BACKGROUND: The study investigated the effect of co-administration of curcumin and donepezil on several markers of cognitive function (such as spatial memory, astrocyte activation, cholinesterase expressions) in the brain cortex and hippocampus of scopolamine-treated rats.
RESULTS: For seven consecutive days, a pre-treatment of curcumin (50 mg/kg) and/or donepezil (2.5 mg/kg) was administered. On the seventh day, scopolamine (1 mg/kg) was administered to elicit cognitive impairment, 30 min before memory test was conducted. This was followed by evaluating changes in spatial memory, cholinesterase, and adenosine deaminase (ADA) activities, as well as nitric oxide (NO) level were determined. Additionally, RT-qPCR for glial fibrillary acidic protein (GFAP) and cholinesterase gene expressions was performed in the brain cortex and hippocampus. Also, GFAP immunohistochemistry  of the brain tissues for neuronal injury were performed in the brain cortex and hippocampus. In comparison to the control group, rats given scopolamine had impaired memory, higher levels of acetylcholinesterase (AChE), butyrylcholinesterase (BChE), and ADA activities, as well as elevated markers of oxidative stress. In addition to enhanced GFAP immunoreactivity, there was also overexpression of the GFAP and BChE genes in the brain tissues. The combination of curcumin and donepezil was, however, observed to better ameliorate these impairments in comparison to the donepezil-administered rat group.
CONCLUSIONS: Hence, this evidence provides more mechanisms to support the hypothesis that the concurrent administration of curcumin and donepezil mitigates markers of cognitive dysfunction in scopolamine-treated rat model.

Pinostrobin, a key bioactive compound found in the medicinal plant Boesenbergia rotunda (L.), has been noted for its beneficial biological properties including antioxidant, anti-inflammation, anti-cancer and anti-amnesia activities. In view of this, the present study purposed to evaluate the neuroprotective potential of pinostrobin in reversing scopolamine-induced cognitive impairment involving oxidative stress and cholinergic function in rats. A total of 30 male Wistar rats were randomly divided into five groups (n=6): Group 1 received vehicle as a control, group 2 received vehicle + scopolamine (3 mg/kg, i.p.), group 3 received pinostrobin (20 mg/kg, p.o.) + scopolamine, group 4 received pinostrobin (40 mg/kg, p.o.) + scopolamine and group 5 received donepezil (5 mg/kg, p.o.) + scopolamine. Treatments were administered orally to the rats for 14 days. During the final 7 days of treatment, a daily injection of scopolamine was administered. Scopolamine impaired learning and memory performance, as measured by the novel object recognition test and the Y-maze test. Additionally, oxidative stress marker levels, acetylcholinesterase (AChE) activity, choline acetyltransferase (ChAT) and glutamate receptor 1 (GluR1) expression were determined. Consequently, the findings demonstrated that the administration of pinostrobin (20 and 40 mg/kg) markedly improved cognitive function as indicated by an increase in recognition index and by spontaneous alternation behaviour. Pinostrobin also modulated the levels of oxidative stress by causing a decrease in malondialdehyde levels accompanied by increases in superoxide dismutase and glutathione activities. Similarly, pinostrobin markedly enhanced cholinergic function by decreasing AChE activity and promoting ChAT immunoreactivity in the hippocampus. Additionally, the reduction in GluR1 expression due to scopolamine was diminished by treatment with pinostrobin. The findings indicated that pinostrobin exhibited a significant restoration of scopolamine-induced memory impairment by regulating oxidative stress and cholinergic system function. Thus, pinostrobin could serve as a potential therapeutic agent for the management of neurodegenerative diseases such as Alzheimer\'s disease.

BACKGROUND: The prevalence of dementia around the world is increasing, and these patients are more likely to have cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorders over their lifetime. Previous studies have proven that melatonin could improve memory loss, but its specific mechanism is still confused.
METHODS: In this study, we used in vivo and in vitro models to examine the neuroprotective effect of melatonin on scopolamine (SCOP)-induced cognitive dysfunction. The behavioral tests were performed. 18F-FDG PET imaging was used to assess the metabolism of the brain. Protein expressions were determined through kit detection, Western blot, and immunofluorescence. Nissl staining was conducted to reflect neurodegeneration. MTT assay and RNAi transfection were applied to perform the in vitro experiments.
RESULTS: We found that melatonin could ameliorate SCOP-induced cognitive dysfunction and relieve anxious-like behaviors or HT22 cell damage. 18F-FDG PET-CT results showed that melatonin could improve cerebral glucose uptake in SCOP-treated mice. Melatonin restored the cholinergic function, increased the expressions of neurotrophic factors, and ameliorated oxidative stress in the brain of SCOP-treated mice. In addition, melatonin upregulated the expression of silent information regulator 1 (SIRT1), which further relieved endoplasmic reticulum (ER) stress by decreasing the expression of phosphorylate inositol-requiring enzyme (p-IRE1α) and its downstream, X-box binding protein 1 (XBP1).
CONCLUSIONS: These results indicated that melatonin could ameliorate SCOP-induced cognitive dysfunction through the SIRT1/IRE1α/XBP1 pathway. SIRT1 might be the critical target of melatonin in the treatment of dementia.

Population aging around the world is rapidly progressing; as a result, cognitive decline developing into dementia is becoming a social problem. There is no drug that can cure dementia, and though drugs that alleviate the symptoms of dementia have been developed, they also have side effects. Therefore, we conducted a study on improving cognitive function using natural products that have secured safety. We confirmed the effect of an extract of Scrophularia buergeriana on scopolamine-induced cognitive impairment through mouse behavioral experiments, and we observed metabolic changes in the cortex and hippocampus via brain tissue dissection after the behavioral experiment. Mitigating effects of S. buergeriana on cognitive impairment caused by scopolamine were observed in passive avoidance and Morris water maze tests. A metabolic analysis revealed biomarkers related to the alleviating effect of cognitive impairment. Niacinamide, tyrosine, uridine, and valine in the cortex and GABA, choline, creatine, formate, fumarate, hypoxanthine, leucine, myo-inositol, pyroglutamate, and taurine in the hippocampus were identified as biomarker candidates for recovering cognitive impairment. In addition to behavioral experiments, this metabolomics study using specific regions of the brain may be helpful in understanding the effects of cognitive improvement.

BACKGROUND: The cholinergic system has been increasingly linked to the pathophysiology of mood disorders such as depression, with the potential involvement of nicotinic and/or muscarinic receptors. Conventional antidepressants usually require weeks of daily dosing to achieve a full antidepressant response. In contrast, clinical studies have shown that scopolamine, a nonselective muscarinic acetylcholine receptor antagonist, can induce potent and rapid antidepressant effects, requiring only a few days of treatment. This study aimed to examine the suitability of the unpredictable chronic mild stress (UCMS) model of depression to reproduce the above scopolamine antidepressant activity patterns.
METHODS: Rapid and sustained antidepressant-like effects were assessed by using the splash test, sucrose preference test (SPT), tail suspension test (TST), and forced swimming test (FST) in animals undergoing the UCMS procedure and stress-naïve C57BL/6J mice. Western Blotting was used to measure tropomyosin receptor kinase B (TrkB), mammalian target of rapamycin (mTOR), eukaryotic elongation factor (eEF2) and postsynaptic density protein 95 (PSD95) levels.
RESULTS: Scopolamine induced antidepressant-like effects in a dose-dependent manner only after subchronic, but not single, administration in the UCMS model of depression in C57BL/6J mice without affecting locomotor activity. Specifically, scopolamine administered at a dose of 0.3 mg/kg for four consecutive days significantly reversed the UCMS-induced depressive-like behavior, such as apathy, anhedonia, and behavioral despair, while scopolamine, given at the same dose but only once, did not relieve the above symptoms. Scopolamine treatment was accompanied by eEF2 protein dephosphorylation and its subsequent reactivation in the prefrontal cortex (PFC).
CONCLUSIONS: Subchronic administration of scopolamine is needed to ameliorate UCMS-induced depressive-like behavior. The suggested mechanism of scopolamine action covers eEF2 protein activity in the PFC.

Alzheimer\'s Disease (AD) is a neurodegenerative disorder mainly characterized by dementia and cognitive decline. AD is essentially associated with the presence of aggregates of the amyloid-β peptide and the hyperphosphorylated microtubule-associated protein tau. The available AD therapies can only alleviate the symptoms; therefore, the development of natural treatments that exhibit neuroprotective effects and correct the behavioral impairment is a critical requirement. The present review aims to collect the natural substances that have been evaluated for their neuroprotective profile against AD-like behaviors induced in zebrafish (Danio rerio) by scopolamine. We focused on articles retrieved from the PubMed database via preset searching strings from 2010 to 2023. Our review assembled 21 studies that elucidated the activities of 28 various natural substances, including bioactive compounds, extracts, fractions, commercial compounds, and essential oils. The listed compounds enhanced cognition and showed several mechanisms of action, namely antioxidant potential, acetylcholinesterase\'s inhibition, and reduction of lipid peroxidation. Additional studies should be achieved to demonstrate their preventive and therapeutic activities in cellular and rodent models. Further clinical trials would be extremely solicited to support more insight into the neuroprotective effects of the most promising drugs in an AD context.

UNASSIGNED: Alzheimer\'s disease (AD) is a neurodegenerative disease specified by chronic and irreversible destruction of neurons. This study aimed to evaluate the effects of different extracts (aqueous, hydroalcoholic, hexane, and ethyl acetate) and manna of Echinops cephalotes (EC) on impaired cognitive function induced by scopolamine in mice. EC is shown to have anti-cholinesterase-butyrylcholinesterase activities.
UNASSIGNED: In this study, aqueous and hydroalcoholic extracts, hexane and ethyl acetate fractions of EC (25, 50, 100 mg/kg, i.p.), and the manna (25, 50, 100 mg/kg, gavage) were administered for 14 days alongside scopolamine (0.7 mg/kg, i.p.). Rivastigmine (reference drug) was administered for 2 weeks i.p. Mice were tested for their memory function using two behavioral models, object recognition test (ORT) and passive avoidance test (PAT).
UNASSIGNED: Administration of scopolamine significantly impaired memory function in both behavioral models. In the PAT model, all extracts at 50 and 100 mg/kg significantly reversed the effect of memory destruction caused by scopolamine. At a lower dose of 25 mg/kg, however, none of the extracts were able to significantly change the step-through latency time. In the ORT model, however, administration of all extracts at 50 and 100 mg/kg, significantly increased the recognition index. Only the manna and the aqueous extract at 25 mg/kg were able to reverse scopolamine-induced memory impairment.
UNASSIGNED: These results suggest that all forms of EC extracts improve memory impairment induced by scopolamine comparably to rivastigmine. Whether the effects are sustained over a longer period remains to be tested in future work.

Muscarinic receptors are G protein-coupled receptors (GPCRs) that play a role in various physiological functions. Previous studies have shown that these receptors, along with other GPCRs, are voltage-sensitive; both their affinity toward agonists and their activation are regulated by membrane potential. To our knowledge, whether the effect of antagonists on these receptors is voltage-dependent has not yet been studied. In this study, we used Xenopus oocytes expressing the M2 muscarinic receptor (M2R) to investigate this question. Our results indicate that the potencies of two M2R antagonists, atropine and scopolamine, are voltage-dependent; they are more effective at resting potential than under depolarization. In contrast, the M2R antagonist AF-DX 386 did not exhibit voltage-dependent potency.Furthermore, we discovered that the voltage dependence of M2R activation by acetylcholine remains unchanged in the presence of two allosteric modulators, the negative modulator gallamine and the positive modulator LY2119620. These findings enhance our understanding of GPCRs\' voltage dependence and may have pharmacological implications.

BACKGROUND: The neuroprotective effects of Dehydroepiandrosterone (DHEA) and Hericium erinaceus (H. erinaceus) mushroom extract against scopolamine-induced Alzheimer\'s disease-like symptoms in male Wistar rats were investigated.
METHODS: Sixty-four male Wistar rats were divided into eight groups (n = 8). Scopolamine (SCO) was intraperitoneally injected at a dose of 1 mg/kg/day for 10 days. The treatment groups orally received DHEA (250 mg/kg/day) and/or H. erinaceus (300 mg/kg/day) for 14 days. Afterward, the Morris water maze (MWM) and novel object recognition tests were implemented. Then, animals were anesthetized and the brain tissue samples were separated. Levels of lipid peroxidation (LPO), total antioxidant capacity (TAC), catalase activity (CAT), and brain-derived neurotrophic factor (BDNF) were determined. Also, histopathological studies were evaluated in the brain tissue samples.
RESULTS: Administration of SCO significantly decreased spatial and cognitive memory (p < 0.001). Not only did SCO injection significantly increase the levels of the LPO but also the SCO markedly reduced the levels of the TAC, CAT activity, and the BDNF in the brain tissue. On the other hand, a combination of the DHEA and H. erinaceus showed higher efficacy than the DHEA or H. erinaceus in attenuating behavioral anomalies and improving the antioxidant defense system and BDNF levels. Histological examination was well correlated with biochemical findings regarding SCO neurodegeneration and DHEA and/or H. erinaceus neuroprotection.
CONCLUSIONS: Interestingly, ADHE and/or H. erinaceus may due to their potential neurotrophic properties be used as a new and beneficial concurrent therapy in the treatment of Alzheimer\'s disease-like symptoms caused by SCO.

Tropane-containing small molecules like scopolamine are a promising class of psychoplastogens. However, their potent antagonism of all muscarinic receptor subtypes presents the potential for undesirable anticholinergic side effects. In an effort to decouple their neuroplasticity-promoting effects from their muscarinic activity, we performed phenotypic structure-activity relationship studies across a variety of structurally distinct subclasses of tropanes. We discovered several novel tropanes capable of significantly increasing cortical neuronal growth while exhibiting drastically reduced activity at all muscarinic receptor subtypes compared to scopolamine.