Single-Nuclei Characterization of Lacrimal Gland in Scopolamine-Induced Dry Eye Disease.

Purpose: The lacrimal gland (LG) is the main organ responsible for tear secretion and an important pathogenic site for dry eye disease (DED). This study aimed to comprehensively characterize LG cellular heterogeneity under normal and DED conditions using single-nucleus RNA sequencing (snRNA-seq). Methods: Single LG nuclei isolated from mice with or without DED induced by scopolamine (SCOP)/desiccating stress (DS) were subjected to snRNA-seq using the 10x Genomics platform. These cells were clustered and annotated using the t-distributed stochastic neighbor embedding (t-SNE) method and unbiased computational informatic analysis. Cluster identification and functional analysis were performed based on marker gene expression and bioinformatic data mining. Results: The snRNA-seq analysis of 30,351 nuclei identified eight major cell types, with acinar cells (∼72.6%) being the most abundant cell type in the LG. Subclustering analysis revealed that the LG mainly contained two acinar cell subtypes, two ductal cell subclusters, three myoepithelial cell (MECs) subtypes, and four immunocyte subclusters. In the SCOP-induced DED model, three major LG parenchymal cell types were significantly altered, characterized by a reduced proportion of acinar cells with a lowered secretion potential and an augmented proportion of ductal cells and MECs. LG immunocytes in DED scenarios showed an intensified inflammatory response and dysregulated intercellular communication with three major LG parenchymal cells. Conclusions: Overall, this study offers a systemic single-nucleus transcriptomic profile of LGs in both normal and DED conditions and an atlas of the complicated interactions of immunocytes with major LG parenchymal cells. The findings also facilitate understanding the pathogenesis of DED.

Occurrence and health risk assessment of tropane alkaloids in cereal foods consumed in Korea.

Tropane alkaloids (TA) are natural toxins found in certain plants, including cereals, of which atropine and scopolamine are the main species of concern due to their acute toxicity. This study aimed to determine the occurrence of TA in cereal foods and assess the potential health risks associated with their consumption in Korea. TA levels were analyzed in 80 raw and 71 processed cereal samples, which were distributed throughout Korea in 2021, using ultra-performance liquid chromatography-tandem mass spectrometry. At least one of the six TA species, namely atropine, scopolamine, pseudotropine, tropinone, scopine, and 6-hydroxytropinone, was detected in 10 out of the 151 samples at levels ranging from 0.12 to 88.10 µg kg-1. Dietary exposure (mean, 0.23 ng kg-1 bw day-1) to atropine and scopolamine in the Korean population was estimated to be low across all age groups. This is despite considering worst-case scenarios using the total concentrations of atropine and scopolamine in a millet sample, both of which were detected, and 95th percentile consumption for consumers of millet only. Both the hazard index and margin of exposure methods indicated that the current levels of TA exposure from millet consumption were unlikely to pose significant health risks to the Korean population.

Development and characterization of an automated behavioral assessment platform for the Göttingen minipig.

The Göttingen minipig is fast becoming the standard for assessing dermal chemical hazards because, like most swine, its skin is predictive of human skin response and because this strain's smaller size makes laboratory manipulations and husbandry easier. Unfortunately, standard behavioral tests and apparatus have not been developed for behavioral assessments of this swine strain. Indeed, computer-controlled automated behavioral testing procedures are much needed. The present research advanced this goal by producing a home-cage behavioral testing system that could accommodate minipigs of various sizes (ages). An aluminum frame housed three levers for recording operant responses, and LEDs above and below each lever served as discriminative stimuli. A commercially available food pellet dispenser was attached to a specialized pellet receptacle capable of measuring pellet retrieval. Two behavioral tests were selected and adapted from our commonly used non-human primate behavioral assessments: delayed match-to-sample (a memory test) and temporal response differentiation (a time-estimation test). Minipigs were capable of learning both tests and attaining stable performance. Next, scopolamine was used to validate the sensitivity of the behavioral tests for gauging behavioral perturbations in this swine strain. Scopolamine dose-effect functions were comparable to those observed in other species, including non-human primates, wherein 37.5 µg/kg of scopolamine (administered intramuscularly) reduced responding approximately 50%. Thus, we were successful in developing the apparatus and automated operant behavioral tests necessary to characterize drug safety in this swine strain. This capability will be valuable for characterizing chemical agent toxicity as well as the safety and efficacy of medical countermeasures.

Quercetin-loaded nanoemulsions prevent Scopolamine-induced neurotoxicity in male rats.

Quercetin (QCT) is well-known as a neuroprotective agent due to its antioxidant capacities and reinstating mitochondrial functions. Scopolamine is commonly used as a model to induce Alzheimer's disease (AD-like) symptoms. The current study develops QCT-loaded nanoemulsion (QCT-NE) accompanied by evaluating its neuro-therapeutic effectiveness against SCO-induced neurotoxicity in male rats. The QCT-NE was prepared by the spontaneous emulsification technique and characterized by using particle size, zeta potential, drug loading, in vitro drug release behavior, and stability studies. In vivo studies were done on adult Wistar rats by applying the Morris water maze (MWM) test to study spatial memory and learning. The levels of lipid peroxidation and reduced glutathione were quantitatively determined to reveal the potential mechanism of SCO-induced oxidative stress. Finally, histological studies were performed using staining techniques. The QCT-NE particle size, zeta potential, polydispersity index (PDI), and DL were obtained at 172.4 ± 16.8 nm, -29 ± 0.26 mV, 0.3 ± 0.07, and 81.42 ± 9.14 %, respectively. The QCT and more effectively QCT-NE reduced the elevation of neurobehavioral abnormalities in the MWM test in SCO-exposed rats. The results of oxidative status showed that SCO significantly could increase the LPO and decrease the GSH levels in the rat's brain. However, QCT-NE treatment was more effective than free QCT to inhibit oxidative damage and was well correlated with histopathological findings. Taken together, QCT-NE, compared to QCT, was superior in ameliorating SCO-induced AD-like symptoms due to its better neuroprotective activity and can be considered a novel supplementary therapeutic agent in AD management.

Ethanol extract of Evodia lepta Merr. ameliorates cognitive impairment through inhibiting NLRP3 inflammasome in scopolamine-treated mice.

Evodia lepta Merr. (Evodia lepta) is a well-known traditional Chinese medicine, which has been widely used in herbal tea. We previously reported that the coumarin compounds from the root of Evodia lepta exhibited neuroprotective effects. However, whether Evodia lepta could inhibit NLRP3 inflammasome in dementia was still unknown. In this study, the components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. We employed a scopolamine-treated mouse model. Evodia lepta extract (10 or 20 mg/kg) and donepezil were treated by gavage once a day for 14 consecutive days. Following the behavioral tests, oxidative stress levels were measured. Then, Western blot and immunofluorescence analysis were used to evaluate the expressions of NLRP3 inflammasome. 14 major components of the Evodia lepta extract were identified by HPLC-Q-TOF HRMS. The results of Morris water maze, object recognition task and open field test indicated that Evodia lepta extract could ameliorate cognitive impairment in scopolamine-treated mice. Evodia lepta extract improved cholinergic system. Moreover, Evodia lepta extract improved the expressions of PSD95 and BDNF. Evodia lepta extract suppressed neuronal oxidative stress and apoptosis. In addition, Evodia lepta extract inhibited NLRP3 inflammasome in the hippocampus of scopolamine-treated mice. Evodia lepta extract could protect against cognitive impairment by inhibiting NLRP3 inflammasome in scopolamine-treated mice.

(m) RVD-hemopressin (α) Ameliorated Oxidative Stress, Apoptosis and Damage to the BDNF/TrkB/Akt Pathway Induced by Scopolamine in HT22 Cells.

Dysfunction in the cholinergic system and oxidative stress are closely related and play roles in Alzheimer's disease (AD). Scopolamine (Scop), which is commonly used to induce cholinergic system damage in cells and animals, also evokes oxidative stress. Our previous study indicated that the peptide (m) RVD-hemopressin (RVD) reversed the memory-impairing effect of Scop in mice by activating cannabinoid receptor 1 (CBR1), but the mechanism was unclear. In this study, we found that RVD inhibited the oxidative stress, apoptosis, decreased cell viability and downregulation of synapse-associated proteins induced by Scop in HT22 cells. The effect was associated with the BDNF/TrkB/Akt pathway, and the effects of RVD outlined above could be blocked by an antagonist of CBR1. These results suggest that RVD may be a potential drug candidate for disorders associated with damage to the cholinergic system and oxidative stress, such as AD.

Capparis spinosa Promoted BDNF and Antioxidant Enzyme Levels to Protect Against Learning and Memory Deficits Induced by Scopolamine.

BACKGROUND: Alzheimer's disease (AD) is a major neurodegenerative disorder with multiple manifestations, including oxidative stress, brain-derived neurotrophic factor (BDNF) depletion, and cholinergic dysfunction. Capparis spinosa (C. spinosa) is identified as a potential source of nutrition for alleviating various ailments. The current study assessed the ameliorating properties of C. spinosa hydroethanolic extract on memory dysfunction and the possible roles of oxidative stress and BDNF in the scopolamine (Scop)-treated rats. METHODS: Forty male Wistar rats were divided into the following four groups: Control, Scop (2 mg/kg, intraperitoneal injection (i.p.)), Scop + C. spinosa 150, and Scop + C. spinosa 300 groups. The rats were given C. spinosa extract (150 or 300 mg/kg, oral) for 3 weeks. During the third week, Passive Avoidance (PA) and Morris Water Maze (MWM) tests were done to assess memory and learning performance. Finally, oxidative stress markers and BDNF in the brain tissue were evaluated. RESULTS: Scop injection was associated with a significant increase in the time latency and travelled distance to reach the platform during the learning phase of MWM In the probe test, the Scoptreated rats showed a lower time and distance in the target area. Furthermore, Scop injection significantly decreased the latency to enter the dark while increasing the dark time and the frequency of entries to the dark zone of the PA task. C. spinosa extract effectively reversed the behavioural changes induced by Scop. Treatment with the extract also significantly increased the levels of superoxide dismutase, catalase, thiols, and BDNF, while decreasing malondialdehyde production in the brains of the Scop-injured rats. CONCLUSION: C. spinosa hydroethanolic extract successfully ameliorated Scop-induced memory impairment by modifying BDNF and oxidative stress markers in the brain of amnesic rats.

Zinc Ortho Methyl Carbonodithioate Improved Pre and Post-Synapse Memory Impairment via SIRT1/p-JNK Pathway against Scopolamine in Adult Mice.

Alzheimer's disease (AD) is globally recognized as a prominent cause of dementia for which efficient treatment is still lacking. New candidate compounds that are biologically potent are regularly tested. We, therefore, hypothesized to study the neuroprotective potential of Zinc Ortho Methyl Carbonodithioate (thereafter called ZOMEC) against Scopolamine (SCOP) induced Alzheimer's disease (AD) model using adult albino mice. We post-administered ZOMEC (30 mg/Kg) into two group of mice for three weeks on daily basis that received either 0.9% saline or SCOP (1 mg/Kg) for initial two weeks. The other two groups of mice received 0.9% saline and SCOP (1 mg/Kg) respectively. After memory related behavioral analysis the brain homogenates were evaluated for the antioxidant potential of ZOMEC and multiple protein markers were examined through western blotting. Our results provide enough evidences that ZOMEC decrease oxidative stress by increasing catalase (CAT) and glutathione S transferase (GST) and decreasing the lipid peroxidation (LPO). The SIRT1 and pre and post synaptic marker proteins, synaptophysin (SYP) as well as post synaptic density protein (PSD-95) expression were also enhanced upon ZOMEC treatment. Furthermore, memory impairment was rescued and ZOMEC appreciably abrogated the Aß accumulation, BACE1 expression C and the p-JNK pathway. The inflammatory protein markers, NF-kß and IL-1ß in ZOMEC treated mice were also comparable with control group. The predicted interaction of ZOMEC with SIRT1 was further confirmed by molecular docking. These findings thus provide initial reports on efficacy of ZOMEC in SCOP induced AD model.

Scopolamine causes delirium-like brain network dysfunction and reversible cognitive impairment without neuronal loss.

Delirium is a severe acute neuropsychiatric syndrome that commonly occurs in the elderly and is considered an independent risk factor for later dementia. However, given its inherent complexity, few animal models of delirium have been established and the mechanism underlying the onset of delirium remains elusive. Here, we conducted a comparison of three mouse models of delirium induced by clinically relevant risk factors, including anesthesia with surgery (AS), systemic inflammation, and neurotransmission modulation. We found that both bacterial lipopolysaccharide (LPS) and cholinergic receptor antagonist scopolamine (Scop) induction reduced neuronal activities in the delirium-related brain network, with the latter presenting a similar pattern of reduction as found in delirium patients. Consistently, Scop injection resulted in reversible cognitive impairment with hyperactive behavior. No loss of cholinergic neurons was found with treatment, but hippocampal synaptic functions were affected. These findings provide further clues regarding the mechanism underlying delirium onset and demonstrate the successful application of the Scop injection model in mimicking delirium-like phenotypes in mice.

Lantana camara leaf extract ameliorates memory deficit and the neuroinflammation associated with scopolamine-induced Alzheimer's-like cognitive impairment in zebrafish and mice.

CONTEXT: Lantana camara Linn. (Verbenaceae) is used for improving memory in certain African societies. OBJECTIVE: This study investigated the effect of prophylactic treatment with hydroethanolic leaf extract of Lantana camara (LCE) on short-term memory deficit and neuroinflammation induced with scopolamine in zebrafish and mice. MATERIALS AND METHODS: Zebrafish (AB strain) and mice (ICR) were given donepezil (0.65 mg/kg, oral) and LCE (10, 30, 100 mg/kg, oral) for 7, and 10 days, respectively, before induction of cognitive impairment with scopolamine immersion (200 µM) and intraperitoneal injection (2 mg/kg), respectively. Spatial short-term memory was assessed in zebrafish using both Y- and T-mazes, whereas Y-maze was used in mice. Mice hippocampal and cortical tissues were analyzed for mRNA expression of proinflammatory genes (IL-1ß, IL-6, TNF-α, COX-2) using qRT-PCR. RESULTS: In the zebrafish Y-maze, LCE (10 and 100 mg/kg) increased time spent in the novel arm by 55.89 ± 5.70%, and 68.21 ± 2.75%, respectively, but not at 30 mg/kg. In the zebrafish T-maze, there was an increase in time spent in the food-containing arm at 30 (44.23 ± 2.13) and 100 mg/kg (52.30 ± 1.94). In the mouse Y-maze, spontaneous alternation increased by 52.89 ± 4.98% at only 10 mg/kg. LCE (10, 30, 100 mg/kg) inhibited proinflammatory gene (IL-1ß, IL-6, TNF-α, COX-2) mRNA expression, with the highest inhibitory effect on IL-6 in both the hippocampus (83.27 ± 2.49%; 100 mg/kg) and the cortex (98.74 ± 0.11%; 10 mg/kg). DISCUSSION AND CONCLUSION: LCE ameliorated scopolamine-induced AD in both zebrafish and mice.

Effects of Sideritis scardica Extract on Scopolamine-Induced Learning and Memory Impairment in Mice.

BACKGROUND: The neurodegenerative process in Alzheimer's disease, one of the most common types of dementia worldwide, mostly affects the cholinergic neurotransmitter system and, to a lesser extent, the monoaminergic one. The antioxidant acetylcholinesterase (AChE) and triple monoamine reuptake inhibitory activity of Sideritis scardica (S. scardica) and other Sideritis species has already been reported. OBJECTIVE: To investigate the effects of S. scardica water extracts on the learning and memory processes, anxiety-like behavior, and locomotor activities in scopolamine (Sco)-induced dementia in mice. METHODS: Male Albino IRC mice were used. The plant extract was administered for 11 consecutive days in the presence or absence of Sco (1 mg/kg, i.p). The behavioural performance of the animals was evaluated by passive avoidance, T-maze, and hole-board tests. The effects of extract on AChE activity, brain noradrenalin (NA), and serotonin (Sero) content, and antioxidant status were also monitored. RESULTS: Our experimental data revealed that the S. scardica water extract caused a reduction in degree of memory impairment and anxiety-like behaviour in mice with scopolamine-induced dementia. The extract did not affect changed by the Sco AChE activity but impact reduced brain NA and Sero levels and demonstrated moderate antioxidant activity. In healthy mice we did not confirm the presence of anxiolytic-like and AChE inhibitory effects of the S. scardica water extract. The extract did not change the control Sero brain levels and reduce those of NA. CONCLUSION: S. scardica water extract demonstrated memory preserving effect in mice with scopolamine-induced dementia and deserve further attention.

Involvement of aberrant acinar cell proliferation in scopolamine-induced dry eye mice.

Dry eye is a multifactorial disease that causes dryness, inflammation and damage of ocular surface. Subcutaneous injection of the muscarinic cholinergic antagonist scopolamine under desiccating stress reduces tear production and induces dry eye symptoms in mice. However, the expression profile and pathogenic changes of the lacrimal gland remain incompletely understood. In the present study, we performed comparative transcriptomic analysis of lacrimal glands from the control and scopolamine-treated mice. Primary analysis identified 677 upregulated genes and 269 downregulated genes in the lacrimal gland of mice with scopolamine treatment. Unexpectedly, KEGG pathway and hierarchical clustering analysis showed the enrichment of "DNA replication" and "cell cycle" categories in the upregulated genes. Subsequently, we confirmed that the acinar cells were the major proliferating cells of lacrimal gland, which exhibited significant increasing of the proliferating cell nuclear antigen (PCNA) expression after scopolamine treatment, accompanied with the upregulation of DNA damage marker γ-H2AX. More importantly, both prophylactic and therapeutic administration of the cyclin-dependent kinase (CDK) inhibitor AT7519 rescued the tear reduction and alleviated dry eye severity in the scopolamine-treated mice, including corneal epithelial barrier function, lacrimal and corneal inflammation, and conjunctival goblet cell density. Therefore, we conclude that aberrant acinar cell proliferation is involved in the scopolamine-induced tear reduction and dry eye onset, which can be improved by AT7519 treatment.

Evaluation of the Effect of Cariprazine on Memory and Cognition in Experimental Rodent Models.

The main symptoms of schizophrenia are categorized as positive, negative, and cognitive. Cognitive impairments do not generally respond to antipsychotics. Cariprazine is a novel antipsychotic conceived with the idea that high affinity for D3 receptors may elicit a favorable response in the management of cognitive deficits. We evaluated the pro-cognitive properties of 14-day long pre-treatment with cariprazine (0.25, 0.5, and 1 mg/kg b.w. intraperitoneally) in experimental rodent models with scopolamine-induced memory impairment employing novel object recognition test (NORT), T-maze, Y-maze, and passive avoidance tasks (step-through and step-down). Statistical analysis was performed with One Way ANOVA. In NORT cariprazine increased the recognition index. In T-maze and Y-maze cariprazine increased the working memory index as well as the percentage of spontaneous alternation. Cariprazine improved learning and memory in both short-term and long-term memory retention tests in step-down and step-through tasks. Cariprazine improves learning, recognition, and spatial memory in rats with scopolamine-induced memory impairment. Cariprazine's beneficial effect on cognition is likely due to its affinity for D3 receptors, as well as agonism at 5-HT1A receptors. Most probably, the cognitive-enhancing properties of cariprazine are the result of integrated modulation in the amygdala, hippocampus, and prefrontal cortex.

Thymus daenensis extract prevents scopolamine­induced memory impairment through declining oxidative stress in rats.

Memory and cognitive impairment induced by oxidative stress are among the main hallmarks of Alzheimer's disease's (AD) pathology. The present study aimed to investigate the potential neuroprotective effects of Thymus daenensis (T. daenensis) extract against scopolamine­induced memory impairment and oxidative stress in rats. T. daenensis, widely distributed in Iran and Europe, is known to be a rich source of natural antioxidants and has been traditionally used for various medical purposes. The present study investigated the post­treatment effects of T. daenensis on learning and memory functions, antioxidant cellular defense, and oxidative stress using the scopolamine rat model of AD. The experiments were performed by intraperitoneal injection of scopolamine for 10 consecutive days in Wistar male rats (180-220 g). Additionally, the animals received T. daenensis extract (50­200 mg/kg) by gavage for 14 consecutive days after induction of memory impairment. The animals were divided into 8 groups, namely: control, 200 mg/kg of T. daenensis extract (D200), donepezil (DON), scopolamine (ALZ), ALZ animals treated with different doses of the extract (ALZ+D50 or 100 or 200 mg/kg) and ALZ animals treated with (ALZ+DON). The animals were then subjected to the Morris water maze (MWM) paradigm as a standard criterion for memory function assessment, and after extracting the brain tissues, the related biochemical oxidative stress parameters were determined in the brain. Our results indicated that T. daenensis extract significantly improved animals' performance in the MWM while significantly reducing oxidative stress and antioxidant imbalance. Furthermore, the extract did not show hepatotoxic effects on treated animals. In addition, the extract treatment significantly decreased both cellular malondialdehyde (MDA) and protein carbonyl (PCO) content while conversely increasing the total reduced glutathione (GSH) content and also the levels of total and endogenous antioxidants in the ferric reducing antioxidant power (FRAP) assay. It seems that the administration of T. daenensis significantly improved both cellular biochemical aspects and memory performance in animal models. Conclusively, it could be beneficial for scopolamine­induced neurotoxicity.

Ellagic Acid Prevents Oxidative Stress and Memory Deficits in a Rat Model of Scopolamine-induced Alzheimer's Disease.

BACKGROUND: Ellagic acid (EA) has various pharmacological effects such as antiinflammatory and anti-oxidant effects. OBJECTIVE: This study aimed to investigate the effects of EA on learning and memory dysfunction as well as oxidative stress in scopolamine-induced amnesic rats. METHODS: The studied rats were treated according to the following protocol: Control (group 1) and scopolamine (group 2) groups received saline (intraperitoneal injection (i.p.)) while the treatment groups (group 3-5) were given EA (25, 50, and 100 mg/kg, i.p.) for 3 weeks. Thereafter, their behavioral performance was evaluated using Morris water maze (MWM) and passive avoidance (PA) tasks. Notably, scopolamine was injected (into groups II-V at a dose of 2 mg/kg, i.p.) before conducting the tasks. Finally, the oxidative stress indicators in the brain were measured. RESULTS: EA reduced the escape latencies and distances during the learning phase of MWM. The results of probe trials also indicated that EA improved memory retrieval and helped animals recall the platform. Moreover, EA increased delay and light time, while decreasing the frequency of entries to the dark area of PA. In the EA-treated groups, the level of malondialdehyde was decreased, while the levels of total thiol groups, superoxide dismutase, and catalase were increased. CONCLUSION: EA prevented the negative effects of scopolamine on learning and memory which is probably mediated via modulating oxidative stress. Hence, EA could be considered as a potential alternative therapy for dementia.

Wasp Venom Ameliorates Scopolamine-Induced Learning and Memory Impairment in Mice.

This study investigated the effects of wasp venom (WV) from the yellow-legged hornet, Vespa velutina, on scopolamine (SCO)-induced memory deficits in mice, as well as the antioxidant activity in HT22 murine hippocampal neuronal cells in parallel comparison with bee venom (BV). The WV was collected from the venom sac, freeze-dried. Both venoms exhibited free radical scavenging capabilities in a concentration-dependent manner. In addition, the venom treatment enhanced cell viability at the concentrations of ≤40 µg/mL of WV and ≤4 µg/mL of BV in glutamate-treated HT22 cells, and increased the transcriptional activity of the antioxidant response element (ARE), a cis-acting enhancer which regulates the expression of nuclear factor erythroid 2-related factor 2 (Nrf2)-downstream antioxidant enzymes. Concurrently, WV at 20 µg/mL significantly increased the expression of a key antioxidant enzyme heme oxygenase 1 (HO-1) in HT22 cells despite no significant changes observed in the nuclear level of Nrf2. Furthermore, the intraperitoneal administration of WV to SCO-treated mice at doses ranged from 250 to 500 µg/kg body weight ameliorated memory impairment behavior, reduced histological injury in the hippocampal region, and reduced oxidative stress biomarkers in the brain and blood of SCO-treated mice. Our findings demonstrate that WV possess the potential to improve learning and memory deficit in vivo while further study is needed for the proper dose and safety measures and clinical effectiveness.

Inhibition of scopolamine-induced memory and mitochondrial impairment by betanin.

Mitochondrial dysfunction and oxidative stress are identified to contribute to the mechanisms responsible for the pathogenesis of Alzheimer's disease (AD). Scopolamine (SCO) as a potent drug for inducing memory and learning impairment is associated with mitochondrial dysfunction and oxidative stress. In AD clinical trials molecules with antioxidant properties have shown modest benefit. Betanin as a multifunctional molecule with powerful antioxidative properties may be effective in the treatment of neurodegenerative. Hence, this study was designed to investigate the possible therapeutic effect of betanin against SCO-induced AD on Wistar rats. SCO (1 mg/kg) was administrated intraperitoneally to induce the AD in Wistar rats. The rats were treated with betanin doses (25 mg/kg and 50 mg/kg) intraperitoneally for 9 consecutive days. At the end of the 9th day, the animals were subjected to behavioral examination such as novel object recognition and passive avoidance tests and killed to study the mitochondrial and histological parameters. The results showed attenuation of SCO-induced memory and learning impairment by betanin at 50 mg/kg dose. Also, mitochondrial toxicity parameters such as mitochondrial membrane potential collapse, mitochondrial swelling, decreased activity of succinate dehydrogenase, and reactive oxygen species (ROS) production were reversed by betanin (50 mg/kg) compared to the SCO group. In addition, the ameliorative effect of betanin against SCO was demonstrated in histopathological results of hippocampus. The present investigation established that the betanin ameliorates the SCO-induced memory impairments, tissue injuries, and mitochondrial dysfunction by reducing mitochondrial ROS, which may be due to the potent antioxidant action of betanin.

Amelioration of oxidative stress, cholinergic dysfunction, and neuroinflammation in scopolamine-induced amnesic rats fed with pomegranate seed.

OBJECTIVE: This study aimed to investigate the effects of pomegranate (Punica granatum L.) seed hydro-ethanolic extract (PSE) on cholinergic dysfunction, neuroinflammation, and oxidative stress in the scopolamine-induced amnesic rats. METHODS: The rats were given PSE (200, 400, and 800 mg/kg, gavage) for 3 weeks. In the third week, scopolamine was administered 30 min before the Morris water maze (MWM) and passive avoidance (PA) tests. Oxidative stress indicators, acetylcholinesterase (AChE) activity, and mRNA expression of necrosis factor (TNF)-α, interleukin (IL)-1ß, AChE, and M1 acetylcholine receptor (CHRM1) in the brain, were measured. RESULTS: PSE reduced the time (maximum 173%) and distance (maximum 332%) required to reach the platform during MWM learning (P < 0.001). In the prob test (P < 0.001), it increased the target area time (maximum 44%) and distance (maximum 30%). PSE also increased delay and light time (maximums of 86 and 48%, respectively) (P < 0.001), while decreasing the time in dark region of PA (maximums 727%) (P < 0.001). PSE also reduced malondialdehyde and AChE in the cortex (maximum 168 and 171%, respectively) and hippocampus (maximum 151 and 182%, respectively) (P < 0.001). In the PSE-treated groups, the levels of thiol and superoxide dismutase were increased in the cortex (maximum 54 and 65%, respectively) and hippocampus (maximum 90 and 51%, respectively) (P < 0.001). TNF-α, IL-1ß, and AChE expressions in the hippocampus were reduced by PSE (maximum 114, 137, and 106%, respectively, P < 0.01). Meanwhile, CHMR expression was increased (66%). CONCLUSION: PSE successfully alleviated scopolamine-induced memory and learning deficits in rats which is probably via modulating cholinergic system function, oxidative stress, and inflammatory cytokines.

Neuromodulatory Mechanisms of a Memory Loss-Preventive Effect of Alpha-Lipoic Acid in an Experimental Rat Model of Dementia.

This study evaluates some of the neuromodulatory mechanisms of the memory loss preventive effect of alpha-lipoic acid (ALA) in a scopolamine (Sco)-induced rat model of Alzheimer's disease (AD) type dementia. Our results confirmed that Sco administration induces significant memory impairment, worsens exploratory behaviour and habituation, increases acetylcholinesterase (AChE) activity, and induces pathological monoamine content changes in the prefrontal cortex and hippocampus. ALA administration largely prevented Sco-induced memory impairment. It also improved exploratory behaviour and preserved habituation, and it decreased AChE activity, reversing it to control group levels, and corrected aberrant monoamine levels in the prefrontal cortex and hippocampus. According to the data available, this is the first time that ALA-induced changes in AChE and monoamine levels in the prefrontal cortex and hippocampus (brain structures related to learning and memory) have been demonstrated in a Sco-induced rat model of AD type dementia.

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.