Amnesia In Mice Research Articles

Amnesia-ameliorative effect of a quinoline derivative through regulation of oxidative/cholinergic systems and Na+/K+-ATPase activity in mice.

The present study evaluated the anti-amnesic activity of 1-(7-chloroquinolin-4-yl)-5-methyl-N-phenyl-1H-1,2,3-triazole-4-carboxamide (QTCA-1) against scopolamine (SCO)-induced amnesia in mice. It was evaluated cholinergic dysfunction, oxidative stress and Na+/K+-ATPase activity in cerebral cortex and hippocampus of mice. Male Swiss mice were treated with QTCA-1 (10mg/kg, intragastrically (i.g.), daily) for nine days. Thirty minutes after the treatment with compound, the animals received a injection of SCO (0.4mg/kg, intraperitoneally (i.p.)). Mice were submitted to the behavioral tasks 30min after injection of SCO (Barnes maze, open-field, object recognition and location, and step-down inhibitory avoidance tasks) during nine days. In day 9, cerebral cortex and hippocampus of mice were removed to determine the thiobarbituric acid reactive species (TBARS) levels, and catalase (CAT), Na+/K+-ATPase and acetylcholinesterase (AChE) activities. SCO caused amnesia in mice for changing in step-down inhibitory avoidance, Barnes maze, and object recognition and object location tasks. QTCA-1 treatment attenuated the behavioral changes caused by SCO. Moreover, SCO increased AChE and CAT activities, decreased Na+/K+-ATPase activity and increased TBARS levels in the cerebral structures of mice. QTCA-1 protected against these brain changes. In conclusion, QTCA-1 had anti-amnesic action in the experimental model used in the present study, through the anticholinesterase effect, modulation of Na+/K+-ATPase activity and antioxidant action.

Bacosides Encapsulated in Lactoferrin Conjugated PEG-PLA-PCL-OH Based Polymersomes Act as Epigenetic Modulator in Chemically Induced Amnesia.

The present study demonstrates the epigenetic mechanisms underlying the effect of Bacoside rich extract of Bacopa monniera-a nootropic herb, on scopolamine treated amnesic mice conferred via chromatin modifying enzymes. The focus of the work was to elucidate the modulation of the chromatin modifying enzymes: DNMT1, DNMT3a, DNMT3b, HDAC2, HDAC5 and CPB in scopolamine induced amnesic mice after treatment with bacoside rich extract of Bacopa monniera (BA) and BA encapsulated in lactoferrin conjugated PEG-PLA-PCL-OH based polymersomes (BAN). We observed remarkable difference between the results obtained after the treatment with BA and BAN. Interestingly BAN was found to be more efficient in downregulating DNA methylation and histone chain deacetylation. Scopolamine treatment showed up-regulation of DNMT1 expression in qRT-PCR by 3.14-fold as compared to the control, which was considerably decreased by 1.5-fold after treatment with BA and remarkably decreased 0.11-fold by BAN treatment. Scopolamine treatment up-regulated the expression of DNMT3a by 1.6-fold while for DNMT3b by 3.13-fold. In DNMT3a and DNMT3b the fold change decreased to 0.64 and 0.76 after BA treatment, whereas the BAN treatment further down-regulated to 0.32- and 0.63-fold, respectively. Similarly scopolamine up-regulated HDAC2 and HDAC5 by 3.12 fold and 3.64-fold, respectively. BA treatment reversed the changes by reducing HDAC2 mRNA to 0.89-fold and HDAC5 mRNA 0.83-fold. BAN further reduced expression of HDAC2 further to 0.39-fold and HDAC5 to 0.31-fold. On the other hand scopolamine down-regulated CBP mRNA expression by 0.28-fold and increased by 1.09 after BA treatment. BAN significantly increased the CPB expression by 1.65-fold as compared to BA treatment. These findings were consolidated by DNMT and HDAC enzyme activity assay, methylation in the promoter region of the memory related genes: ARC and BDNF and Dot blot assay for DNA methylation. The percent activity increase of DNMT and HDAC after scopolamine administration was 375.74 and 240.90 respectively. After treatment with BA the downfall in percent activity was observed as 167.99 in DMNT and 130.57 in HDAC. BAN treatment further decreased the percent enzyme activity of DNMT and HDAC significantly by 30.0 and 61.81 respectively. The potency of BAN in reversing the epigenetic changes of scopolamine induced amnesic mouse brain, can be attributed to the brain specific delivery of BA through polymersomes which are able to cross the blood brain barrier (BBB) via receptor mediated endocytosis.

Aqueous Root Bark Extract of Daniellia oliveri (Hutch. & Dalz.) (Fabaceae) Protects Neurons against Diazepam‐Induced Amnesia in Mice

Daniellia oliveri (DO) is a traditional medicinal plant used for the treatment of diseases such as inflammation, schizophrenia, and epilepsy in Nigeria, Kenya, Congo, and Cameroon. This study was carried out to evaluate the potential neuroprotection effect of the aqueous root bark extract of Daniellia oliveri against diazepam-induced amnesia in mice. Thirty-six adult male mice were distributed into six groups: the three test groups received Daniellia oliveri root bark extract (100, 200, and 300 mg/kg), the normal control group received distilled water (10 ml/kg), a positive control group received piracetam (150 mg/kg), and the negative control received diazepam (2.5 mg/kg). Learning and memory were evaluated using the radial arm maze and the T-maze. Biomarkers of oxidative stress were also quantified in mice brains. Statistical analyses were performed using two-way ANOVA followed by Tukey's post hoc test. Daniellia oliveri root bark aqueous extract decreased the number of working memory errors and number of reference memory errors in amnesic mice evaluated in the radial arm maze. Also, an increase in glutathione activity and a decrease in malondialdehyde levels were noted in the hippocampi homogenate of the extract-treated mice as compared to the diazepam-demented but untreated group. Moreover, pretreatment with Daniellia oliveri aqueous root bark extract reversed the decrease in hippocampal cell density observed in the nontreated diazepam group. Taken together, these results suggest that the aqueous extract of DO leaves possesses antioxidant potential and might provide an opportunity for the management of neurological abnormalities in amnesic conditions.

Cortico-Hippocampal Memory Enhancing Activity of Hesperetin on Scopolamine-Induced Amnesia in Mice: Role of Antioxidant Defense Systems, Cholinergic Neurotransmission and Expression of BDNF

Alzheimer disease (AD) is an age related neurodegenerative disease causing severe cognitive and memory decline in elderly people. Flavonoids play neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) or tau peptide into oligomers and fibrils. This study sought to investigate the effect of hesperetin (HPT) on scopolamine-induced memory impairments in mice. Mice were orally pretreated with HPT (1, 5 or 50 mg/kg) or vehicle (normal saline; 10 ml/kg) for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3 mg/kg, i.p.) was administered 5 min before locomotor activity (open field test) and memory function (novel object recognition test (NORT) for 2 consecutive days and Morris water maze task (MWM) for 5 consecutive days). Levels of oxidative stress markers / brain derived neurotrophic factors (BDNF) and acetylcholinesterase activity were determined in the hippocampus and prefrontal cortex after completion of MWM task. Scopolamine caused no significant change in mice exploration of the familiar or novel object in the test session whereas the HPT-treated mice spent more time exploring the novel object more than familiar object in NORT. Scopolamine also increased the escape latency in acquisition phase and decreases time spent in target quadrant in probe phase which were ameliorated by the pretreatment with HPT. Scopolamine-induced alteration of oxidant-antioxidant balance, acetylcholinesterase activity and neurogenesis in the hippocampus and prefrontal cortex were attenuated by HPT treatment. This study showed that HPT ameliorated non-spatial/spatial learning and memory impairment by scopolamine possibly through enhancement of antioxidant defense, cholinergic and BDNF signaling.

M1 muscarinic receptor is a key target of neuroprotection, neuroregeneration and memory recovery by i-Extract from Withania somnifera

Memory loss is one of the most tragic symptoms of Alzheimer’s disease. Our laboratory has recently demonstrated that ‘i-Extract’ of Ashwagandha (Withania somnifera) restores memory loss in scopolamine (SC)-induced mice. The prime target of i-Extract is obscure. We hypothesize that i-Extract may primarily target muscarinic subtype acetylcholine receptors that regulate memory processes. The present study elucidates key target(s) of i-Extract via cellular, biochemical, and molecular techniques in a relevant amnesia mouse model and primary hippocampal neuronal cultures. Wild type Swiss albino mice were fed i-Extract, and hippocampal cells from naïve mice were treated with i-Extract, followed by muscarinic antagonist (dicyclomine) and agonist (pilocarpine) treatments. We measured dendritic formation and growth by immunocytochemistry, kallikrein 8 (KLK8) mRNA by reverse transcription polymerase chain reaction (RT-PCR), and levels of KLK8 and microtubule-associated protein 2, c isoform (MAP2c) proteins by western blotting. We performed muscarinic receptor radioligand binding. i-Extract stimulated an increase in dendrite growth markers, KLK8 and MAP2. Scopolamine-mediated reduction was significantly reversed by i-Extract in mouse cerebral cortex and hippocampus. Our study identified muscarinic receptor as a key target of i-Extract, providing mechanistic evidence for its clinical application in neurodegenerative cognitive disorders.

CH(II), a cerebroprotein hydrolysate, exhibits potential neuro-protective effect on Alzheimer's disease.

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder, and is the most common type of cognitive impairment and dementia. There is a pressing need to improve the clinical efficacy and quality of life for AD patients, as limited treatments options for AD patients have been developed until now. In this study, we aim to investigate the protective effect of CH(II), a cerebroprotein hydrolysate consisted of abundant biological peptides, on preclinical model of AD. We found that CH(II) treatment effectively protects oxygen glucose deprivation (OGD)-induced N2A cell viability impairment and cell apoptosis. In addition, CH(II) significantly reduces H2O2-induced ROS accumulation and exhibits the protective activities against H2O2-induced oxidative injury. Intriguingly, we found that CH(II) treatment can effectively promote neurite outgrowth of N2A cells. Moreover, CH(II) obviously improve the cognitive and memorial function in scopolamine-induced amnesia mice model. Taken together, this study provides evidences of the neuroprotective activities of CH(II) and offers a potential therapeutic strategy for AD patients.

Ameliorating effect of Citrusaurantium extracts and nobiletin on β‑amyloid (1‑42)‑induced memory impairment in mice.

The aim of the present study was to evaluate the neuroprotective effect of Citrusaurantium extract (CAE) and nobiletin against amyloid β 1‑42 (Aβ 1‑42)‑induced spatial learning and memory impairment in mice. After injecting Aβ 1‑42 (5µl/2.5min, intracerebroventricular injection), amnesic mice were orally administered CAE and nobiletin for 28days. Memory, spatial and cognitive ability were measured using passive avoidance and a Morris water maze task. Acetylcholinesterase (AchE) activity was investigated in the hippocampus and cortex using commercial kits and the analysis of Bax, Bcl‑2, and cleaved caspase‑3 protein expression by western blot assays was used to confirm the anti‑apoptotic mechanism of CAE and nobiletin. The present study confirmed impairments in learning and memory in the Aβ‑induced neurodegenerative mice with increased AchE activity in the brain. However, the daily administration of CAE and nobiletin reduced the spatial learning deficits and increased the AchE activity in the cortex and hippocampus. Furthermore, CAE and nobiletin significantly downregulated the Bax and cleaved caspase‑3 protein expression and upregulated the Bcl‑2 and Bcl‑2/Bax expression in the cortex and hippocampus of Aβ‑treated mice. These results suggest that CAE and nobiletin exert a neuroprotective effect by regulating anti‑apoptotic mechanisms, including reduced AchE activity in the cortex and hippocampus of the cognitive deficit mouse model.

Identification of a Novel Peptide from β-Casein That Enhances Spatial and Object Recognition Memory in Mice.

An increase in the aging population has spurred recent efforts to identify diet and lifestyle changes that help prevent cognitive decline. Several epidemiological investigations and clinical studies have indicated that consuming fermented dairy products prevents cognitive decline. Some peptides from whey including β-lactolin improve memory impairment; the intake of Camembert cheese has been shown to prevent Alzheimer's in mouse models. To elucidate the molecular mechanisms underlying these preventive effects, we screened peptides from digested casein protein for their ability to improve spatial memory in a scopolamine-induced amnesia mouse model. Administration of KEMPFPKYPVEP peptide from β-casein at 0.5 mg/kg (54.8 ± 2.5) and 2 mg/kg (57.9 ± 3.7) improved memory impairment in the amnesia mice in comparison with control (44.9 ± 3.4; p = 0.031 and p = 0.042, respectively) and increased dopamine (5.9 ± 3.8 [control] and 12.4 ± 6.2 [KEMPFPKYPVEP peptide]) and norepinephrine (7.7 ± 0.8 [control] and 9.9 ± 2.0 [KEMPFPKYPVEP peptide]) levels in the frontal cortex (p = 0.039 and p = 0.031, respectively). Collectively, our findings suggest that peptides in fermented dairy products prevent cognitive decline and support previously reported observations.

The memory and learning enhancing effects of Atristamine

The object of the present study, 2-methyl-3-(phenylaminomethyl)-1H-quinolin-4-one (Atristamine), has been deeply studied as a promising antidepressant with the unique spectrum of additional neuropharmacological properties. Previously, the memory-enhancing effects of Atristamine have already been studied in the passive-avoidance test after scopolamine-induced amnesia in mice. Thus, the study of the effects of Atristamine on the spatial learning and memory in the Morris water maze under physiological conditions was the next logical step of our research. According to the results obtained, Atristamine (100 mg/kg) has almost the same effect on the main markers of the memory-enhancing activity (the escape latency and distance moved) as Piracetam (300 mg/kg) and Phenibut (20 mg/kg) chosen as the well-studied and widely-used memory enhancers. The escape latency decreased in the Atristamine group by 3.2 times compared to the vehicle control group, whereas Piracetam and Phenibut caused a significant reduction of this indicator by 4.3 and 3.7 times, respectively. Moreover, the rats from the Atristamine group swam 5.1 times shorter distance to the platform in the probe trial compared to animals from the vehicle control group. The distance moved was 3-fold shorter in the Piracetam group and decreased by 5.2 times in the Phenibut group. All drugs used in this study caused considerable changes of inter-quadrant preferences of animals. Based on the analysis of the inter-quadrant behaviour of rats, it has been found that there are considerable differences in search strategies associated, probably, with distinct mechanisms of the memory and learning enhancing action of the drugs used.

Matured hop bitter acids improve spatial working and object recognition memory via nicotinic acetylcholine receptors.

Cognitive decline and dementia are major concerns in today's aging society. As limited treatments are available, measures to prevent cognitive decline and dementia are needed. We previously demonstrated that matured hop bitter acids (MHBA), bitter components of beer, increase norepinephrine in the hippocampus and improve memory in amnesia model mice induced by scopolamine (SCP), an antagonist of muscarinic receptor. However, other neurotransmitters involved in the effects of MHBA on memory improvement remain unknown. This study aimed to assess the role of acetylcholine receptors (AChR) in the effects of MHBA on memory. The involvement of AChR on the effects of MHBA (10mg/kg) on cognitive function was evaluated using AChR antagonists, SCP, mecamylamine hydrochloride (MEC), a non-competitive antagonist of nicotinic-AChR (nAChR), and methyllycaconitine citrate (MLA), an α7nAChR antagonist, for the Y-maze test and the novel object recognition test (NORT). A separate population of mice, which underwent vagotomy or sham operation, was subjected to NORT to elucidate further mechanism. In addition, the effect of MHBA on acetylcholinesterase (AChE) activity was measured in vitro. In accordance with previous reports, MHBA improved spontaneous alternations of the Y-maze test in SCP-induced amnesia mice and increased discrimination index evaluated by the NORT in normal mice. On the other hand, treatment with MEC or MLA attenuated the effects of MHBA on memory improvement in the Y-maze test and the NORT. Vagotomized mice also showed attenuated memory enhancement by MHBA in the NORT. In addition, MHBA did not alter AChE activity in vitro. The results support the involvement of nAChRs in memory improvement in mice by MHBA. MHBA is thus thought to activate the vagal nerve and enhance hippocampus-dependent memory via nAChRs.

Cortico-hippocampal memory enhancing activity of hesperetin on scopolamine-induced amnesia in mice: role of antioxidant defense system, cholinergic neurotransmission and expression of BDNF.

Alzheimer disease (AD) is an age related neurodegenerative disease causing severe cognitive and memory decline in elderly people. Flavonoids play neuroprotective role by inhibiting and/or modifying the self-assembly of the amyloid-β (Aβ) or tau peptide into oligomers and fibrils. This study sought to investigate the effect of hesperetin (HPT) on scopolamine-induced memory impairments in mice. Mice were orally pretreated with HPT (1, 5 or 50mg/kg) or vehicle (normal saline; 10ml/kg) for 3 consecutive days. One hour post-treatment on day 3, scopolamine (3mg/kg, i.p.) was administered 5min before locomotor activity (open field test) and memory function (novel object recognition test (NORT) for 2 consecutive days and Morris water maze task (MWM) for 5 consecutive days). Levels of oxidative stress markers / brain derived neurotrophic factors (BDNF) and acetylcholinesterase activity were determined in the hippocampus and prefrontal cortex after completion of MWM task. Scopolamine caused no significant change in mice exploration of the familiar or novel object in the test session whereas the HPT-treated mice spent more time exploring the novel object more than familiar object in NORT. Scopolamine also increased the escape latency in acquisition phase and decreases time spent in target quadrant in probe phase which were ameliorated by the pretreatment with HPT. Scopolamine-induced alteration of oxidant-antioxidant balance, acetylcholinesterase activity and neurogenesis in the hippocampus and prefrontal cortex were attenuated by HPT treatment. This study showed that HPT ameliorated non-spatial/spatial learning and memory impairment by scopolamine possibly through enhancement of antioxidant defense, cholinergic and BDNF signaling.

Tryptophan-Tyrosine Dipeptide, the Core Sequence of β-Lactolin, Improves Memory by Modulating the Dopamine System.

Tryptophan-tyrosine (WY)-related peptides including the β-lactopeptide of the glycine-threonine-tryptophan-tyrosine peptide, β-lactolin, improve spatial memory. However, whether and how the WY dipeptide as the core sequence in WY-related peptides improves memory functions has not been investigated. This study assessed the pharmacological effects of the WY dipeptide on memory impairment to elucidate the mechanisms. Here, we showed that oral administration of dipeptides of WY, tryptophan-methionine (WM), tryptophan-valine, tryptophan-leucine, and tryptophan-phenylalanine improved spontaneous alternation of the Y-maze test in scopolamine-induced amnesic mice. In contrast, tyrosine-tryptophan, methionine-tryptophan, tryptophan, tyrosine, and methionine had no effect. These results indicated that the conformation of dipeptides with N-terminal tryptophan is required for their memory improving effects. WY dipeptide inhibited the monoamine oxidase B activity in vitro and increased dopamine levels in the hippocampus and frontal cortex, whereas tryptophan did not cause these effects. In addition, the treatment with SCH-23390, a dopamine D1-like receptor antagonist, and the knockdown of the hippocampal dopamine D1 receptor partially attenuated the memory improvement induced by the WY dipeptide. Importantly, WY dipeptide improved the spontaneous alternations of the Y-maze test in aged mice. These results suggest that the WY dipeptide restores memory impairments by augmenting dopaminergic activity. The development of supplements rich in these peptides might help to prevent age-related cognitive decline.

A Polysaccharide Extract from Maitake Culinary-Medicinal Mushroom, Grifola frondosa (Agaricomycetes) Ameliorates Learning and Memory Function in Aluminum Chloride-Induced Amnesia in Mice.

Maitake (Grifola frondosa) is an edible mushroom exhibiting high nutritional value in terms of containing health-beneficial bioactive compounds. Previously, we reported that a protein-bound polysaccharide bioactive component of G. frondosa (PGM) could enhance the expression of α-amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid receptor (AMPAR), which is critical for learning and memory. However, the potential benefits of PGM on learning and memory function have never been investigated. In the current study, we aimed to explore the beneficial effect of PGM on learning and memory function in aluminum chloride (AlCl3)-induced amnesia in mice and to explore the underlying mechanisms. Mice were intraperitoneally administered with AlCl3 (60 mg/kg/d) and PGM (5, 10, or 20 mg/kg/d) for 6 weeks consecutively, and then the Morris water maze (MWM) test was conducted to assess the learning and memory function. Hematoxylin-eosin staining was performed to observe the morphology of neurons in the hippocampal dentate gyrus (DG). The expression of p-Tau (Ser396), Tau, p-GluA1 (S845), GluA1, and brain-derived neurotrophic factor (BDNF) proteins was evaluated with western blot. We found that PGM (5 and 10 mg/kg/d) significantly improved learning and memory function and attenuated histopathological abnormalities in the hippocampal DG region in the AlCl3-treated mice. Furthermore, PGM treatment significantly enhanced the level of AMPAR and BDNF in the hippocampus, while suppressing the tau protein hyperphosphorylation at the Ser396 site. These findings indicated that PGM could significantly attenuate the AlCl3-induced amnesia through the synergistic action of its active component on tau pathology, AMPAR and BDNF signaling pathway.

Stability towards the gastrointestinal simulated digestion and bioactivity of PAYCS and its digestive product PAY with cognitive improving properties.

The peptide derived from Anchovy hydrolysates, Pro-Ala-Tyr-Cys-Ser (PAYCS), was reported to display a neuroprotective effect in vitro in our previous study. The in vivo memory improving effects of PAYCS were investigated in this study. Prior to the scopolamine-induced amnesia mice trial, the stability of PAYCS during digestion was detected and the digestive products were identified. The results showed that PAYCS was susceptible to proteolytic degradation after incubation with pepsin and pancreatin and Pro-Ala-Tyr (PAY) was released and survived during the simulated GI digestion. The results of scopolamine-induced amnesia model trials showed that PAYCS and PAY treatment exhibited cognitive improvement effects in the behavioral tests and different pathways were determined. The results indicated that only PAYCS facilitated cholinergic activity by up-regulating the amount of acetylcholine (Ach) and acetylcholine receptor (AChR). Additionally, both PAYCS and PAY enhanced the superoxide dismutase (SOD) activity. Furthermore, PAYCS was found to be beneficial for the expression of the nuclear factor (erythroid-derived2)-like 2 protein (Nrf2), brain-derived neurotrophic factor (BDNF) and cAMP response element binding protein (CREB). This indicated that PAYCS could regulate the oxidative stress by activating the Nrf2/antioxidant response elements (Nrf2/ARE) pathway. In our study, we demonstrated that the memory improving effects conferred by PAYCS on amnesia mice were linked to the attenuation of the cholinergic system and the activation of Nrf2/ARE and BDNF/CREB signaling.

Garlic Gongjin-Dan Ameliorates Scopolamine-Induced AMNESIA in Mice

Gongjin-Dan is a traditional oriental medicine herbal drug that has been used tonics. In the present study, we investigated the effects of the hot...

Biphenyl-3-oxo-1,2,4-triazine linked piperazine derivatives as potential cholinesterase inhibitors with anti-oxidant property to improve the learning and memory

A series of novel piperazine tethered biphenyl-3-oxo-1,2,4-triazine derivatives were designed, and synthesized. Amongst the synthesized analogs, compound 6g showed significant non-competitive inhibitory potential against acetylcholinesterase (AChE, IC50; 0.2 ± 0.01 μM) compared to standard donepezil (AChE, IC50: 0.1 ± 0.002 μM). Compound 6g also exhibited significant displacement of propidium iodide from the peripheral anionic site (PAS) of AChE (22.22 ± 1.11%) and showed good CNS permeability in PAMPA-BBB assay (Pe(exp), 6.93 ± 0.46). The in vivo behavioral studies of compound 6g indicated significant improvement in cognitive dysfunctions against scopolamine-induced amnesia mouse models. Further, ex vivo studies showed a significant AChE inhibition and reversal of the scopolamine-induced oxidative stress by compound 6g. Moreover, molecular docking and dynamics simulations of compound 6g showed a consensual binding affinity and active site interactions with the PAS and active catalytic site (CAS) residues of AChE.

Melatonin Rescue Oxidative Stress-Mediated Neuroinflammation/ Neurodegeneration and Memory Impairment in Scopolamine-Induced Amnesia Mice Model.

Cognitive decline and memory impairment induced by oxidative brain damage are the critical pathological hallmarks of Alzheimer's disease (AD). Based on the potential neuroprotective effects of melatonin, we here explored the possible underlying mechanisms of the protective effect of melatonin against scopolamine-induced oxidative stress-mediated c-Jun N-terminal kinase (JNK) activation, which ultimately results in synaptic dysfunction, neuroinflammation, and neurodegeneration. According to our findings, scopolamine administration resulted in LPO and ROS generation and decreased the protein levels of antioxidant proteins such as Nrf2 and HO-1; however, melatonin co-treatment mitigated the generation of oxidant factors while improving antioxidant protein levels. Similarly, melatonin ameliorated oxidative stress-mediated JNK activation, enhanced Akt/ERK/CREB signaling, promoted cell survival and proliferation, and promoted memory processes. Immunofluorescence and western blot analysis indicated that melatonin reduced activated gliosis via attenuation of Iba-1 and GFAP. We also found that scopolamine promoted neuronal loss by inducing Bax, Pro-Caspase-3, and Caspase-3 and reducing the levels of the antiapoptotic protein Bcl-2. In contrast, melatonin significantly decreased the levels of apoptotic markers and increased neuronal survival. We further found that scopolamine disrupted synaptic integrity and, conversely, that melatonin enhanced synaptic integrity as indicated by Syntaxin, PSD-95, and SNAP-23 expression levels. Furthermore, melatonin ameliorated scopolamine-induced impairments in spatial learning behavior and memory formation. On the whole, our findings revealed that melatonin attenuated scopolamine-induced synaptic dysfunction and memory impairments by ameliorating oxidative brain damage, stress kinase expression, neuroinflammation, and neurodegeneration. Graphical Abstract The proposed schematic diagram showing the neuroprotective effect of melatonin against scopolamine-induced oxidative stress-mediated synaptic dysfunction, memory impairment neuroinflammation and neurodegeneration.

Lavandula stoechas (L) a Very Potent Antioxidant Attenuates Dementia in Scopolamine Induced Memory Deficit Mice.

The objective of the current project was to explore the pharmacotherapeutic role of Lavandula stoechas (L) for the management of dementia. Dementia is considered a global challenge of current century seeking special attention of pharmacologists to explore its best remedies. Methanolic extract of aerial parts of L. stoechas was tested for phytochemical analysis along with free radical scavenging activity. Behavioral studies were performed on scopolamine induced amnesic mice by using elevated plus maze (EPM), light and dark test and hole board paradigms. Biochemical investigations were made after decapitating the mice. Their brains were isolated for biochemical estimation of acetylcholinesterase (AChE), malondialdehyde (MDA), superoxide dismutase (SOD), catalase (CAT), and glutathione (GSH). Phytochemical study ensured the presence of total phenolic contents (285.91 ± 0.75 mg of GAE/g of extract), total flavonoids (134.06 ± 0.63 mg of RE/g of extract), total tannins (149.60 ± 0.93 mg of TAE/g of extract) and free radical scavenging activity (IC50 value = 76.73 μg/ml found by DPPH method). Behavioral studies indicated that animals of GVII showed higher inflexion ratio (0.40 ± 0.03) for EPM, spent most of time (227.17 ± 2.13 s) in dark area of light dark test and had many hole pockings (39.83 ± 1.88) for hole board paradigm. Moreover, biochemical studies revealed that methanolic extract of L. stoechas (800 mg/kg/p.o.) significantly (P < 0.001) reduced brain AChE and MDA levels while improved SOD, CAT, and GSH levels. Thus the findings suggest that L. stoechas stabilizes memory by enhancing cholinergic neurotransmission and by providing defense against oxidative stress in mice brain.

Potentiation of nootropic activity of EGCG loaded nanosuspension by piperine in swiss male albino mice

The present study deals with preparation of nanoformulations of epigallocatchin gallate (EGCG) alone and with piperine, and evaluation of in vivo cognitive effect on Swiss albino male mice. EGCG (25 mg) was nanoencapsulated into a biocompatible and biodegradable protein nanocarrier, zein and was also separately nanoencapsulated with piperine (5 mg), a bioenhancer. Anti-solvent precipitation method was used for formulation of EGCG loaded nanosuspension and EGCG-Piperine nanocomplex. EGCG loaded nanosuspension (25 mg kg−1) and EGCG-Piperine nanocomplex (25 mg kg−1) were administered per se to mice for 3 successive weeks. The behaviour models i.e. Elevated plus maze and Morris water maze were used for assessing the cognitive behaviour. The influence of various drug treatments on locomotor activity of mice was also studied. The mice were sacrificed on 21st day followed by estimation of brain acetylcholinesterase activity. The significant reversion in scopolamine-induced amnesia in mice was observed after administration of EGCG loaded nanosuspension (25 mg kg−1) and EGCG-Piperine nanocomplex (25 mg kg−1). A significant reduction in brain acetylcholinesterase level in mice was observed after the administration of physostigmine (0.1 mg kg−1), EGCG loaded nanosuspension (25 mg kg−1) and EGCG-Piperine nanocomplex (25 mg kg−1). The oral administration of EGCG loaded nanosuspension for three successive weeks significantly improved cognitive behaviour in mice; and piperine potentiated the cognitive effect of EGCG loaded nanosuspension. Further, EGCG loaded nanosuspension showed improved cognitive behaviour in mice probably through inhibition of brain acetylcholinesterase activity, and facilitation of cholinergic pathways.

Matured Hop-Derived Bitter Components in Beer Improve Hippocampus-Dependent Memory Through Activation of the Vagus Nerve

Improving and maintaining memory function is effective in preventing cognitive decline and dementia. Previously, we demonstrated that iso-α-acids, the hop-derived bitter components in beer, prevent cognitive impairment in an Alzheimer’s disease mouse model. In this report, we investigated the effects of matured hop bitter acids (MHBA) containing components of oxides derived from α- and β-acids, and structurally similar to iso-α-acids, on cognitive function using behavioral pharmacological procedures. MHBA and the representative components of MHBA, 4′-hydroxyallohumulinone (HAH) and 4′-hydroxy-cis-alloisohumulone (HAIH) improved spatial working memory in scopolamine-induced amnesia mice. MHBA also enhanced episodic memory in the novel object recognition test (NORT). The administration of MHBA increased the amount of norepinephrine (NE) and NE release into cerebrospinal fluid (CSF) in hippocampus. The MHBA activity in improving memory function was attenuated by treatment with a β-adrenergic receptor inhibitor. In addition, vagotomized mice did not display the memory improvement induced by MHBA. Together, our results suggest that MHBA improves memory function via stimulation of the vagus nerve and enhancement of NE release in the hippocampus. Vagus nerve activation by the intake of food materials including MHBA may be a safe and effective approach for improving cognitive function.