Amnesia In Rats Research Articles

Minocycline attenuates cholinergic dysfunction and neuro-inflammation-mediatedcognitive impairmentin scopolamine-induced Alzheimer's rat model.

Minocycline, a semisynthetictetracycline-derivedantibiotic, has various pharmacological effect such as anti-inflammatory, anti-oxidative stress, and anti-apoptotic effects. The current study investigated the involvement of neuro-inflammatory, oxidative stress, and cholinergic markers in neuroprotection by minocycline against scopolamine-induced brain damage. Minocycline was administered (oral, 10, 15, and 30mg/kg, daily) to groups of amnesic rats for 21days. Passive avoidance memory and spatial learning and memory were assessed. Following that, oxidative stress, cholinergic function, and neuro-inflammation markers were evaluated in the brain tissue. According to our biochemical data, treatment of the scopolamine-injured rats with minocycline decreased the levels of malondialdehyde and acetylcholinesterase (AChE) as well as mRNA expression of AChE and neuro-inflammation markers (tumor necrosis factor-α, interleukin (IL)-1β, IL-6). It also increased the total thiol levels and superoxide dismutase activity as well as mRNA expression of cholinergic receptor M1 (ChRM1). Moreover, minocycline modified distance and latencies in Morris water maze, prolonged latency to enter the black zone and light time while decreasing time spent and frequency of entries to darkness. Taken together, the data indicate that treatment with minocycline improved memory dysfunction mediated possibly through restoring AChE and ChRM1 levels, oxidant/antioxidant balance, as well as inhibiting inflammatory responses.

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

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. The rats were given PSE (200, 400, and 800mg/kg, gavage) for 3weeks. In the third week, scopolamine was administered 30min 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)-1β, AChE, and M1 acetylcholine receptor (CHRM1) in the brain, were measured. 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-1β, 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%). PSE successfully alleviated scopolamine-induced memory and learning deficits in rats which is probably via modulating cholinergic system function, oxidative stress, and inflammatory cytokines.

Acute Toxicity Test and Nootropic Activity of Ethanolic Extract of Astragalus membranaceus Bunge on Scopolamine-Induced Amnesia in Rats

The dried roots of Astragalus membranaceus Bunge, belongs to the family fabaceae enhances the memory function and this could be mediated through brain cholinergic system. Historically in China it is used as a medicine for treatment of different types of diseases. It gives good protection against aging and age related diseases. Astragalus membranaceus Bunge root extract was investigated to reveal its nootropic effect and acute toxicity study. The powdered roots were tested for the phytochemical constituents. Carbohydrates, proteins, amino acids, glycosides, saponins, volatile oils, alkaloids, sterols and flavonoids were present. The acute toxicity study of ethanolic extract was carried out according to the OECD test guideline 423. There were no signs of toxicity of rats even with a maximum dose of 2000 mg/kg of the extract during 14 days. For evaluation of nootropic activity, ethanolic extract was administered by oral route to scopolamine induced amnesic rat model. The reduction of acetylcholinesterase activity in the rat brain supports the elevated plus maze (EPM) and passive avoidance test by improving memory function by lowering acetylcholinesterase activity. Present study shows Astragalus membranaceus Bunge root extract possesses significant nootropic activity in scopolamine induced amnesia rat models.&#x0D; Keywords: Astragalus membranaceus Bunge, EPM, passive avoidance, nootropic, acetyl Cholinesterase and Scopolamine.

Therapeutic Effect of Novel Cyanopyrrolidine-Based Prolyl Oligopeptidase Inhibitors in Rat Models of Amnesia.

Prolyl oligopeptidase (POP) is a large cytosolic serine peptidase that is altered in patients with Alzheimer’s disease, Parkinsonian syndrome, muscular dystrophies, and other denervating diseases. Thus, POP may represent a relevant therapeutic target for treatment of neuropsychiatric disorders and neurodegenerative diseases. Here, we report the characterization of five novel cyanopyrrolidine-based compounds (BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, CbzGlnPrdN, and CbzAlaPrdN) and show that they are potent inhibitors of POP and are predicted to penetrate the blood-brain barrier (BBB). Indeed, we show that CbzMetPrdN penetrates the rat BBB and effectively inhibits POP in the brain when administered intraperitoneally. Furthermore, molecular modeling confirmed these compounds likely inhibit POP via interaction with the POP catalytic site. We evaluated protective effects of the cyanopyrrolidine-based POP inhibitors using scopolamine- and maximal electroshock-induced models of amnesia in rats and showed that BocTrpPrdN, BocGlyPrdN, CbzMetPrdN, and CbzGlnPrdN significantly prolonged conditioned passive avoidance reflex (CPAR) retention time when administered intraperitoneally (1 and 2 mg/kg) before evaluation in both models of amnesia, although CbzAlaPrdN was not effective in scopolamine-induced amnesia. Our data support previous reports on the antiamnesic effects of prolinal-based POP inhibitors and indicate an important role of POP in the regulation of learning and memory processes in the CNS.

Cognition enhancing abilities of vitamin D, epalrestat and their combination in diabetic rats with and without scopolamine induced amnesia

Persistent hyperglycaemia and scopolamine were used to inflict amnesia in rats. Chronic hyperglycaemia causes metabolic impairment, neuronal dysfunction and oxidative stress causing cognitive impairment. This study aimed to determine anti amnesic activities of vitamin D, epalrestat and their combination against diabetes and scopolamine induced cognitive dysfunction. A total of eighty-eight Wistar albino rats, eleven groups, and 8 rats/Gr., were used. Type 2 diabetes mellitus was induced in all groups, except Gr.1 which was treated with 2 ml normal saline. Gr. 2 to 11 by feeding high fat diet for 28 days followed by single dose streptozotocin 35 mg/kg i.p. Hyperglycemic rats were screened with blood sugar level > 200 mg/dL. Gr. 2 rats were treated with only streptozotocin and Gr. 3 to 6 were treated with streptozotocin and test drugs donepezil 1 mg/kg, vitamin D, 27 mcg/kg, epalrestat 57 mg/kg, vitamin D + epalrestat, per oral, respectively. Gr. 7 rats were treated with only streptozotocin + scopolamine and all others from Gr. 8 to 11 were treated with streptozotocin + scopolamine and donepezil, vitamin D, epalrestat, vitamin D + epalrestat respectively. The gold standard behavioural tests were conducted by using Morris water maze and passive avoidance paradigms after 30–60 min of inj. scopolamine, 0.5 mg/kg, intra-peritoneal. Hippocampal tissue was taken for histopathological and biochemical evaluation. Rats treated with donepezil, vitamin D, epalrestat and vitamin D + epalrestat showed significant improvement in behavioural, biochemical and histopathological parameters as compared to streptozotocin and (streptozotocin + scopolamine) treated rats. This study underscores cognition enhancing abilities of vitamin D and epalrestat, and their combination in diabetic rats with and without scopolamine.

Chemical characterization and evaluation of the neuroprotective potential of Indigofera sessiliflora through in-silico studies and behavioral tests in scopolamine-induced memory compromised rats.

In the current study, we investigated the phytochemical and neuropharmacological potential of Indigofera sessiliflora, an indigenous least characterized plant widely distributed in deserted areas of Pakistan. The crude extract of the whole plant Indigofera sessiliflora (IS.CR) was preliminary tested in-vitro for the existence of polyphenol content, antioxidant and anticholinesterase potential followed by detailed chemical characterization through UHPLC-MS. Rats administered with different doses of IS.CR (100–300 mg/kg) for the duration of 4-weeks were behaviorally tested for anxiety and cognition followed by biochemical evaluation of dissected brain. The in-silico studies were employed to predict the blood–brain barrier crossing tendencies of secondary metabolites with the elucidation of the target binding site. The in-vitro assays revealed ample phenols and flavonoids content in IS.CR with adequate anti-oxidant and anticholinesterase potential. The dose-dependent anxiolytic potential of IS.CR was demonstrated in open field (OFT), light/dark (L/D) and elevated plus maze (EPM) tests as animals spent more time in open, illuminated and elevated zones (P < 0.05). In the behavioral tests for learning/memory, the IS.CR reversed the scopolamine-induced cognitive deficits, as animals showed better (P < 0.05) spontaneous alternation and discrimination index in y-maze and novel object recognition (NOR) tests. Similarly, as compared to amnesic rats, the step-through latencies were increased (P < 0.05) and escape latencies were decreased (P < 0.05) in passive avoidance (PAT) and Morris water maze (MWM) tests, respectively. Biochemical analysis of rat brains showed significant reduction in malondialdehyde and acetylcholinesterase levels, alongwith preservation of glutathione peroxidase and superoxide dismutase activity. The docking studies further portrayed a possible interaction of detected phytoconstituents with acetylcholinesterase target. The results of the study show valuable therapeutic potential of phytoconstituents present in IS.CR to correct the neurological disarrays which might be through antioxidant activity or via modulation of GABAergic and cholinergic systems by artocommunol, 1,9-dideoxyforskolin and 6E,9E-octadecadienoic acid.

Bay Leaf (Laurus Nobilis L.) Incense Improved Scopolamine-Induced Amnesic Rats by Restoring Cholinergic Dysfunction and Brain Antioxidant Status

Bay leaf (Laurus nobilis L.) has been shown to possesses various biological activities such as wound healing activity, antioxidant activity, antibacterial activity, antiviral activity, immunostimulant activity, anticholinergic activity, antifungal activity, insect repellant activity, anticonvulsant activity, antimutagenic activity, and analgesic and anti-inflammatory activity. The present study aimed to investigate whether the bay leaf incense (BL) elicits the memory formation via the action on the cholinergic system using a scopolamine (Sco)-induced rat model. Rats were exposed to BL over 5 min in a smoking chamber apparatus once daily for 22 days, whereas memory impairment was induced by Sco (0.7 mg/kg), a muscarinic receptor antagonist, delivered 30 min before each behavioral test. The phytochemical composition of BL was achieved by gas chromatograph–mass spectrometry (GCMS). Behavioral effects in rats were assessed by Y-maze, radial arm maze (RAM), and novel object recognition (NOR) paradigms. Additionally, the acetylcholinesterase (AChE) activity and the oxidative stress markers in the rat hippocampus were also evaluated. Exposure to BL significantly ameliorated Sco-induced cognitive impairment and oxidative stress in the rat hippocampus. The obtained results suggested that BL-induced ameliorative cognitive effects are mediated by enhancement of the cholinergic system and antioxidant activities.

Protective effect of co-administration of caffeine and piracetam on scopolamine-induced amnesia in Wistar rats

Alzheimer's disease is a cerebrovascular disorder characterized by progressive loss of the mental capabilities. The novel therapeutic agent piracetam is a cyclic derivative of γ-aminobutyric acid and one of the oldest recognized synthetic nootropics. Piracetam improves cognitive function without stimulation or sedation. Caffeine is a central nervous system stimulant with nootropic activity. Caffeine promotes the performance of tasks that involve working memory to a limited extent, and it also retards cognitive decline in healthy individuals. The present study aimed to determine the protective effect of co-administering piracetam and caffeine on scopolamine-induced amnesia in rats. Pre-treatment with caffeine and piracetam decreased scopolamine-induced cognitive damage and amnesia. The preventive response was demonstrated by an improved learning tendency. The mechanism responsible for these effects requires further investigation. The co-administration of caffeine and piracetam has potential as a novel therapeutic strategy for combating amnesia.

Potential ameliorative effect of Cynodon dactylon (L.) pers on scopolamine-induced amnesia in rats: Restoration of cholinergic and antioxidant pathways.

AIM:The present study explored Cynodon dactylon hydro-ethanolic extract (CDE) effect on scopolamine-induced amnesic rats.MATERIALS AND METHODS:C. dactylon extract was subjected to antioxidant (DPPH and H2O2) and acetylcholinesterase enzyme tests by in vitro methods. Scopolamine (1 mg/kg, i.p) was administered to rats except for normal control. Donepezil (3 mg/kg, p.o), CDE (100, 200, and 400 mg/kg p.o) were administered to treatment groups. Behavioral paradigm: Morris water maze (MWM), elevated plus maze (EPM), and passive avoidance test (PAT) were conducted. Later, rats were sacrificed and brain homogenate was tested for levels of acetylcholinesterase, glutathione, and lipid peroxidase. Histopathology examination of cortex and hippocampus of all the groups was done.STATISTICAL METHOD:The statistical methods used were ANOVA and Tukey's post hoc test.RESULTS:CDE antioxidant activity was demonstrated by decreasing DPPH and H2O2 levels confirmed through in vitro analysis. Treatment group rats reversed scopolamine induced amnesia by improvement in spatial memory, decreased transfer latency and increased step through latency significantly (P<0.001) in behavior models such as morris water maze, elevated plus maze and passive avoidance task respectively. CDE modulated acetylcholine transmission by decreased acetylcholinesterase enzyme level (P < 0.001) and scavenging scopolamine-induced oxidative stress by increased reduced glutathione levels and decreased lipid peroxidation levels in the rat brain. CDE and donepezil-treated rats showed mild neurodegeneration in comparison to scopolamine-induced severe neuronal damage on histopathology examination.CONCLUSION:C. dactylon extract provides evidence of anti-amnesic activity by the mechanism of decreased acetylcholinesterase enzyme level and increased antioxidant levels in scopolamine-induced amnesia in rats.

Effect of coenzyme Q10 and/or epigallocatechin gallate on memantine-treated amnesia model in rats

Background Alzheimer’s dementia is a progressive, fatal neurodegenerative disease that manifests as a disintegration of perception and memory. Objectives The current study evaluated the possible therapeutic effect of coenzyme Q10 (CoQ10) and/or epigallocatechin-3-gallate (EGCG) combined with memantine on scopolamine-induced amnesia in rats by evaluating the behavioral, biochemical, and histopathological changes. Materials and methods Rats were randomly allocated to 11 groups, each of which contained 16 rats. Six rats were used for biochemical tests, while ten rats were used for behavioral and histological examinations. Two behavioral assessments were conducted: an object-recognition test and a conditioned-avoidance test. The dopamine (DA) content of brain tissues was determined, as well as oxidative stress markers, such as superoxide dismutase, lipid peroxide end product malondialdehyde, and reduced glutathione. Besides, the activity of acetylcholine esterase (AchE), total antioxidant capacity, and inflammatory markers, such as tumor necrosis factor-alpha and interleukin-one beta, were determined in serum. Furthermore, histological examinations of whole-brain tissues were made. Results Scopolamine-treated rats were administered memantine at a dose of 20 mg/kg, coenzyme Q10 at a dose of 10 mg/kg, and EGCG at a dose of 10 mg/kg, individually or in combination, resulting in an enhancement of cognitive impairment in the condition-avoidance and object-recognition tests, as well as an improvement in all oxidative stress biomarkers, inflammatory biomarkers, and histological examination. Conclusion Rats were administered memantine and pretreated by the combination of CoQ10 and EGCG, resulting in potentiating the memantine action in scopolamine-induced amnesia in rats. The improvement in cognitive memory could be due to the synergistic effect of these drugs by decreasing AchE activity, DA level, anti-inflammatory, and antioxidant effects.

Electroacupuncture reduces scopolamine-induced amnesia via mediating the miR-210/SIN3A and miR-183/SIN3A signaling pathway

BackgroundThe expression of SIN3A is closely correlated with electroacupuncture (EA) treatment efficacy of scopolamine-induced amnesia (SIA), but its underlying mechanisms remain to be further explored.MethodsQuantitative real-time PCR was performed to analyze the expression of candidate microRNAs (miRNAs) and SIN3A mRNA in a rat model of SIA. Western blot was carried out to evaluate the differential expression of SIN3A proteins under different circumstances. Luciferase assay was used to explore the inhibitory role of certain miRNAs in SIN3A expression. A novel object recognition (NOR) test was performed to assess the memory function of SIA rats undergoing EA treatment. Immunohistochemistry was carried out to evaluate the expression of SIN3A in the hippocampus of SIA rats.ResultsRno-miR-183-5p, rno-miR-34c-3p and rno-miR-210-3p were significantly up-regulated in SIA rats treated with EA. In addition, rno-miR-183-5p and rno-miR-210-3p exerted an inhibitory effect on SIN3A expression. EA treatment of SIA rats effectively restored the dysregulated expression of rno-miR-183-5p, rno-miR-210-3p and SIN3A. EA treatment also promoted the inhibited expression of neuronal IEGs including Arc, Egr1, Homer1 and Narp in the hippocampus of SIA rats. Accordingly, the NOR test also confirmed the effect of EA treatment on the improvement of memory in SIA rats.ConclusionIn summary, the findings of this study demonstrated that scopolamine-induced amnesia was associated with downregulated expression of miR-210/miR-183 and upregulated expression of SIN3A. Furthermore, treatment with EA alleviated scopolamine-induced amnesia in rats and was associated with upregulated expression of miR-210/miR-183 and downregulated expression of SIN3A.

EVALUATION OF NEUROPROTECTIVE EFFECT OF AZILSARTAN AS MEMORY ENHANCER AGAINST SCOPOLAMINE AND SODIUM NITRITE-INDUCED AMNESIA IN SWISS ALBINO MALE RATS

Objective: The objective of the study was to assess the neuroprotective effect of azilsartan as a memory enhancer against scopolamine-induced amnesia in rats.&#x0D; Methods: Albino Swiss male rats in equal numbers per group (n=6) were taken. Scopolamine hydrobromide was administered to induce amnesia within the rats. Control group rats were administered normal, negative control groups were administered with scopolamine to induce amnesia and nitrite during trials, positive control group rats were administered piracetam+ scopolamine and piracetam nitrite during trials, and test control group rats were administered azilsartan +sodium nitrite and azilsartan nitrite. Exteroceptive behavioral models just like the elevated plus-maze model, Morris water maze model, acquisition trials, and retrieval trial were wont to evaluate the neuroprotective effect of azilsartan.&#x0D; Results: The scopolamine and azilsartan have a significantly decreasing effect on time spent within the target quadrant (TSTQ) but piracetam has an increasing effect. The effect of azilsartan on transfer latency time (TLT) was observed against scopolamine-induced amnesia in rats using the elevated plus-maze test. Piracetam was found to decrease the TLT and restore memory function at a better dose. Within the case of scopolamine treated rats, a big increase in TLT was noted. Azilsartan treated group also increased TLT within the elevated plus maze. It is noted that the scopolamine features a significantly increasing effect on escape latency time (ELT). Piracetam features a decreasing effect on ELT. A rise in ELT was seen because of azilsartan.&#x0D; Conclusion: This study suggested that the azilsartan features a significant decreasing effect on TSTQ, azilsartan treated group also increased TLT and ELT.

Amelioration of Cognitive Deficits, Oxidative Damage, Neurochemical Alteration by Bauhinia purpurea (stem bark) on Scopolamine Induced Amnesia

Aim: To evaluate the anti-amnesia effect of Bauhinia purpurea in Scopolamine induced amnesia in rats. Materials and Methods: A total of 30 rats were divided into 5 groups 6 rats in each. Group I considered as normal control. Group II served as negative control. Group III, IV and V were treated with Donepezil (3 mg/kg), ethanolic extract of Bauhinia purpurea 200mg/kg and 400 mg/kg respectively for 14 consecutive days followed by single administration of Scopolamine (3 mg/kg) to all the groups except group I. Cognitive performance was assessed by the Morris water maze, elevated plus maze and passive avoidance paradigm. Acetyl cholinesterase enzyme level, biochemical markers such as lipid peroxidation, reduced glutathione and β amyloid 1 42 level, Neurotransmitters including dopamine and serotonin and histopathological study of rat brain were estimated. Results: Bauhinia purpurea and Donepezil rats showed significant increase in escape latency, step-through latency and decreased transfer latency in respective cognitive models of the Morris water maze, passive avoidance test and elevated plus maze. Additionally, Bauhinia purpurea extract remarkably promoted the cholinergic neurotransmission, decreasing β amyloid protein and protected against the oxidative stress damage as indicated by, increasing reduced glutathione level, lowering the level of lipid peroxidation, restored dopamine and serotonin level in the brain. Furthermore, histopathological studies revealed the reversal of neuronal damage in the treatment group compared to Scopolamine treated rats. Conclusion: Bauhinia purpurea extract showed promising antiamnesia activity against scopolamine induced amnesia in rats. This could be attributed to its brain acetyl cholinesterase level, β amyloid level inhibition, antioxidant activity and alteration in neurotransmitters level. Key words: Bauhinia purpurea, Neuroprotective, Acetylcholinesterase, β amyloid protein, Scopolamine.

Shaddock (Citrus maxima) peels extract restores cognitive function, cholinergic and purinergic enzyme systems in scopolamine-induced amnesic rats

This study investigated the effect of shaddock peels extract on cognitive function in scopolamine-induced amnesic rats. Wistar rats were pretreated with shaddock peels extract (50 and 100 mg/kg) and donepezil (5 mg/kg) for fourteen days via oral administration. Memory impairment was induced at the end of the treatment period via a single intraperitoneal administration of scopolamine (3 mg/kg). Thereafter, the animals were subjected to behavioral studies (Morris water maze and Y-maze tests). Finally, the rats were sacrificed and the hippocampus of the rat's brain was isolated for biochemical analyses. The results showed a significant decrease in memory and cognitive function as revealed by Morris water maze and Y-maze tests in scopolamine-induced rats which were reversed by shaddock peels extract. Also, there was a significant decrease in the activity of adenosine monophosphohydrolase (AMPase) with a simultaneous increase in activities of adenosine deaminase (ADA), adenosine triphosphate diphosphohydrolase (ATPdase), acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in scopolamine-induced rats when compared with the control. Besides, a significant increase in malondialdehyde (MDA) and reactive oxygen species (ROS) levels were observed in scopolamine-induced rats. However, donepezil or shaddock peels extract (50 and 100 mg/kg) caused a significant inhibitory effect on AChE, and ADA activities when compared to scopolamine-induced rats. Rats treated with shaddock peels extract also showed a significant reduction in MDA and ROS levels compared to scopolamine-induced rats. Therefore, our findings showed that the cognitive-enhancing effects of shaddock peels extract could be due to antioxidant activities and modulation of some enzymes linked with cognitive dysfunction.

Cognitive improvements in a rat model with polyunsaturated fatty acids EPA and DHA through α7-nicotinic acetylcholine receptors

ABSTRACT The α7-nicotinic acetylcholine receptor (α7-nAChR) is a recognized target for the treatment of dementia associated with aging and certain developmental disorders. This study evaluates memory improvement in a rat model by the effects of polyunsaturated fatty acids EPA and DHA mediated by α7-nAChR, as well as identifying the minimum dose of EPA/DHA required to generate an effect in the improvement of cognition through α7-nAChR in rats. The modified Y-maze and object recognition behavioral tests were performed in scopolamine-induced amnesic rats, in order to study the effects of long-term supplementation (10, 15, 30, and 60 mg/kg) of the two polyunsaturated fatty acids in improving cognitive impairment. Cognitive enhancement by EPA and DHA is mediated through α7-nAChRs, as evidenced by memory recovery after treatment with a selective α7-nAChR antagonist, methyllycaconitine (MLA). Tacrine, a centrally active acetylcholinesterase inhibitor, and PNU282987, an α7-nAChR agonist, are employed as reference standards. Our data demonstrate that 15 mg/kg EPA and DHA can affect cholinergic neurotransmission positively through memory and cognition and, thus, can exert a beneficial action on learning and memory deficits.

Rational design of new multitarget histamine H3 receptor ligands as potential candidates for treatment of Alzheimer's disease.

Design and development of multitarget-directed ligands (MTDLs) has become a very important approach in the search of new therapies for Alzheimer's disease (AD). In our present research, a number of xanthone derivatives were first designed using a pharmacophore model for histamine H3 receptor (H3R) antagonists/inverse agonists, and virtual docking was then performed for the enzyme acetylcholinesterase. Next, 23 compounds were synthesised and evaluated invitro for human H3R (hH3R) affinity and inhibitory activity on cholinesterases. Most of the target compounds showed hH3R affinities in nanomolar range and exhibited cholinesterase inhibitory activity with IC50 values in submicromolar range. Furthermore, the inhibitory effects of monoamine oxidases (MAO) A and B were investigated. The results showed low micromolar and selective human MAO B (hMAO B) inhibition. Two azepane derivatives, namely 23 (2-(5-(azepan-1-yl)pentyloxy)-9H-xanthen-9-one) and 25 (2-(5-(azepan-1-yl)pentyloxy)-7-chloro-9H-xanthen-9-one), were especially very promising and showed high affinity for hH3R (Ki=170nM and 100nM respectively) and high inhibitory activity for acetylcholinesterase (IC50=180nM and 136nM respectively). Moreover, these compounds showed moderate inhibitory activity for butyrylcholinesterase (IC50=880nM and 394nM respectively) and hMAO B (IC50=775nM and 897nM respectively). Furthermore, molecular docking studies were performed for hH3R, human cholinesterases and hMAO B to describe the mode of interactions with these biological targets. Next, the two most promising compounds 23 and 25 were selected for invivo studies. The results showed significant memory-enhancing effect of compound 23 in dizocilpine-induced amnesia in rats in two tests: step-through inhibitory avoidance paradigm (SIAP) and transfer latency paradigm time (TLPT). In addition, favourable analgesic effects of compound 23 were observed in neuropathic pain models. Therefore, compound 23 is a particularly promising structure for further design of new MTDLs for AD.

Effect of Andrographis paniculata leaves extract on neurobehavioral and biochemical indices in scopolamine-induced amnesic rats.

Andrographis paniculata is a medicinal herb that is used to treat various disease conditions due to its pharmacological properties. Thus, this study sought to assess the effect of A. paniculata extract on neurobehavioral and some biochemical parameters in scopolamine-induced amnesic rats. Thirty-five male rats were divided into seven groups and treated with aqueous extract of A. paniculata (50 and 500mg/kg) and donepezil (5mg/kg) for 14days before administration of scopolamine. Behavioral studies (Morris water maze and Y-maze) were carried out to evaluate cognitive dysfunction in scopolamine-induced rats. Biochemical assays such as cholinesterases (AChE and BChE), monoamine oxidase (MAO), and purinergic activities were determined. Results revealed the presence of orientin, quercetin, caffeic acid, apigenin, and gallic acid in A. paniculata. Also, findings from this study showed that aqueous extract of A. paniculata had a modulatory effect on scopolamine-induced cognitive impairment and could be used in the management of memory loss. PRACTICAL APPLICATIONS: Aqueous extract of A. paniculata characterized revealed the presence of polyphenols which are antioxidants. The inhibitory activity possessed by A. paniculata on some enzymes linked to neurodegeneration could be due to the antioxidant activity. Given this, we recommend that results gotten from this study could be used to develop treatment therapy for neurodegeneration. However, in-depth studies should be carried out on the toxic effect of A. paniculata to ascertain a safe dose for treatment.

Cognitive Facilitation and Antioxidant Effects of an Essential Oil Mix on Scopolamine-Induced Amnesia in Rats: Molecular Modeling of In Vitro and In Vivo Approaches.

The present study investigated the capability of an essential oil mix (MO: 1% and 3%) in ameliorating amnesia and brain oxidative stress in a rat model of scopolamine (Sco) and tried to explore the underlying mechanism. The MO was administered by inhalation to rats once daily for 21 days, while Sco (0.7 mg/kg) treatment was delivered 30 min before behavioral tests. Donepezil (DP: 5 mg/kg) was used as a positive reference drug. The cognitive-enhancing effects of the MO in the Sco rat model were assessed in the Y-maze, radial arm maze (RAM), and novel object recognition (NOR) tests. As identified by gas chromatography–mass spectrometry (GC–MS), the chemical composition of the MO is comprised by limonene (91.11%), followed by γ-terpinene (2.02%), β-myrcene (1.92%), β-pinene (1.76%), α-pinene (1.01%), sabinene (0.67%), linalool (0.55%), cymene (0.53%), and valencene (0.43%). Molecular interactions of limonene as the major compound in MO with the active site of butyrylcholinesterase (BChE) was explored via molecular docking experiments, and Van der Waals (vdW) contacts were observed between limonene and the active site residues SER198, HIS438, LEU286, VAL288, and PHE329. The brain oxidative status and acetylcholinesterase (AChE) and BChE inhibitory activities were also determined. MO reversed Sco-induced memory deficits and brain oxidative stress, along with cholinesterase inhibitory effects, which is an important mechanism in the anti-amnesia effect. Our present findings suggest that MO ameliorated memory impairment induced by Sco via restoration of the cholinergic system activity and brain antioxidant status.

Amelioration of Scopolamine-Induced Amnesic, Anxiolytic and Antidepressant Effects of Ficus Benghalensis in Behavioral Experimental Models.

Background and Objectives: Ficus benghalensis (FB) is a commonly found tree in Pakistan and its various parts have folkloric importance in managing neurological ailments. In the present study, methanolic extract of its bark has been tested on an experimental animal model to evaluate memory-enhancing, anxiolytic and antidepressant activities to validate the claimed therapeutic potential. Materials and Methods: Methanolic extract of freshly isolated bark was prepared and subjected to preliminary phytochemical studies and gas chromatography–mass spectrometry (GC–MS) analysis for the presence of phytocomponents. To evaluate its effect on spatial learning, passive-avoidance test–step through (PAT-ST), Y-maze and Morris water maze (MWM) tests were carried out. Open-field (OFT) and elevated plus maze (EPM) tests were employed to explore the anti-anxiety potential of FB while a forced swimming test (FST) was utilized to assess its anti-depressant prospective. FB doses of 100, 200 and 300 mg/kg with positive and negative controls given to Sprague Dawley (SD) rats. Results: phytochemical studies showed the presence of various phytoconstituents including alkaloids, flavonoids, terpenes, phenolics and anthraquinones. The presence of synephrine, aspargine, glucose, fructose and fatty acids was revealed by GC–MS analysis. FB administration led to significant improved memory retention when evaluated through passive avoidance (p < 0.05), Y-maze (p < 0.05) and Morris water maze (p < 0.05) tests in a scopolamine model of amnesic rats. When tested by open field and elevated plus maze tests, FB demonstrated anxiety-resolving characteristics (p < 0.05) as animals dared to stay in open areas more than a control group. Mobility time was increased and immobility time was reduced (p < 0.05–0.01) in rats treated with FB, unveiling the anti-depressant importance of F. benghalensis. Conclusion: methanolic extract of F. benghalensis bark furnished scientific proof behind folkloric claims of the memory improving, anxiety-reducing and depression-resolving characteristics of the plant. These activities might be possible due to interaction of its phytoconstituents with serotonergic, glutamatergic, cholinergic and GABAergic systems in the brain.

Antiamnesic effects of tofisopam against scopolamine-induced cognitive impairments in rats

In this study, we investigated the potential therapeutic effects of tofisopam, a 2,3-benzodiazepine derivative anxiolytic, on cognitive deficits in rats with scopolamine-induced amnesia. Cognitive performance of the rats was investigated by using the Morris water maze and passive avoidance tests. Changes in motor activity were assessed by using the activity cage and Rota-rod tests and then morphological changes in the hippocampus were assessed via immunohistochemical stainings. The results indicated that scopolamine impaired learning and memory parameters in rats. Worsened cognitive performance, neuronal loss, and decreased hippocampal synaptophysin, Ki-67, and glial fibrillary acidic protein density were observed. Tofisopam administration at a dose of 50 mg/kg for seven days improved the impaired cognitive performance, enhanced the attenuated synaptic transmission in the hippocampus, increased proliferation in subgranular zones, and improved the decrease in astrocytes in amnesic rats. These findings point out the anti-amnesic effects of tofisopam with concomitant improvements in the hippocampal synaptogenesis, neurogenesis, and glial plasticity, for the first time. Presented beneficial effects of tofisopam on cognitive dysfunctions may have a notable clinical value considering the fact that one of the most important side effects of 1,4-benzodiazepines, which are classical anxiolytic drugs, is amnesia. However, these preclinical results need to be confirmed with further clinical studies, first.