Centella asiatica improves memory and executive function in middle-aged rats by controlling oxidative stress and cholinergic transmission.

ETHNOPHARMACOLOGICAL RELEVANCE: Centella asiatica (L.) Urban, is a medicinal herb with rich history of traditional use in Indian subcontinent. This herb has been valued for its diverse range of medicinal properties including memory booster, and also as a folk treatment for skin diseases, wound healing and mild diuretic. AIM OF STUDY: Aging is a gradual and continuous process of natural decay in the biological systems, including the brain. This work aims to evaluate the effectiveness of ethanolic extract of Centella asiatica (CAE) on age-associated cognitive impairments in rats, as well as the underlying mechanism. MATERIAL AND METHODS: Rats were allocated into five distinct groups of 5 animals each: Young rats (3 months old rats), middle-aged (m-aged) rats (13-14 months old), and the remaining three groups were comprised of m-aged rats treated with different concentrations of CAE, viz., 150, 300, and 450 mg/kg b. w., orally for 42 days. Y-maze, open field, novel object recognition, and elevated plus maze tests were used to assess animal behavior. The malondialdehyde (MDA), superoxide dismutase (SOD), and acetylcholinesterase (AChE) assays; and H&E staining were done in the rat brain to assess the biochemical and structural changes. CAE was also subjected to HPLC analysis, in vitro antioxidant and anti-cholinergic activity. The active compounds of CAE were docked with AChE and BuChE in molecular docking study. RESULTS: The results showed that CAE treatment improves behavioral performance; attenuates the age-associated increase in MDA content, SOD, and AChE activity; and reduces neuronal loss. In vitro study showed that CAE has concentration-dependent antioxidant and anti-AChE activity. Furthermore, the presence of Asiatic acid and Madecassic acid in CAE and their good binding with cholinergic enzymes (in silico) also suggest the anticholinergic effect of CAE. CONCLUSION: The findings of the current study show that the anticholinergic and antioxidant effects of CAE are attributable to the presence of Asiatic acid and Madecassic acid, which not only provide neuroprotection against age-associated cognitive decline but also reverse it.

Phytochemical Extract from Carica papaya Leaves and Punica granatum Seeds as Therapy Against Cognitive Impairment in a Murine Model.

Mild cognitive impairment (MCI) is defined as inter-stage between normal cognitive aging and major neurocognitive disorder (MND). This state of decay is a crucial factor in treatment to prevent the progression to MND. In this study, our group developed a virtual screening process to evaluate 2568 phytochemical compounds against 5 key proteins associated with MCI and MND. As a result, two potential candidates were identified: carpaine, found in Carica papaya leaves, and punicalagin, present in Punica granatum. A model of cognitive impairment (CI) was developed in 10-month-old male Sprague Dawley rats by administering aluminum chloride (AlCl3) at a dose of 100 mg/kg/day for 30 days. After AlCl3 administration period, one of the groups received carpaine and punicalagin in a phytochemical extract (PE) by oral gavage for 30 days. Novel object recognition test (NOR) was assessed at three different time points (T1 - before CI, T2 - after CI, and T3 - after PE treatment). Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) were identified in the hippocampus of rats at the end of the study period. After administration of AlCl3, a reduction in discrimination index vs control rats (CI = 0.012 ± 0.08 vs Control = 0.076 ± 0.03), was observed. After phytochemical extract treatment, a significant increase in discrimination index values was observed in the PE group 0.4643 ± 0.13 vs CI group 0.012 ± 0.08. Additionally, the evaluation of immunohistochemistry showed an increase in GFAP positivity in the hippocampus of the CI groups, while a slight decrease was observed in the PE group. This work addressed a comprehensive methodology that utilized in silico tools to identify phytochemical compounds (carpaine and punicalagin) as potential candidates for affecting key proteins in CI. The phytochemical extract containing carpaine and punicalagin resulted in a trend in the decrease of GFAP expression in the hippocampus and improved recognition memory in rats with CI induced by age and AlCl3 administration.

Effect of D-pinitol on MK-801-induced schizophrenia-like behaviors in mice.

Schizophrenia is a chronic brain disorder characterized by positive symptoms (delusions or hallucinations), negative symptoms (impaired motivation or social withdrawal), and cognitive impairment. In the present study, we explored whether D-pinitol could ameliorate schizophrenia-like behaviors induced by MK-801, an N-methyl-D-aspartate receptor antagonist. Acoustic startle response test was conducted to evaluate the effects of D-pinitol on sensorimotor gating function. Social interaction and novel object recognition tests were employed to measure the impact of D-pinitol on social behavior and cognitive function, respectively. Additionally, we examined whether D-pinitol affects motor coordination. Western blotting was conducted to investigate the mechanism of action of D-pinitol. Single administration of D-pinitol at 30, 100, or 300 mg/kg improved the sensorimotor gating deficit induced by MK801 in the acoustic startle response test. D-Pinitol also reversed social behavior deficits and cognitive impairments induced by MK-801 without causing any motor coordination deficits. Furthermore, D-pinitol reversed increased expression levels of pNF-kB induced by MK-801 treatment and consequently increased expression levels of TNF-α and IL-6 in the prefrontal cortex. These results suggest that D-pinitol could be a potential candidate for treating sensorimotor gating deficits and cognitive impairment observed in schizophrenia by down-regulating transcription factor NF-κB and pro-inflammatory cytokines in the prefrontal cortex.

Assessment of Antidepressant-like, Anxiolytic Effects and Impact on Memory of Pimpinella anisum L. Total Extract on Swiss Albino Mice.

Mental disorders are psychological symptoms that impact multiple areas of an individual's life. Depression and anxiety are chronic illnesses described as the most prevalent stress-related mood disorders that cause injury and early death. In Morocco, Anise "Pimpinella anisum L." is one of the most traditionally used condiment plants, which has long been used to cure various illnesses and in phytotherapy. The present study was designed to investigate the antidepressant, anxiolytic, and memory impact of the total extract of Pimpinella anisum (PATE) at the doses of 100 and 200 mg/kg, using the Forced Swimming Test (FST), Tail Suspension Test (TST), Open Field Test (OFT), and Light-Dark Box Test (LDBT) as an experimental paradigm of anxiety and depression, and Novel Object Recognition Test (NORT) and the Morris Water Maze Test (MWMT) as memory tests on Swiss albino mice. The tests were carried out on the 1st, 7th, 14th, and the 21st days of the study, and the extract groups were compared with normal controls and positive controls (receiving bromazepam and paroxetine at the doses of 1 mg/kg and 11.5 mg/kg for anxiety and depression, respectively). The daily oral gavage of the mice by the PATE induced a significant anxiolytic and antidepressant-like effect by shortening immobility time and decreasing downtime in the different tests. PATE at both doses was shown to have no impact on memory following the NORT and MWM tests. Different compounds, such as gallic acid, catechin, chlorogenic acid, caffeic acid, oleuropein, p-coumaric acid, trans-4-hydroxy-3-methoxycinnamic acid, myricetin, and quercetin, were identified during the phytochemical analysis carried out using HPLC analysis. This research supports and promotes the extract's traditional use, suggesting its use as a phytomedicine against depression and anxiety, and calls for further research to clarify its mode of action.

Probiotics treatment improves cognitive impairment in patients and animals: A systematic review and meta-analysis.

The gut-brain axis has received considerable attention in recent years, and the "psychobiotics" concept indicates that probiotics have a potential positive effect on cognitive function. Therefore, the aim of this study was to quantitatively evaluate the influence of probiotics on cognition. We conducted a random-eff ;ects meta-analysis of 7 controlled clinical trials and 11 animals studies to evaluate the eff ;ects of probiotics on cognitive function. Probiotics supplementation enhanced cognitive function in both human (0.24 [0.05-0.42]; I2 = 0 %) and animal studies (0.90 [0.47-1.34]; I2 = 74 %). Subgroup analyses indicated that the effects of probiotics on cognitively impaired individuals (0.25 [0.05-0.45]; I2 = 0 %) were greater than those on healthy ones (0.15 [-0.30 to 0.60]; I2 = 0 %). Furthermore, compared with a multiple-probiotic supplement, a single strain of probiotics was more effective in humans. The meta-analysis provided some suggestions for probiotics intervention and tended to support a customized approach for different individuals to ameliorate cognitive disorders. Future additional clinical trials are necessary to evaluate therapeutic effect and influencing factors.

Effects of Hippeastrum reticulatum on memory, spatial learning and object recognition in a scopolamine-induced animal model of Alzheimer's disease.

CONTEXT: The methanol extracts from Hippeastrum reticulatum (L'Hér.) Herb. (Amaryllidaceae) (HR) display acetylcholinesterase inhibitory (AChEI) activity. OBJECTIVE: AChEI of alkaloids isolated from HR bulbs and the ameliorating effects of the alkaloid fraction (AHR) on memory and cognitive dysfunction in scopolamine-treated mice were investigated. MATERIALS AND METHODS: Alkaloids were isolated by column chromatography and identified by spectroscopy. AChEI was evaluated using the modified Ellman's method. Sixty Swiss male mice were randomly divided into six groups, received samples for 15 days. Normal group received saline, scopolamine-treated group scopolamine (1.5 mg/kg, intraperitoneal injection). Test groups received AHR (5, 10 and 15 mg/kg, per os) and positive control group donepezil (5 mg/kg, per os), administered 1 h before the test, scopolamine was injected 30 min prior to testing. The cognitive-enhancing activity of AHR against scopolamine-induced memory impairments was investigated using Y-maze, the novel object recognition test (NORT) and the Morris water maze (MWM) test. RESULTS: Seven alkaloids were isolated for the first time from the genus Hippeastrum: trans-dihydronarciclasine (1), N-chloromethylnarcissidinium (2), narciprimin (3), narciclasine-4-O-ß-d-xylopyranoside (4), N-methyltyramine (5), 3ß,11α-dihydroxy-1,2-dehydrocrinane (6) and brunsvigine (7); three are new compounds (2, 5, 6). Among them, 2-3 and 5-6 showed AChEI in vitro with IC50 values of 29.1, 46.4, 70.1 and 104.5 µg/mL, respectively. The anti-AChEI of 2, 5 and 6 are reported for the first time. In in vivo test, AHR (15 mg/kg) significantly increased in spontaneous alternation performance in the Y-maze test (p < 0.01), it significantly increased the time spent exploring the novel object (p < 0.05) comparison with scopolamine-treated group. The administration of AHR at doses 10 and 15 mg/kg significantly decreased escapes latency and swimming distance to the platform on day 6 compared to these in day 1 (p < 0.01 and p < 0.05, respectively). CONCLUSIONS: AHR could be a potential candidate of future trials for treatment of memory and cognitive dysfunction in Alzheimer's disease.

Evaluation of neuroprotective and anti-amnesic effects of Elaeagnus umbellata Thunb. On scopolamine-induced memory impairment in mice.

BACKGROUND: Elaeagnus umbellata is abundantly found in Himalayan regions of Pakistan which is traditionally used to treat various health disorders. However, the experimental evidence supporting the anti-amnesic effect is limited. Therefore the study was aimed to evaluate the prospective beneficial effect of E. umbellata on learning and memory in mice. OBJECTIVES: To assess neuroprotective and anti-amnesic effects of E. umbellata fruit extracts and isolated compounds on the central nervous system. METHODS: Major phytochemical groups present in methanolic extract of E. umbellata were qualitatively determined. The total phenolic and flavonoid contents were also determined in extract/fractions of E. umbellata. On the basis of in vitro promising anticholinesterases (AChE & BChE) and antioxidant activities observed for CHF. Ext and isolated compound-I (Chlorogenic acid = CGA), they were further evaluated for learning and memory in normal and scopolamine-induced cognitive impairment in mice using memory behavioral tests such as the Y maze and Novel object recognition using standard procedures. The test sample were further assessed for in vivo anticholinesterases (AChE & BChE) and DPPH free radical scavenging activities in mice brain sample and finally validated by molecular docking study using GOLD software. RESULTS: The extract/fractions and isolated compounds were tested for their anticholinesterase and antioxidant potentials. The CHF. Ext and CGA showed maximum % inhibition of tested cholinesterases and free radicals. The CHF. Ext and CGA reversed the effects of scopolamine in mice. The CHF. Ext and CGA significantly increased the alternate arm returns and % spontaneous alteration performance while escape latency times (second) significantly decreased in Y maze test. The CHF. Ext and CGA significantly increased the time spent with novel object and also increased the discrimination index in the Novel object recognition test. Furthermore, molecular docking was used to validate the mechanism of cholinesterases inhibition of isolated compounds. CONCLUSION: The data obtained from behavioral and biochemical studies (AChE/BChE and DPPH/ABTS inhibition) have shown that E. umbellata possessed significant memory enhancing potency. These results suggest that E. umbellata extract possess potential antiamnesic effects and amongst the isolated compounds, compound I could be more effective anti-amnesic therapeutics. However, further studies are needed to identify the exact mechanism of action.

Synthesis and characterization of newly synthesized neodymium zirconate zinc sulfide nanocomposite and its effect on selected aspects of albino mice behavior.

Present study was conducted to report the effect of variable doses of neodymium zirconate zinc sulfide nanocomposite on behavior of albino mice of both sexes. Five-week-old albino mice (C57BL/6 strain) of both sexes were orally treated either with 10 mg (low dose) or 20 mg/ml saline/kg body weight (high dose) of neodymium zirconate zinc sulfide nanocomposite for 11 days. An untreated control group was maintained in parallel for same duration that received saline solution orally. A series of neurological (rotarod, light and dark box, open field, and novel object recognition) tests were conducted in all treatments. Oral supplementation of both low and high dose of nanocomposite significantly reduced the rotarod test performance as well as stretch attend reflex in male mice during light dark box test. Male mice treated with high dose of neodymium zirconate zinc sulfide nanocomposite had significantly increased time mobile and decreased time immobile than control group during open field test. Female mice treated with 10 mg/ml saline/kg body weight of neodymium zirconate zinc sulfide nanocomposite had significantly more line crossing during trial 1, and they spend more time with object A during trial 2 of novel object recognition test than their saline-treated control group. Change in body weight remained unaffected when compared between nanocomposite treated and untreated albino mice. In conclusion, we are reporting that both the applied doses of neodymium zirconate zinc sulfide nanocomposite are drastically affecting the muscular activity and exploratory behavior in male albino mice, while the studied behavioral tests, in general, remained unaffected in female albino mice.

Regulation of Neprilysin Activity and Cognitive Functions in Rats After Prenatal Hypoxia.

The amyloid-degrading enzyme neprilysin (NEP) is one of the therapeutic targets in prevention and treatment of Alzheimer's disease (AD). As we have shown previously NEP expression in rat parietal cortex (Cx) and hippocampus (Hip) decreases with age and is also significantly reduced after prenatal hypoxia. Following the paradigms for enhancement of NEP expression and activity developed in cell culture, we analysed the efficacy of various compounds able to upregulate NEP using our model of prenatal hypoxia in rats. In addition to the previous data demonstrating that valproic acid can upregulate NEP expression both in neuroblastoma cells and in rat Cx and Hip we have further confirmed that caspase inhibitors can also restore NEP expression in rat Cx reduced after prenatal hypoxia. Here we also report that administration of a green tea catechin epigallocatechin-3-gallate (EGCG) to adult rats subjected to prenatal hypoxia increased NEP activity in blood plasma, Cx and Hip as well as improved memory performance in the 8-arm maze and novel object recognition tests. Moreover, EGCG administration led to an increased number of dendritic spines in the hippocampal CA1 area which correlated with memory enhancement. The data obtained allowed us to conclude that the decrease in the activity of the amyloid-degrading enzyme NEP, as well as a reduction in the number of labile interneuronal contacts in the hippocampus, contribute to early cognitive deficits caused by prenatal hypoxia and that there are therapeutic avenues to restore these deficits via NEP activation which could also be used for designing preventive strategies in AD.

Antidepressant Effect and Recognition Memory Improvement of Two Novel Plant Extract Combinations - Antistress I and Anti-stress II on Rats Subjected to a Model of Mild Chronic Stress.

BACKGROUND: Chronic stress is one of the main factors which lead to depression - a psychiatric disorder affecting millions of people and predicted to be the second ranked cause of premature death in 2020. Depression is often associated with cognitive disturbances and memory deficit. Plant based therapy could be effective in the treatment of mild to moderate depression due to its low level of adverse reaction, its good tolerability and compliance. MATERIALS AND METHODS: 72 male Wistar rats, divided in 9 groups were given orally for 8 weeks two combinations of dry plant extracts - Antistress I and Antistress II and five individual dry extracts obtained from Serratula coronata, Hypericum perforatum, Valeriana officinalis, Crataegus monogyna and Melissa officinalis. The animals were exposed to a chronic unpredictable mild stress for 8 weeks. The depression-like symptoms were evaluated with Forced swim test while the assessment of the memory deficit was performed with Novel object recognition test. RESULTS: Antistress II demonstrates antidepressant effect while Antistress I doesn't improve the depressive-like symptoms. The individual extracts of Hypericum perforatum and Valeriana officinalis also possess antidepressant properties. Antistress II improves the cognition as well as the individual extracts of Hypericum perforatum, Valeriana officinalis and especially Serratula coronata. Dry extract from Serratula tend to have the best effect regarding the recognition memory. The effect of Antistress I on memory deficit is negligible. CONCLUSIONS: Antistress II possesses antidepressant effect and improves the recognition memory while Antistress I doesn't demonstrate any of the above-described effects.

Molecular docking and antiamnesic effects of nepitrin isolated from Rosmarinus officinalis on scopolamine-induced memory impairment in mice.

Rosmarinus officinalis has long been known as the herb of remembrance. The present study was undertaken to investigate the anti-amnesic effects of nepitrin isolated from Rosmarinus officinalis using in-vivo models of Y-maze and novel object recognition test (NORT) along with in vitro antioxidant and acetylcholinesterase (AChE) and buterylcholinesterase (BuChE) inhibition potential. Nepitrin showed a concentration dependent inhibition of AChE and BuChE enzymes with IC50 values of 65 and 72µg/mL, respectively and antioxidant activity against 2,2-diphenyl-1-picrylhydrazyl (DPPH) and 2, 2'-azinobis-3-ethylbenzothiazoline-6-sulfonic acid (ABTS) with IC50 values 270 and 210µg/mL, respectively. In mice, nepitrin reversed the amnesia induced by scopolamine as indicated by a dose-dependent increase in spontaneous alternation performance in the Y-maze task (p <0.05 versus scopolamine) and increase in the discrimination index in the novel object recognition test (NORT) comparable to the standard drug donepezil 2mg/kg. Molecular docking studies were performed and the GlideScore of nepitrin was consistent with its experimental AChE inhibitory activities. Nepitrin occupied the same binding site forming similar interactions to those formed by donepezil in the crystal structure. Thus, nepitrin could provide a lead for the development of therapeutic agent useful in cognition and memory disorders such as Alzheimer's disease.

Deferiprone Rescues Behavioral Deficits Induced by Mild Iron Exposure in a Mouse Model of Alpha-Synuclein Aggregation.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder, and its causes remain unknown. A major hallmark of the disease is the increasing presence of aggregated alpha-synuclein (aSyn). Furthermore, there is a solid consensus on iron (Fe) accumulation in several regions of PD brains during disease progression. In our study, we focused on the interaction of Fe and aggregating aSyn in vivo in a transgenic mouse model overexpressing human aSyn bearing the A53T mutation (prnp.aSyn.A53T). We utilized a neonatal iron-feeding model to exacerbate the motor phenotype of the transgenic mouse model. Beginning from day 100, mice were treated with deferiprone (DFP), a ferric chelator that is able to cross the blood-brain barrier and is currently used in clinics as treatment for hemosiderosis. Our paradigm resulted in an impairment of the learning abilities in the rotarod task and the novel object recognition test. DFP treatment significantly improved the performance in both tasks. Although this was not accompanied by alterations in aSyn aggregation, our results support DFP as possible therapeutic option in PD.

Curcuma treatment prevents cognitive deficit and alteration of neuronal morphology in the limbic system of aging rats.

Curcuma is a natural compound that has shown neuroprotective properties, and has been reported to prevent aging and improve memory. While the mechanism(s) underlying these effects are unclear, they may be related to increases in neural plasticity. Morphological changes have been reported in neuronal dendrites in the limbic system in animals and elderly humans with cognitive impairment. In this regard, there is a need to use alternative therapies that delay the onset of morphologies and behavioral characteristics of aging. Therefore, the objective of this study was to evaluate the effect of curcuma on cognitive processes and dendritic morphology of neurons in the prefrontal cortex (PFC), the CA1 and CA3 regions of the dorsal hippocampus, the dentate gyrus, and the basolateral amygdala (BLA) of aged rats. 18-month-old rats were administered curcuma (100 mg/kg) daily for 60 days. After treatment, recognition memory was assessed using the novel object recognition test. Curcuma-treated rats showed a significant increase in the exploration quotient. Dendritic morphology was assessed by Golgi-Cox staining and followed by Sholl analysis. Curcuma-treated rats showed a significant increase in dendritic spine density and dendritic length in pyramidal neurons of the PFC, the CA1 and CA3, and the BLA. The preservation of dendritic morphology was positively correlated with cognitive improvements. Our results suggest that curcuma induces modification of dendritic morphology in the aforementioned regions. These changes may explain how curcuma slows the aging process that has already begun in these animals, preventing deterioration in neuronal morphology of the limbic system and recognition memory.

Effect of Variable Doses of Zinc Oxide Nanoparticles on Male Albino Mice Behavior.

Zinc oxide nanoparticles (ZnO NPs) have diverse utility these days ranging from being part of nanosensors to be ingredient of cosmetics. Present study was designed to report the effect of variable doses of ZnO NPs on selected aspects of male albino mice behavior. Nano particles were synthesized by sol-gel auto-combustion method (Data not shown here). 10 week old male albino mice were divided into four experimental groups; group A, B and C were orally supplemented with 50 (low dose), 300 (medium dose) and 600 mg/ml solvent/kg body weight (high dose) of ZnO NPs for 4 days. Group D (control) orally received 0.2 M sodium phosphate buffer (solvent for ZnO NPs) for the same duration. A series of neurological tests (Rota rod, open field, novel object and light-dark box test) were conducted in all groups and performance was compared between ZnO NPs treated and control group. Muscular functioning during rota rod test was significantly improved in all ZnO NPs treated mice as compared to control group. While no significant differences in open field, novel object and light-dark box test performance were observed when data from studied parameters of specific ZnO NPs treatment were compared with the control group indicating that applied doses of ZnO NPs did not affect the exploratory, anxiolytic behavior and object recognition capability of adult male albino mice.

Tualang honey supplement improves memory performance and hippocampal morphology in stressed ovariectomized rats.

Recently, our research team has reported that Tualang honey was able to improve immediate memory in postmenopausal women comparable with that of estrogen progestin therapy. Therefore the aim of the present study was to examine the effects of Tualang honey supplement on hippocampal morphology and memory performance in ovariectomized (OVX) rats exposed to social instability stress. Female Sprague-Dawley rats were divided into six groups: (i) sham-operated controls, (ii) stressed sham-operated controls, (iii) OVX rats, (iv) stressed OVX rats, (v) stressed OVX rats treated with 17ß-estradiol (E2), and (vi) stressed OVX rats treated with Tualang honey. These rats were subjected to social instability stress procedure followed by novel object recognition (NOR) test. Right brain hemispheres were subjected to Nissl staining. The number and arrangement of pyramidal neurons in regions of CA1, CA2, CA3 and the dentate gyrus (DG) were recorded. Two-way ANOVA analyses showed significant interactions between stress and OVX in both STM and LTM test as well as number of Nissl-positive cells in all hippocampal regions. Both E2 and Tualang honey treatments improved both short-term and long-term memory and enhanced the neuronal proliferation of hippocampal CA2, CA3 and DG regions compared to that of untreated stressed OVX rats.