic size and spherical morphology. They significantly reduced the number of animals experiencing the most severe seizures, showed enhanced bioavailability and membrane integrity. Protection of tissues by MACNPs on PC toxicity in mice was assessed by histopathology on challenged mice brain. mRNA overexpression of MAPK1, MAPK14 genes together with bcl2, caspase 3 and hspa1b for oxidative stress and inflammation was observed. However, regulated expression of mRNA in p53 gene was noted. Our results describing the anti-seizure profile, combined with its observed mRNA expression and biodistribution, strongly support MACNP as a therapeutic candidate for a diverse range of epilepsies and related stress-inflammation.

The effects of the combination of Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata on learning and memory deficit and oxidative damage in brain tissue of hypothyroid rats.

In the present study, the impact of a combination of four memory-enhancer herbs on cognitive impairment and brain tissue oxidative damage due to hypothyroidism was evaluated. Propylthiouracil (PTU; 0.05%) was administrated in drinking water. Rats were treated with a combination of four herbal products (Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata) mixed with honey at two doses (640 and 1,280mg/kg) or donepezil (0.5mg/kg), for 6weeks. Memory performance on the Morris water maze (MWM) and avoidance behavior in passive avoidance was impaired by hypothyroidism, and brain tissue oxidative damage occurred. Herbal combination and donepezil significantly improved memory impairment, reduced malondialdehyde concentration, and nitric oxide metabolites while increased the thiol contents and catalase and superoxide dismutase enzymes activity in the brain. Our findings suggest that the mixture of herbal products improves learning and memory deficits caused by hypothyroidism, probably by reducing the brain tissue oxidative damage. PRACTICAL APPLICATIONS: Learning and memory impairment is a common feature of thyroid hormones deficiency. Several studies are showing that hypothyroidism in juvenile and mature rats induces significant cognitive impairment. Likewise, in humans, a close relationship between thyroid hormone deficiency and cognitive impairment has been reported. We used a mixture of herbal products, including Cyperus rotundus, Crocus sativus, Piper nigrum, and Boswellia serrata, to treat hypothyroidism-induced memory impairment. All these herbs are widely used as a food additive across the world. In Iranian traditional medicine, this herbal combination traditionally used to treat cognitive impairments. Numerous studies have indicated that these herbs show neuroprotective and memory-enhancing properties. Our finding indicated that a traditionally used herbal combination could potentially use as a treatment of cognitive impairment induced by thyroid hormone deficiency.

Azetidine-based selective glycine transporter-1 (GlyT1) inhibitors with memory enhancing properties

A strategy to conformationally restrain a series of GlyT1 inhibitors identified potent analogs that exhibited slowly interconverting rotational isomers. Further studies to address this concern led to a series of azetidine-based inhibitors. Compound 26 was able to elevate CSF glycine levels in vivo and demonstrated potency comparable to Bitopertin in an in vivo rat receptor occupancy study. Compound 26 was subsequently shown to enhance memory in a Novel Object Recognition (NOR) behavioral study after a single dose of 0.03 mg/kg, and in a contextual fear conditioning (cFC) study after four QD doses of 0.01–0.03 mg/kg.

Neuro-Behavioral Profile and Toxicity of the Essential Oil of Dorema ammoniacum Gum as an Anti-seizure, Anti-nociceptive, and Hypnotic Agent with Memory-enhancing Properties in D-Galactose Induced Aging Mice.

In this study, we focused on the neuro-behavioral profile, toxicity, and possible mechanisms of action of Dorema ammoniacum gum essential oil (DAG-EO). For this purpose, passive avoidance and Y-maze tests were performed to evaluate the potential effect of DAG-EO in the attenuation of memory impairment induced by 49 days administration of D-galactose and acute injection of scopolamine. Anticonvulsant and anti-nociceptive activities of DAG-EO were evaluated in the pentylenetetrazole and ‎maximal electroshock-induced models of seizure and acetic acid-induced writhing tests, respectively. To find the possible mechanism of action, flumazenil and naloxone were used. Furthermore, the possible side effects were determined in the open field, grip strength, and ‎rotarod tests. Our findings supported that 7-day administration of DAG-EO (50 and 100 mg/kg) improves memory impairment induced following administration of D-galactose and scopolamine. It was also revealed that DAG-EO possesses a dose-dependent sedative-hypnotic (100 mg/kg), anticonvulsant (ED50 ≈ 170 mg/kg), and anti-nociceptive (ED50 ≈ 175 mg/kg) activities possibly mediated via directly and/or indirectly modulation of GABAA and opioid receptors. No side effect was observed except muscle relaxation which was less than that of diazepam. The output of this study confirms anti-seizure, anti-nociceptive, sedative-hypnotic, and memory-enhancing properties of DAG-EO by modulation of GABAA receptors.

Ashwagandha: A rasayana from ayurveda

The Rasayanas are rejuvenators, nutritional supplements and possess strong antioxidant activity. They also have antagonistic action on the oxidative stress which leads to the formation of different free radicals. One popular and highly valued herb in Ayurveda, Withania somnifera (L.) Dunal (Ashwagandha) is classified as a rasayana (rejuvenator) in various Ayurvedic classical texts. Various parts of the plant are used in the preparation of different Ayurvedic formulations and home remedy recipes to increase health and longevity. It provides defence against diseases, adverse environmental factors and helps to retard the ageing process. Ashwagandha exhibits a wide range of therapeutic properties by tuning the endocrine, cardiopulmonary, central nervous system and sexual behaviour without any toxicity. The root has been used most frequently for therapeutic purposes and is a constituent of over 200 formulations in Ayurveda, Siddha and Unani medicines. There are several reports to establish its immune-modulatory, anti-inflammatory, anti-stress, memory enhancing, anti-parkinsonian, hypolipidemic, antibacterial, cardiovascular, antioxidant, antitumor and adaptogenic properties. These properties are because of present of bioactive phytochemicals such as alkaloids and phytosterols in the plant. Present communication deals with traditional uses, phytochemical composition and pharmacological properties of Ashwagandha with special reference to its Rasayana properties.

Learning and memory enhancing properties of coenzyme Q10 in amnestic albino Wistar rats

Background: The brain is the important part of the nervous system in all vertebrates. The hippocampus in the humans serves as a major component of the brain. It is a part of the limbic system and plays major roles in acquiring long-term memory and spatial navigation. Among all dementia, Alzheimer’s dementia is most common. The affected person experiences inability to learn new information, has nominal and comprehensive aphasia, apraxia, agnosia, and impairment in execution of functioning. Coenzyme Q10 (Co-Q10) is a lipophilic molecule found, especially in high concentration in the mitochondrial inner membrane. The importance of Co-Q10 in mitochondrial function and its role as an antioxidant have led to therapeutic applications and clinical trials in degenerative diseases. Aim and Objective: This study aims to evaluate the learning and memory enhancing properties of Co-Q10 in albino Wistar rats. Materials and Methods: Eighteen healthy rats were selected for the study, which were divided into three groups. Scopolamine was used as amnestic agent, elevated plus maze (EPM), pole climbing test, and novel object recognition (NOR) tests were used for testing the learning and memory processes. Results: Co-Q10 at higher doses (400 mg/kg) showed significant activity in EPM, pole climbing test, and NOR test for assessing the learning and memory skills when compared to the control group. Conclusion: The present study results revealed that Co-Q10 high doses potentiated the process of learning and memory skills when tested using EPM, pole climbing test, and NOR test which are considered as standard paradigms of learning and memory screening models. The results of this study need to be further evaluated by comprehensive experimental studies and further validated by clinical trials.

The Tripeptide RER Mimics Secreted Amyloid Precursor Protein-Alpha in Upregulating LTP.

Secreted amyloid precursor protein-alpha (sAPPα), generated by enzymatic processing of the APP, possesses a range of neurotrophic and neuroprotective properties and plays a critical role in the molecular mechanisms of memory and learning. One of the key active regions of sAPPα is the central APP domain (E2) that contains within it the tripeptide sequence, RER. This sequence is exposed on the surface of a coiled coil substructure of E2. RER has by itself displayed memory-enhancing properties, and can protect newly formed engrams from interference in a manner similar to that displayed by sAPPα itself. In order to determine whether RER mimics other properties of sAPPα, we investigated the electrophysiological effects of the N-terminal protected acetylated RER (Ac-RER) and an isoform containing a chiral switch in the first amino acid from an l- to a d-orientation (Ac-rER), on synaptic plasticity. We found that, like sAPPα, exogenous perfusion with nanomolar concentrations of Ac-RER or Ac-rER enhanced the induction and stability of long-term potentiation (LTP) in area CA1 of rat and mouse hippocampal slices, in a protein synthesis- and trafficking-dependent manner. This effect did not occur with a control Ac-AAA or Ac-IFR tripeptide, nor with a full-length sAPPα protein where RER was substituted with AAA. Ac-rER also protected LTP against amyloid-beta (Aβ25–35)-induced LTP impairment. Our findings provide further evidence that the RER-containing region of sAPPα is functionally significant and by itself can produce effects similar to those displayed by full length sAPPα, suggesting that this tripeptide, like sAPPα, may have therapeutic potential.

Bacopa monnieri (L.) wettst. Extract protects against glutamate toxicity and increases the longevity of Caenorhabditis elegans

BackgroundNeurodegenerative diseases, such as Alzheimer’s disease, cause a great deal of suffering for both patients and carers. Bacopa monnieri (L.) wettst. Is known for its memory-enhancing properties, and is of great interest in treating neurodegenerative disease. AimsThis study aimed to evaluate B.monnieri against glutamate toxicity, and identify whether B.monnieri reduces mitochondrial and ER stress, as well as to measure B.monnieri’s effect on the life span and aging of Caenorhabditis elegans. We hypothesized that B.monnieri would prevent cellular oxidative stress, prevent mitochondrial/ER stress, and increase the life span while reducing signs of aging in C.elegans. Experimental proceduresGlutamate toxicity was measured using viable cell staining assays and the MTT assay. ROS and mitochondrial stress were assessed by H2DCFDA and Rodamine123 staining, with fluorescence/confocal microscopy. C.elegans’ median and maximum life span were measured, in response to B.monnieri treatment, along with lipofuscin imaging to measure the health of the C.elegans population. ResultsB.monnieri hexane extract (but not ethanol extract) prevented the toxicity of 5 mM glutamate in HT-22 cells. We found that the mechanism involves the reduction of ROS production and the prevention of mitochondrial and ER stress. Furthermore, we showed that B.monnieri could increase the median and maximal lifespan of wild type C.elegans, maintain a younger appearing phenotype in the aged C.elegans. ConclusionsIn conclusion, B.monnieri prevents mitochondrial, and oxidative stress in the cultured cells. Furthermore, it can prolong the healthy lifespan of C.elegans, indicating that B.monnieri the potential for therapeutic and preventative use in neurodegenerative disease.

Memory-enhancing Properties of Hypericum scabrum Essential Oil in a Rat Model of Dementia

Hypericum species are known to be used in traditional therapies. H. scabrum L. is one of the Hypericum species distributed in Turkey. In this study, we evaluated the effects of Hypericum scabrum essential oil inhalation on spatial memory in scopolamine-induced amnesic rats. The essential oil was characterized by GC-FID and GC-MS system. Male wistar rats were divided into 6 groups: control; scopolamine-alone treated; diazepam-treated (positive control); tramadol-treated (positive control); scopolamine with Hypericum scabrum essential oil 1%-treated; and scopolamine with Hypericum scabrum essential oil 3%-treated group. All rats were tested behaviorally to evaluate spatial memory peformances in Y-maze task and radial-arm maze task. The most abundant component of the essential oil was identified as α-pinene (51.3%). Hypericum scabrum essential oil application significantly improved spatial memory as compared to scopolamine-alone treated rats as evidenced by increases in spontaneous alternation behavior in Y-maze task and decreases in the number of working memory errors and reference memory errors in the radial-arm maze task in this study. Hypericum scabrum essential oil inhalation could be used as a complementary therapy to reduce memory impairments in the patients with dementia and related diseases.

Nepeta menthoides Boiss. & Buhse, an endemic species in Iran: A review of traditional uses, phytochemistry and pharmacology

Nepeta menthoides Boiss & Buhse is one of the endemic species in Iran. Named Ostokhodus, it is almost used as substitute of the Lavandula stoechas –the original Ostokhodus- in traditional Persian medicine (TPM) over the time and widely used for the management of some ailments such as anxiety, depression, dementia and chronic pain. The aim of this study is to review the pharmacological and phytochemical evidence on Nepeta menthoides for the assessment of the recommended traditional indications of this herb. In this review, all the relevant articles that met our inclusion criteria [English or Persian articles, having full text, evaluating therapeutic effects of N. menthoides and dated mainly from the year 1980 to 2018] were included by searching studies in PubMed, Scopus, Google Scholar, Web of Science, and SID. The search terms were "Nepeta menthoides, "Ostokhodus". Triterpenes and monoterpenes were the most chemicals reported from essential oil of N. menthoides. Several pharmacological properties via in vitro, in vivo and clinical studies have been reported including antioxidant, anti-inflammatory, anti-nociceptive, antidepressant and anxiolytic, anticholinesterase, neuroprotective, memory enhancing, anti-Alzheimer’s disease, anticancer and effect on opioid dependence. Some proposed traditional indications of this herb in TPM books are in accordance with pharmacological evidence like anti-nociceptive, anti-seizure, anti-Alzheimer’s disease, memory enhancing, neuroprotective, antidepressant, anxiolytic activity and anti-infective properties. Although some properties in TPM, such as anti-tussive and gastrotonic effects are not supported by scientific evidence, they need more investigations.

Isorhamnetin enhanced cortico-hippocampal learning and memory capability in mice with scopolamine-induced amnesia: Role of antioxidant defense, cholinergic and BDNF signaling

Isorhamnetin (IRN), a 3′-O-methylated metabolite of quercetin has antioxidant, anti-inflammatory and neuroprotective properties. In this study, we investigated the learning and memory enhancing effects of IRN on spatial and non-spatial learning and memory deficits induced by scopolamine (3 mg/kg, i.p; muscarinic antagonist) using the novel object recognition test (NORT) and Morris water maze (MWM) task. IRN (1, 5 or 50 mg/kg, p.o.) or vehicle was administered to male albino for 3 consecutive days, scopolamine was given 1 h after last administration on day 3. Five minutes post scopolamine administration the behavioural test of cognitive function was carried out. One hour after probe test (MWM task) on day 7, the brains were isolated to assay for oxidative stress, cholinesterase activity and brain derived neurotrophic factor (BDNF) levels in the prefrontal cortex (PFC) and hippocampus (HIPPO). IRN treatment significantly improved scopolamine-induced learning and memory impairment in behavioural tests. IRN reduced malondialdehyde and nitrite generation induced by scopolamine through increase in glutathione (GSH) level, superoxide dismutase (SOD) and catalase (CAT) activities in the prefrontal cortex and hippocampus. In addition, IRN attenuates scopolamine induced cholinesterase activity and BDNF level in the prefrontal cortex and hippocampus of mice. Findings from this study showed that IRN possesses cognition and memory enhancing properties possibly through enhancement of antioxidant defense system, cholinergic signaling and synaptic plasticity.

마우스에서 국내 육성 신품종 ‘신예감’ 추출물의 기억력 증진 효과

A new mandarin hybrid cultivar called ‘Shinyegam’ was developed from a cross between ‘Kiyomi’ (Citrus unshiu × C. sinensis) and ‘Wilking’ (Citrus reticulata) at the Citrus Research Institute of the National Institute of Horticultural and Herbal Science in 2012. The ‘Shinyegam’ was extracted with 70% ethanol (SYGE), and polyphenol content was measured to assess total antioxidant activity of flavonoids. Radical scavenging activities of the extracts were examined using a-a-diphenyl-β-picrylhydrazyl (DPPH), 2,2-azino-bis 3-ethylbenzthiazoline-6-sulfonic acid (ABTS), and ferric reducing antioxidant power (FRAP) assays. SYGE showed high polyphenol and flavonoid content as well as strong DPPH, ABTS, and FRAP radical scavenging activity. We used a mouse model to assess the memory enhancing properties of SYGE and its ameliorating activities on learning and memory impairments. Drug-induced amnesia was initiated by scopolamine treatment (2 mg/kg, interperitoneal). SYGE administration (25 mg/kg, oral) significantly enhanced cognitive function and attenuated scopolamine-induced cognitive impairments as determined by novel object recognition, passive avoidance and Y-maze tasks. In addition, SYGE increased brain-derived neurotrophic factor (BDNF) expression in the hippocampus. These results suggest that SYGE enhances learning and memory in normal states and attenuates memory loss caused by cholinergic dysfunction.

Possible neuroprotective mechanisms of action involved in the neurobehavioral property of naringin in mice

Flavonoids are naturally occurring bioactive phytochemical metabolites widely known to prevent and suppress several human diseases, and are important sources of therapeutic compounds from plants. Evidence derived from previous studies suggests that naringin, a neuroactive flavonoid possess functional beneficial neurobehavioral effects including anxiolytic, antidepressant and memory enhancing properties. However, literature search revealed that no studies have been carried out to evaluate the possible biochemical mechanisms involved in the neurobehavioral property of naringin alone following repeated treatment. Hence, this study was designed to evaluate the possible neuro-biochemical mechanisms involved in the neurobehavioral property of naringin following repeated administration in mice. The effects of naringin (2.5, 5 and 10 mg/kg), diazepam (2 mg/kg), imipramine (15 mg/kg) and donepezil (1 mg/kg) or vehicle on neurobehavioral and biochemical effects were evaluated in mice following repeated intraperitoneal injection for 7 consecutive days. Neurobehavioral activities consisting of open-field (locomotor), elevated-plus maze (anxiolytic), forced swim and social interaction (antidepressant and social preference), and Y-maze (memory enhancing) tests were assessed. Thereafter, brains levels of biomarkers of oxidative, nitrosative and cholinergic parameters were determined. Repeated treatment with naringin produced increased locomotor activity, and demonstrated antidepressant-like effects evidenced by decreased immobility time in forced swim test and increased % social preference in the social interaction test relative to controls. Also, naringin induced anxiolytic-like effect and increased cognitive performance in mice. Mechanistically, naringin significantly increased the activities of superoxide dismutase and catalase, and glutathione concentration relative to vehicle-controls. However, naringin significantly decreased malondialdehyde and nitrite contents, and reduced brain acetylcholinesterase activity in mice brains in a significant manner relative to controls. Taken together, these findings suggest that treatment with naringin might be useful to produce functional behavioral effects via mechanisms related to enhancement of cholinergic transmission, antioxidant defense systems, inhibition of lipid peroxidation and nitrosative processes.

Memory enhancing, anticholinesterase and antimicrobial activities of β-phenylnitroethane and essential oil of Dennettia tripetala Baker f

Ethnopharmacological relevanceDennettia tripetala Baker f. belonging to the family Annonaceae is an important food and medicinal plant used in some local communities in Southwest Nigeria. Aims of the studyThe study aims at determining the chemical composition of the essential oil of different morphological parts of D. tripetala, the memory enhancing and anticholinesterase activities as well as the antimicrobial properties. Materials and methodsEssential oil of the morphological parts namely the fresh fruits, dried fruits, dried seeds and fresh leaves were obtained by hydrodistillation and analysed by GC-FID and GC-MS. The oil samples were evaluated for memory enhancement using Y-maze and in vitro anticholinesterase activities. The antimicrobial properties were also evaluated by nutrient broth method. ResultsGC analysis identifies β-ocimene, linalool, β-phenylnitroethane and humulene as common constituents of the fresh fruits, dried fruits, dried seeds and fresh leaves. β-Phenylnitroethane (BPNE) was the predominant constituent of all the parts; with the dried seed containing 87.4% BPNE, followed by the dried fruit (78.1%), fresh leaf (62.9%) and the fresh fruit content was 61.6%. The second most predominant constituent, linalool, was highest in the fresh fruit (29.9%), followed by the fresh leaf (16.0%), the dried fruit (14.9%) and the dried seed had least linalool content (8.8%). (Z)- β-Ocimene and humulene were other common components. The seed oil and BPNE exhibited high memory enhancing activities in the Y-maze test. However, the seed oil exhibited the best inhibition against the test bacteria and it had a broad spectrum of antimicrobial activity. Bioactivities demonstrated by the various essential oils were not solely due to BPNE; rather, synergistic effects of other components are quite obvious. ConclusionThe most abundant component - β-phenylnitroethane of D. tripetala was totally responsible for its memory enhancing properties but could not solely account for its antimicrobial activity.