Scopolamine-induced Cognitive Impairment In Mice Research Articles

Neuroprotective and Antiamnesic Effects of Mitragyna inermis Willd (Rubiaceae) on Scopolamine-Induced Memory Impairment in Mice.

Aim. To assess memory improvement and neuroprotective and antioxidant effects of Mitragyna inermis (M. inermis) leaf decoction on the central nervous system. Methodology. Leaf decoction of M. inermis was tested on learning and memory in normal and scopolamine-induced cognitive impairment in mice using memory behavioral tests such as the Morris water maze, object recognition task, and elevated plus maze. Oxidative stress enzymes—catalase, superoxide dismutase, and the thiobarbituric acid reactive substance, a product of lipid peroxidation—were quantified. In each test, mice 18 to 25 g were divided into groups of 5. Results. The extract reversed the effects of scopolamine in mice. The extract significantly increased discrimination index in the object recognition task test and inflexion ratio in the elevated plus maze test. The times spent in target quadrant in MWM increased while the transfer latency decreased in mice treated by M. inermis at the dose of 196.5 mg/kg. The activity levels of superoxide dismutase and catalase were significantly increased, whereas the thiobarbituric acid reactive substance was significantly decreased after 8 consecutive days of treatment with M. inermis at the dose of 393 mg/kg. Conclusion. These results suggest that M. inermis leaf extract possess potential antiamnesic effects.

Antioxidant and acetylcholinesterase inhibitory activities in vitro of different fraction of Huperzia squarrosa (Forst.) Trevis extract and attenuation of scopolamine-induced cognitive impairment in mice

Ethnopharmacological relevanceHuperzia squarrosa (Forst.) Trevis is used in traditional medicine for improving memory deficits. Alkaloids, triterpenoids, flavonoids are main bioactive compounds of Huperzia squarrosa (Forst.) Trevis. Aim of the studyThis study aimed to investigate the antioxidant, AChE inhibitory activities in vitro of differents fraction of Huperzia squarrosa (Forst.) Trevis extract and neuroprotective effects of EtOAc fraction on scopolamine-induced cognitive impairment in mice. Materials and methodsAntioxidant activity was measured by DPPH assay. AChE inhibitory effect in vitro and detail kinetic inhibition mechanism was evaluated by Ellman's assay. For in vivo assay, mice were administrated orally EtOAc fraction (150 and 300mg/kg) for fourteen days, and injected scopolamine at a dose of 1mg/kg intraperitoneally for four days to induce memory injured. The memory behaviors were evaluated using the Morris water maze. ACh levels were measured in brain tissue. Superoxide dismutase (SOD), glutathione peroxidase (GPx) activities, malondialdehyde and protein thiol groups were also evaluated in the brains. ResultsOur data also demonstrated that EtOAc fraction had the strongest antioxidant with an IC50 value of 9.35±1.68µg/mL and AChE inhibitory activity with an IC50 value of 23.44±3.14μg/mL in a concentration-dependent manner. Kinetic inhibition analysis indicated that EtOAc fraction was mixed inhibition type with Ki (representing the affinity of the enzyme and inhibitor) was 34.75±1.42µg/mL. Scopolamine significantly increased the escape latency time, reduced the crossings number, and swimming time in the target quadrant, while EtOAc fraction reversed these scopolamine-induced effects. EtOAc fraction significantly increased levels of acetylcholine in the brain. EtOAc fraction also significantly decreased oxidative stress in mice. ConclusionOur data suggest that EtOAc fraction of Huperzia squarrosa extract exhibited a strong neuroprotective effect on cognitive impairment, and may be a potential candidate for the treatment of Alzheimer.

Polygalasaponin XXXII, a triterpenoid saponin from Polygalae Radix, attenuates scopolamine-induced cognitive impairments in mice.

Recent studies show that the extract of a Chinese herb Polygalae Radix exerts cognition-enhancing actions in rats and humans. The aim of this study was to characterize the pharmacological profiles of active compounds extracted from Polygalae Radix. Two fractions P3 and P6 and two compounds PTM-15 and polygalasaponin XXXII (PGS32) were prepared. Neuroprotective effects were evaluated in primary cortical neurons exposed to high concentration glutamate, serum deficiency or H2O2. Anti-dementia actions were assessed in scopolamine-induced amnesia in mice using step-through avoidance tests and channel water maze tests. After conducting the channel water maze tests, TrkB phosphorylation in mouse hippocampus was detected using Western blotting. Long-term potentiation (LTP) was induced in the dentate gyrus in adult rats; PGS32 (5 μL 400 μmol/L) was injected into the lateral cerebral ventricle 20 min after high frequency stimulation (HFS). Compared to the fraction P6, the fraction P3 showed more prominent neuroprotective effects in vitro and cognition-enhancing effects in scopolamine-induced amnesia in mice. One active compound PGS32 in the fraction P3 exerted potent cognition-enhancing action: oral administration of PGS32 (0.125 mg·kg(-1)·d(-1)) for 19 days abolished scopolamine-induced memory impairment in mice. Furthermore, PGS32 (0.5 and 2 mg·kg(-1)·d(-1)) significantly stimulated the phosphorylation of TrkB in the hippocampus. Intracerebroventricular injection of PGS32 significantly enhanced HFS-induced LTP in the dentate gyrus of rats. PGS32 attenuates scopolamine-induced cognitive impairments in mice, suggesting that it has a potential for the treatment of cognitive dysfunction and dementia.

Sunitinib, a Clinically Used Anticancer Drug, Is a Potent AChE Inhibitor and Attenuates Cognitive Impairments in Mice.

Sunitinib, a tyrosine kinase inhibitor, is clinically used for the treatment of cancer. In this study, we found for the first time that sunitinib inhibits acetylcholinesterase (AChE) at submicromolar concentrations in vitro. In addition, sunitinib dramatically decreased the hippocampal and cortical activity of AChE in a time-dependent manner in mice. Molecular docking analysis further demonstrates that sunitinib might interact with both the catalytic anion and peripheral anionic sites within AChE, which is in accordance with enzymatic activity results showing that sunitinib inhibits AChE in a mixed pattern. Most importantly, we evaluated the effects of sunitinib on scopolamine-induced cognitive impairments in mice by using novel object recognition and Morris water maze tests. Surprisingly, sunitinib could attenuate cognitive impairments to a similar extent as donepezil, a marketed AChE inhibitor used for the treatment of Alzheimer's disease. In summary, our results have shown that sunitinib could potently inhibit AChE and attenuate cognitive impairments in mice.

Fucoxanthin, a Marine Carotenoid, Reverses Scopolamine-Induced Cognitive Impairments in Mice and Inhibits Acetylcholinesterase in Vitro.

Fucoxanthin, a natural carotenoid abundant in edible brown seaweeds, has been shown to possess anti-cancer, anti-oxidant, anti-obesity and anti-diabetic effects. In this study, we report for the first time that fucoxanthin effectively protects against scopolamine-induced cognitive impairments in mice. In addition, fucoxanthin significantly reversed the scopolamine-induced increase of acetylcholinesterase (AChE) activity and decreased both choline acetyltransferase activity and brain-derived neurotrophic factor (BDNF) expression. Using an in vitro AChE activity assay, we discovered that fucoxanthin directly inhibits AChE with an IC50 value of 81.2 μM. Molecular docking analysis suggests that fucoxanthin likely interacts with the peripheral anionic site within AChE, which is in accordance with enzymatic activity results showing that fucoxanthin inhibits AChE in a non-competitive manner. Based on our current findings, we anticipate that fucoxanthin might exhibit great therapeutic efficacy for the treatment of Alzheimer’s disease by acting on multiple targets, including inhibiting AChE and increasing BDNF expression.

The memory-enhancing effect of erucic acid on scopolamine-induced cognitive impairment in mice

Erucic acid is a monounsaturated omega-9 fatty acid isolated from the seed of Raphanus sativus L. that is known to normalize the accumulation of very long chain fatty acids in the brains of patients suffering from X-linked adrenoleukodystrophy. Here, we investigated whether erucic acid enhanced cognitive function or ameliorated scopolamine-induced memory impairment using the passive avoidance, Y-maze and Morris water maze tasks. Erucic acid (3mg/kg, p.o.) enhanced memory performance in normal naïve mice. In addition, erucic acid (3mg/kg, p.o.) ameliorated scopolamine-induced memory impairment, as assessed via the behavioral tasks. We then investigated the underlying mechanism of the memory-enhancing effect of erucic acid. The administration of erucic acid increased the phosphorylation levels of phosphatidylinositide 3-kinase (PI3K), protein kinase C zeta (PKCζ), extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB) and additional protein kinase B (Akt) in the hippocampus. These results suggest that erucic acid has an ameliorative effect in mice with scopolamine-induced memory deficits and that the effect of erucic acid is partially due to the activation of PI3K–PKCζ–ERK–CREB signaling as well as an increase in phosphorylated Akt in the hippocampus. Therefore, erucic acid may be a novel therapeutic agent for diseases associated with cognitive deficits, such as Alzheimer's disease.

Improvement of cognitive performance and cholinergic transmission by development of novel acridine-piperazine hybrids

s / Parkinsonism and Related Disorders 22 (2016) e149ee192 e178 3. O'Leary TP, Savoie V, Brown RE. Learning, memory and search strategies of inbred mouse strains with different visual abilities in the Barnes maze. Behavioural brain research. 2011;216:531-542. 4. Andrade C. Quantifying the ECT dose: the right unit remains elusive. The journal of ECT 2001;17:75. P 6.009. IMPROVEMENT OF COGNITIVE PERFORMANCE AND CHOLINERGIC TRANSMISSION BY DEVELOPMENT OF NOVEL ACRIDINE-PIPERAZINE HYBRIDS Anuradha Sharma, Poonam Piplani. University Institute of Pharmaceutical Sciences, Panjab University, Chandigarh, 160014, Chandigarh, India Objective: The objective of the present study was to design and synthesize some novel acridine-piperazine hybrids and evaluation of their ability to improve scopolamine induced cognitive deficit. Further, to elucidate mechanism of action using acetylcholinesterase inhibitory assay. Methods: 1. In-silico studies: Vlife, Phase and QikProp (Maestro) softwares were employed to design novel hybrids. 2. Synthesis: Alkylation of substituted aniline with o-bromobenzoic acid was done to afford substituted phenylamino benzoic acid derivatives. These intermediates were cyclized to form substituted acridone analogues, which were subsequently chlorinated in the presence of phosphorus oxychloride and then refluxed with fluoropiperazines to afford the final compounds (1-5). 3. Pharmacological Evaluation: Behavioral studies were carried out using elevated plus maze and passive avoidance tests on mice. Biochemical studies were carried out to study their acetylcholinesterase inhibitory profile using Ellman method. Results: Four point pharmacophore (ADHR) was developed using Phase to design the hybrids, which were docked at the defined cavity of enzyme to understand the possible interactions as shown in the figure (Vlife). Compounds bearing fluoro halogen substituent at 4th position of phenylpiperazine ring enhances the binding interactions. The calculated ADME properties confirmed the druglikeness using QikProp. Conclusion: The compound 1 was found to be most potent with IC50 0.33 out of all the synthesized hybrids. Rational design of novel series of potent acridine-piperazine hybrids as cognition enhacers, binding to the active site of AChE structure was disclosed which can act as a future lead in this area.

Japanese Huperzia serrata extract and the constituent, huperzine A, ameliorate the scopolamine-induced cognitive impairment in mice.

Huperzia serrata has been used as a Chinese folk medicine for many years. It contains huperzine A, which has a protective effect against memory deficits in animal models; however, it is unclear if H. serrata extract exerts any effects in Alzheimer's disease (AD) models. We used H. serrata collected in Japan and determined its huperzine A content using HPLC. We determined its inhibitory effects on acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE) activity. H. serrata extract (30mg/kg/day) and donepezil (10mg/kg/day) were orally administrated for 7days. After repeated administration, we performed the Y-maze and passive avoidance tests. H. serrata extract contained 0.5% huperzine A; H. serrata extract inhibited AChE, but not BuChE. H. serrata extract ameliorated cognitive function in mice. These results indicate that Japanese H. serrata extract ameliorates cognitive function deficits by inhibiting AChE. Therefore, H. serrata extract may be valuable for the prevention or treatment of dementia in AD.

Water-soluble ginseng oligosaccharides protect against scopolamine-induced cognitive impairment by functioning as an antineuroinflammatory agent

BackgroundPanax ginseng root is used in traditional oriental medicine for human health. Its main active components such as saponins and polysaccharides have been widely evaluated for treating diseases, but secondary active components such as oligosaccharides have been rarely studied. This study aimed to assess the impact of water-soluble ginseng oligosaccharides (WGOS), which were isolated from the warm-water extract of Panax ginseng root, on scopolamine-induced cognitive impairment in mice and its antineuroinflammatory mechanisms. MethodsWe investigated the impact of WGOS on scopolamine-induced cognitive impairment in mice by using Morris water maze and novel object recognition task. We also analyzed the impact of WGOS on scopolamine-induced inflammatory response (e.g., the hyperexpression of proinflammatory cytokines IL-1β and IL-6 and astrocyte activation) by quantitative real-time polymerase chain reaction and glial fibrillary acid protein (GFAP) immunohistochemical staining. ResultsWGOS pretreatment protected against scopolamine-induced learning and memory deficits in the Morris water maze and in the novel object recognition task. Furthermore, WGOS pretreatment downregulated scopolamine-induced hyperexpression of proinflammatory cytokines interleukin (IL)-1β and IL-6 mRNA and astrocyte activation in the hippocampus. These results indicate that WGOS can protect against scopolamine-induced alterations in learning and memory and inflammatory response. ConclusionOur data suggest that WGOS may be beneficial as a medicine or functional food supplement to treat disorders with cognitive deficits and increased inflammation.

Methyl jasmonate enhances memory performance through inhibition of oxidative stress and acetylcholinesterase activity in mice.

Current research effort focuses on the development of safer natural compounds with multipronged mechanisms of action that could be used to ameliorate memory deficits in patients with Alzheimer's disease, as cure for the disease still remains elusive. In this study, we evaluated the effect of methyl jasmonate (MJ), a naturally occurring bioactive compound on memory, acetylcholinesterase activity and biomarkers of oxidative stress in mice. Male Swiss mice were treated with intraperitoneal injection of MJ (10-40 mg/kg) alone or in combination with scopolamine (3mg/kg) once daily for 7 days. Thirty minutes after the last treatment, memory functions were assessed using Y-maze and object recognition tests. Thereafter, acetylcholinesterase activity and levels of biomarkers of oxidative stress were assessed in mice brains using standard biochemical procedures. MJ significantly enhanced memory performance and reversed scopolamine-induced cognitive impairment in mice. MJ demonstrated significant inhibition of acetylcholinesterase activity suggesting increased cholinergic neurotransmission. It further decreased malondialdehyde concentrations in mouse brain indicating antioxidant activity. Moreover, MJ significantly increased glutathione levels and activity of antioxidant enzymes (catalase and superoxide dismutase) in mice brains. The increased oxidative stress; evidenced by elevated levels of malondialdehyde and decreased antioxidant defense systems in scopolamine-treated mice was attenuated by MJ. The results of this study suggest that MJ may be useful in conditions associated with memory dysfunctions or age-related cognitive decline. The positive effect of MJ on memory may be related to inhibition of oxidative stress and enhancement of cholinergic neurotransmission through inhibition of acetylcholinesterase activity.

Multifunctional scutellarin–rivastigmine hybrids with cholinergic, antioxidant, biometal chelating and neuroprotective properties for the treatment of Alzheimer’s disease

To discover multifunctional agents for the treatment of Alzheimer’s disease (AD), a series of scutellarein carbamate derivatives were designed and synthesized based on the multitarget-directed ligand strategy. Their acetylcholinesterase and butyrylcholinesterase inhibitory activities, antioxidant activities, metal-chelating properties and neuroprotective effects against hydrogen peroxide induced PC12 cell injury were evaluated in vitro. The results showed that most of the synthetic compounds exhibited good multifunctional activities. In particular, compound 15c exhibited dual inhibitory potency on acetylcholinesterase and butyrylcholinesterase with IC50 values of 0.57 and 22.6μM, respectively, and good antioxidative activity, with a value 1.3-fold of Trolox. In addition, 15c acted as a selective biometal chelator and possessed neuroprotective effects. Furthermore, 15c could cross the blood–brain barrier (BBB) in vitro and had significant neuroprotective effects in scopolamine-induced cognitive impairment in mice. Taken together, these results suggest that compound 15c might be a potential multifunctional agent for the treatment of AD.

Amyrin Attenuates Scopolamine-Induced Cognitive Impairment in Mice

Alzheimer's disease, a neurodegenerative disorder, is characterized by progressive cognitive impairment associated with the disruption of cholinergic neurotransmission. The aim of the present study was to evaluate the effect of α- or β-amyrin, a type of pentacyclic triterpene, on the cognitive impairment induced by scopolamine, a muscarinic acetylcholine receptor antagonist. To measure the abilities of various types of learning and memory, we conducted step-through passive avoidance task. Scopolamine induced deficits in learning and memory processes in mice, which were antagonized by a single administration of α-amyrin (2 or 4 mg/kg) or β-amyrin (4 mg/kg), respectively. Additionally, in vitro analysis revealed that acetylcholinesterase activity was inhibited by β-amyrin, but not by α-amyrin. Furthermore, Western blot analysis revealed that the expression levels of phosphorylated extracellular signal-regulated kinase 1/2 (pERK) and phosphorylated glycogen synthase kinase-3β (pGSK-3β) were significantly enhanced by a single administration of α- and β-amyrin in the hippocampus. Finally, the memory ameliorating effects of α- or β-amyrin on the scopolamine-induced cognitive impairments were significantly blocked by ERK inhibitor U0126. The present study suggests that α- and β-amyrin may ameliorate the cognitive impairment induced by hypocholinergic neurotransmission via the activation of ERK as well as GSK-3β signaling.

Neuro-protective effect of Carvedilol, an adrenergic antagonist against scopolamine-induced cognitive impairment in mice

Impact analysis of inclusion complexation on micromeritic properties and dissolution behavior of carvedilolKhandaker Sagir Ahmed, Md. Abdullah Al Masum, Sabiha Sultana, Mohiuddin Ahmed Bhuiyan, Md. Selim Reza

<i>Angelica keiskei</i> Ameliorates Scopolamine-Induced Memory Impairments in Mice

Memory impairment is the most common symptom in patients with Alzheimer's disease (AD). Angelica keiskei (AK) has traditionally been used as a diuretic, laxative, analeptic and galactagogue. However, the anti-amnesic effects of AK and its molecular mechanisms have yet to be clearly elucidated. The aim of the present study is to evaluate the effects of AK on scopolamine-induced memory impairments in mice. The regulatory effect of AK on memory impairment was investigated using passive avoidance, Y-maze and the Morris water maze tasks. Acetylcholinesterase (AChE) activity assay was performed to investigate the cholinergic antagonistic effect of AK in the hippocampus. The effect of AK on phosphorylation of cAMP response element-binding protein (CREB) and expression of brain-derived neurotrophic factor (BDNF) were evaluated by Western blot assays and immunohistochemistry. The findings showed that AK significantly attenuated scopolamine-induced cognitive impairment in mice. Increase of AChE activity caused by scopolamine was significantly attenuated by AK. Additionally, AK significantly recovered the phosphorylation of CREB and expression of BDNF reduced by scopolamine in the hippocampus. Taken together, these results provide experimental evidence that AK might be a useful agent in preventing deficit of learning and memory caused by AD and aging.

Effect of resveratrol on scopolamine-induced cognitive impairment in mice

BackgroundResveratrol (3,4’,5-trihydroxystilbene) is a naturally occurring compound found in grapes, wine, peanuts and cranberries. Recently, in vitro and cell culture studies have reported beneficial effects of resveratrol in the neurodegenerative process in Alzheimer’s disease (AD). However, in vivo effect of resveratrol in models of learning and memory is not yet evaluated. The present study was performed to examine the effect of resveratrol on cognitive impairment induced by scopolamine, a muscarinic antagonist, in mice. MethodsScopolamine was administered in a dose of 1mg/kg intraperitoneally (ip). Cognitive functions were assessed using transfer latency (TL) on elevated plus maze, step-down latency (SDL) on a passive avoidance apparatus and escape latency (EL) in Morris water maze test. ResultsScopolamine produced significant prolongation of TL, reduction in SDL as well as EL showing cognitive impairment in mice. Pre-treatment with resveratrol (10mg/kg and 20mg/kg, ip) for 21 days showed no difference in TL, SDL and EL. ConclusionResveratrol treatment does not reverse scopolamine-induced deficit in cognitive functions in mice.

The Cyanine Dye NK-4 Improves Scopolamine-Induced Memory Impairments in Mice

The aim of this study is to evaluate the effects of NK-4, a kind of cyanine dye, on cholinergic memory deficits in mice. We examined whether NK-4 could reverse scopolamine-induced amnesia in mice since NK-4 displays a potent and selective inhibitory effect on acetylcholinesterase (AChE) in vitro. Intraperitoneal administration of NK-4 significantly reversed scopolamine-induced cognitive impairments in mice in the Y maze and the passive avoidance tests, and NK-4 also improved spatial learning ability in the Morris water maze test. Despite NK-4 displaying remarkable AChE inhibitory activity in vitro, we could not detect a significant reduction of AChE activity in brain homogenates of NK-4-treated mice. Although the mechanism through which NK-4 reverses cognitive impairments in scopolamine-treated mice remains unclear, these data suggest that NK-4 may have potential as a therapeutic agent for the treatment of dementia.

Polygalasaponin XXXII from Polygala tenuifolia root improves hippocampal-dependent learning and memory

The aim of this study was to investigate the cognition-enhancing activity and underlying mechanisms of a triterpenoid saponin (polygalasaponin XXXII, PGS32) isolated from the roots of Polygala tenuifolia Willd. The Morris water maze was used to evaluate the spatial learning and memory of mice. To detect the basic properties of synaptic transmission and long-term potentiation (LTP) in the dentate gyrus of rats, electrophysiological recordings were made of evoked potentials. Western blotting analysis and immunofluorescence assays were used to determine the phosphorylation of extracellular signal-regulated kinase (ERK), cAMP response element-binding protein (CREB), synapsin I and the expression of brain derived neurotrophic factor (BDNF). When administered at 0.125, 0.5, or 2 mg/kg, PGS32 could significantly prevent scopolamine-induced cognitive impairments in mice. Intracerebroventricular (icv) administration of PGS32 greatly enhanced basic synaptic transmission in the dentate gyrus of rats and induced LTP. In primary hippocampal neurons, as well as in the hippocampus of maze-trained mice, PGS32 activated the mitogen-activated protein (MAP) kinase cascade by promoting phosphorylation of ERK, CREB and synapsin I. The expression of BDNF was also greatly enhanced in the hippocampus. Our findings suggest that PGS32 can improve hippocampus-dependent learning and memory, possibly through improvement of synaptic transmission, activation of the MAP kinase cascade and enhancement of the level of BDNF. Therefore, PGS32 shows promise as a potential cognition-enhancing therapeutic drug.

Gomisin A improves scopolamine-induced memory impairment in mice

Gomisin A is a component of the fruits of Schizandra chinesis which are widely used as a tonic in traditional Chinese medicine. In the present study, we assessed the effect of gomisin A on the learning and memory impairments induced by scopolamine. The cognition-enhancing effect of gomisin A was investigated using a passive avoidance test, the Y-maze test, and the Morris water maze test in mice. Drug-induced amnesia was induced by treating animals with scopolamine (1 mg/kg, i.p.). Gomisin A (5 mg/kg, p.o.) administration significantly reversed scopolamine-induced cognitive impairments in mice by the passive avoidance test and the Y-maze test ( P < 0.05), and also improved escape latency in the Morris water maze test at 5 mg/kg ( P < 0.05). Moreover, in an in vitro study, gomisin A was found to inhibit acetylcholinesterase activity in a dose-dependent manner (IC 50 value; 15.5 μM). These results suggest that gomisin A may be a useful cognitive impairment treatment, and its beneficial effects are mediated, in part, via enhancing the cholinergic nervous system.