Learning Ability Of Mice Research Articles

Structural identification and anti-neuroinflammatory effect of a heteropolysaccharide ATP50-3 from Acorus tatarinowii rhizome

Acorus tatarinowii, a famous traditional Chinese medicine, is used for the clinical treatment of memory impairment and dementia. In this research, AT50, the crude polysaccharide extracted from A. tatarinowii rhizome, significantly improved the memory and learning ability of mice with Alzheimer's disease (AD) and exerted excellent anti-neuroinflammatory effects. More importantly, AT50 returned the levels of NO, TNF-α, IL-1β, PGE-2, and IL-6 in AD mouse brains to normal levels. To identify the active ingredients in AT50, a heteropolysaccharide ATP50–3 was obtained from AT50. Structural analysis indicated ATP50–3 consisted of α-L-Araf-(1→, →2)-α-L-Araf-(1→, →3)-α-L-Araf-(1→, →5)-α-L-Araf-(1→, α-D-Xylp-(1→, →3,4)-β-D-Xylp-(1→, →3)-α-D-Galp-(1→, →3,6)-α-D-Galp-(1→, →6)-4-OAc-α-D-Galp-(1→, →3,4,6)-α-D-Galp-(1→, →4)-α-D-Glcp-(1→, →2,3,6)-β-D-Glcp-(1→, →4,6)-α-D-Manp-(1→, →3,4)-α-L-Rhap-(1→, →4)-α-D-GalpA-(1→, and →4)-α-D-GlcpA-(1 → residues and terminated with Xyl and Ara. Additionally, ATP50–3 significantly inhibited the release of proinflammatory factors in lipopolysaccharide-stimulated BV2 cells. ATP50–3 may be an active constituent of AT50, responsible for its anti-neuroinflammatory effects, with great potential to treat AD.

Appetitively motivated tasks in the IntelliCage reveal a higher motivational cost of spatial learning in male than female mice.

The IntelliCage (IC) permits the assessment of the behavior and learning abilities of mice in a social home cage context. To overcome water deprivation as an aversive driver of learning, we developed protocols in which spatial learning is motivated appetitively by the preference of mice for sweetened over plain water. While plain water is available at all times, only correct task responses give access to sweetened water rewards. Under these conditions, C57BL/6J mice successfully mastered a corner preference task with the reversal and also learned a more difficult time-place task with reversal. However, the rate of responding to sweetened water decreased strongly with increasing task difficulty, indicating that learning challenges and reduced success in obtaining rewards decreased the motivation of the animals to seek sweetened water. While C57BL/6J mice of both sexes showed similar initial taste preferences and learned similarly well in simple learning tasks, the rate of responding to sweetened water and performance dropped more rapidly in male than in female mice in response to increasing learning challenges. Taken together, our data indicate that male mice can have a disadvantage relative to females in mastering difficult, appetitively motivated learning tasks, likely due to sex differences in value-based decision-making.

Brain-Targeted Liposomes Loaded with Monoclonal Antibodies Reduce Alpha-Synuclein Aggregation and Improve Behavioral Symptoms in Parkinson's Disease.

Monoclonal antibodies (mAbs) hold promise in treating Parkinson's disease (PD), although poor delivery to the brain hinders their therapeutic application. In the current study, it is demonstrated that brain-targeted liposomes (BTL) enhance the delivery of mAbs across the blood-brain-barrier (BBB) and into neurons, thereby allowing the intracellular and extracellular treatment of the PD brain. BTL are decorated with transferrin to improve brain targeting through overexpressed transferrin-receptors on the BBB during PD. BTL are loaded with SynO4, a mAb that inhibits alpha-synuclein (AS) aggregation, a pathological hallmark of PD. It is shown that 100-nm BTL cross human BBB models intact and are taken up by primary neurons. Within neurons, SynO4 is released from the nanoparticles and bound to its target, thereby reducing AS aggregation, and enhancing neuronal viability. In vivo, intravenous BTL administration results in a sevenfold increase in mAbs in brain cells, decreasing AS aggregation and neuroinflammation. Treatment with BTL also improve behavioral motor function and learning ability in mice, with a favorable safety profile. Accordingly, targeted nanotechnologies offer a valuable platform for drug delivery to treat brain neurodegeneration.

Effects of FB1 and HFB1 on Autonomous Exploratory and Spatial Memory and Learning Abilities in Mice.

Fumonisin B1 (FB1) is a representative form of fumonisin and is widely present in food and feed. Hydrolyzed fumonisin B1 (HFB1) emerges as a breakdown product of FB1, which is accompanied by FB1 alterations. While previous studies have primarily focused on the liver or kidney toxicity of FB1, with limited studies existing on its neurotoxicity and even fewer on the toxicity of HFB1, this study focuses on the neurotoxicity of FB1 and HFB1 exposure in mice investigated by the open field test, Morris water maze test, histopathological analysis, and nontargeted metabolomics. Further, the levels of oxidative stress-related indices, neurotransmitters, and sphingolipids in the brain were measured to analyze their correlation with behavioral outcomes. The results showed that both FB1 (5 mg/kg) and HFB1 (2.8 mg/kg) reduced autonomous exploratory behavior in mice, impaired spatial learning and memory, and caused mild abnormalities in the brain structure. Quantitative analysis further indicated that exposure to FB1 and HFB1 disrupted neurotransmitter homeostasis, exacerbated oxidative stress, and significantly increased the sphinganine/sphingosine (Sa/So) ratio. Moreover, HFB1 exhibited neurotoxic effects similar to those of FB1, emphasizing the need to pay attention to the neurotoxicity effect of HFB1. These findings underscore the importance of understanding the risks and potential neurological damage associated with FB1 and HFB1 exposure, highlighting the necessity for further research in this crucial field.

Protective effect of Huanglianjiedu Decoction on microcystin-LR induced nerve injury

Microcystin-LR (MC-LR) presented in eutrophic water has been identified as having the capacity to induce damage to the mammalian nervous system by crossing the blood-brain barrier through organic anion transporting polypeptides. However, the lack of effective preventive and protective strategies remains a concern. Huanglianjiedu Decoction (HLJD), a classical Chinese traditional formula originating from the Tang Dynasty and comprising Rhizoma Coptidis, Radix Scutellariae, Cortex Phellodendri, and Fructus Gardeniae, has exhibited neuroprotective effects attributed to its antioxidant properties. In this study, we investigated the potential of HLJD in counteracting the neurotoxic effects induced by MC-LR. Our findings revealed that MC-LR dose-dependently inhibited the activity of the PP2A enzyme in PC 12 cells and significantly elevated the phosphorylation levels of JNK, ERK1/2, and p38. Moreover, MC-LR administration resulted in synaptic damage in mouse neurons, hyperphosphorylation of the microtubule-related protein Tau, cognitive impairment, and deficits in learning and memory in C57BL/6J mice. Notably, HLJD effectively reversed the cytotoxicity caused by MC-LR in PC 12 cells, and attenuated MC-LR-induced neuronal damage while improving learning ability in mice. These results highlight the potential of HLJD as a promising protective strategy against MC-LR-induced neurological injury.

TRIM62 knockdown by inhibiting the TLR4/NF-κB pathway and NLRP3 inflammasome attenuates cognitive impairment induced by diabetes in mice.

The tripartite motif 62 is an E3 ubiquitin ligase protein that regulates cellular processes, including differentiation, immunity, development and apoptosis, leading to various disease states, such as cancer and inflammatory diseases. However, the role and mechanism of the tripartite motif 62 in the process of diabetic-induced cognitive impairment have not been reported. Therefore, the aim of this study was to investigate the role and mechanism of the tripartite motif 62 in diabetic-induced cognitive impairment. The results showed that the expression of the tripartite motif 62 was up-regulated in diabetic mice. Silencing of TRIM62 increased body weight and decreased fasting blood glucose in diabetic mice. In addition, knockdown of the tripartite motif 62 inhibited STZ-induced inflammation, apoptosis and oxidative stress. Further studies showed that the TLR4/NF-κB pathway and NLRP3 inflammasomes were involved in the regulation of diabetic mice by the tripartite motif 62. More importantly, inhibition of the tripartite motif 62 improved cognitive impairment and learning ability in mice. In conclusion, inhibition of TRIM62 inhibits STZ-induced inflammation, cell apoptosis and oxidative stress, and improves the cognitive ability of mice. Therefore, the tripartite motif 62 may be an important target for the treatment of diabetes-induced cognitive impairment.

High Morphine Use Disorder Susceptibility Is Predicted by Impaired Learning Ability in Mice.

An obvious reason for substance uses disorders (SUDs) is drug craving and seeking behavior induced by conditioned context, which is an abnormal solid context memory. The relationship between susceptibility to SUD and learning ability remains unclear in humans and animal models. In this study, we found that susceptibility to morphine use disorder (MUD) was negatively correlated with learning ability in conditioned place preference (CPP) in C57 mice. By using behavioral tests, we identified the FVB mouse as learning impaired. In addition, we discovered that learning-relevant proteins, such as the glutamate receptor subunits GluA1, NR1, and NR2A, were decreased in FVB mice. Finally, we assessed the context learning ability of FVB mice using the CPP test and priming. We found that FVB mice had lower learning performance with respect to normal memory but higher performance of morphine-reinstatement memory. Compared to C57 mice, FVB mice are highly sensitive to MUDs. Our results suggest that SUD susceptibility is predicted by impaired learning ability in mice; therefore, learning ability can play a simple and practical role in identifying high-risk SUD groups.

Outer membrane vesicles of Porphyromonas gingivalis trigger NLRP3 inflammasome and induce neuroinflammation, tau phosphorylation, and memory dysfunction in mice.

Background Porphyromonas gingivalis (Pg), the keystone pathogen in chronic periodontitis, is reported to initiate Alzheimer’s disease pathologies in preclinical studies. However, the specific mechanisms and signaling pathways acting on the brain still need to be further explored. Outer membrane vesicles are derived from Gram-negative bacteria and contain many virulence factors of bacteria. We hypothesized that outer membrane vesicles are an important weapon of Porphyromonas gingivalis to initiate Alzheimer’s disease pathologies.MethodsThe outer membrane vesicles of Porphyromonas gingivalis (Pg OMVs, 4 mg/kg) or saline were delivered to 14-month-old mice by oral gavage every other day for eight weeks. Behavioral alterations were assessed by the open field test, Morris water maze, and Y-maze test. Blood–brain barrier permeability, neuroinflammation, tau phosphorylation, and NLRP3 inflammasome-related protein were analyzed.ResultsPg OMVs impaired memory and learning ability of mice and decreased tight junction–related gene expression ZO-1, occludin, claudin-5, and occludin protein expression in the hippocampus. Pg OMVs could be detected in the hippocampus and cortex three days after oral gavage. Furthermore, Pg OMVs activated both astrocytes and microglia and elevated IL-1β, tau phosphorylation on the Thr231 site, and NLRP3 inflammasome–related protein expression in the hippocampus. In in vitro studies, Pg OMV (5 µg/ml) stimulation increased the mRNA and immunofluorescence of NLRP3 in BV2 microglia, which were significantly inhibited by the NLRP3 inhibitor MCC950. In contrast, the tau phosphorylation in N2a neurons was enhanced after treatment with conditioned media from Pg OMV-stimulated microglia, which was attenuated after pretreatment with MCC950.ConclusionsThese results indicate that Pg OMVs prompt memory dysfunction, neuroinflammation, and tau phosphorylation and trigger NLRP3 inflammasome in the brain of middle-aged mice. We propose that Pg OMVs play an important role in activating neuroinflammation in the AD-like pathology triggered by Porphyromonas gingivalis, and NLRP3 inflammasome activation is a possible mechanism.

Neuroinflammation-mediated mitochondrial dysregulation involved in postoperative cognitive dysfunction

Neuroinflammation following peripheral surgery is a pivotal pathogenic mechanism of postoperative cognitive dysfunction (POCD). However, the key site of inflammation-mediated neural damage remains unclear. Impaired mitochondrial function is a vital feature of degenerated neurons. Dynamin-related protein 1 (DRP1), a crucial regulator of mitochondrial dynamics, has been shown to play an essential role in synapse formation. Here, we designed experiments to assess whether Drp1-regulated mitochondrial dynamics and function are involved in the pathological processes of POCD and elucidate its relationship with neuroinflammation. Aged mice were subjected to experimental laparotomy under isoflurane anesthesia. Primary neurons and SH-SY5Y cells were exposed to tumor necrosis factor (TNF). We found an increase in Drp1 activation as well as mitochondrial fragmentation both in the hippocampus of mice after surgery and primary neurons after TNF exposure. Pretreatment with Mdivi-1, a Drp1 specific inhibitor, reduced this mitochondrial fragmentation. Drp1 knockdown with small interfering RNA blocked TNF-induced mitochondrial fragmentation in SH-SY5Y cells. However, the application of Mdivi-1 exhibited a negative impact on mitochondrial function and neurite growth in primary neurons. Calcineurin activity was increased in primary neurons after TNF exposure and contributed to the Drp1 activation. The calcineurin inhibitor FK506 exhibited a Drp1-independent function that mitigated mitochondrial dysfunction. Finally, we found that FK506 pretreatment ameliorated the neurite growth in neurons treated with TNF and the learning ability of mice after surgery. Overall, our research indicated a crucial role of mitochondrial function in the pathological processes of POCD, and neuronal metabolic modulation may represent a novel and important target for POCD.

Cultivation and extraction of omega 3-6 fatty acids from the heterotrophic marine microalga Schizochytrium mangrovei TB17 to make a functional food

The objective of this study was to investigate the different fermentation conditions for Schizochytrium mangrovei TB17 biomass production rich in omega-3 and omega-6 fatty acids to determine the optimal conditions for bio-oil extraction from the algal biomass and to study the pharmacological effects of this bio-oil in experimental animal models. After 108 h of fed-batch fermentation, the cell density, dry biomass, lipid contents and docosahexaenoic acid (DHA) contents reached 392.53±3.89×106 cells/mL, 100.41±3.17 g/L, 41.04±0.87% dry cell weight (DCW) and 33.33±1.96% total fatty acids (TFAs) respectively. The in situ transesterification producing bio-oil rich in omega 3-6 fatty acids from the biomass of the TB17 strain reached a yield of TFAs of 45.02±1.37% DCW. The yields of PUFAs and SFAs were 30.02±0.38% and 69.98±0.53% of TFA respectively. The bio-oil mainly contains DHA and EPA accounting for 74.04±0.25% and 10.97±0.43% of the TFAs respectively. The bio-oil met the Vietnam food safety standard. According to the results of the acute in mice and the subchronic oral toxicity in rats for 90 days, the bio-oil rich in omega 3-6 fatty acids is safe and has the ability to improve memory and learning ability in mice which can be made functional food oil capsules for human.

Atrophy of lacunosum moleculare layer is important for learning and memory in APP/PS1 transgenic mice

Changes in the hippocampus are closely associated with learning and memory in Alzheimer's disease; however, it is not clear which morphological and cellular and subcellular changes are essential for learning and memory. Here, we accurately quantitatively studied the hippocampal microstructure changes in Alzheimer's disease model mice and analyzed the relationship between the hippocampal microstructure changes and learning and memory. Ten-month-old male APP/PS1 transgenic mice and age-matched nontransgenic littermate mice were randomly selected. The spatial learning and memory abilities were assessed using the Morris water maze. The volumes of each layer and numbers of neurons, dendritic spines and oligodendrocytes in the hippocampal subregions were investigated using unbiased stereological techniques. The APP/PS1 transgenic mice showed a decline in hippocampus-dependent spatial learning and memory abilities, smaller volumes of each layer (other than stratum radiatum) and fewer numbers of neurons, dendritic spine synapses and mature oligodendrocytes in the hippocampal subregions than nontransgenic mice. In particular, the decline of spatial learning ability was significantly correlated with the atrophy of lacunosum moleculare layer (LMol) and the decrease of hippocampal neurons and mature oligodendrocytes rather than dendritic spines. The CA1-3 fields (including LMol) atrophy was significantly correlated with the decrease both of neurons, dendritic spines and mature oligodendrocytes. However, the dentate gyrus atrophy was significantly correlated with the decrease of neurons and mature oligodendrocytes rather than dendritic spines. The loss of neurons, dendritic spines synapses and mature oligodendrocytes together caused the LMol atrophy and then led to a decline in hippocampus-dependent spatial learning ability in mice with Alzheimer's disease.

P53 and clock genes play an important role in memory and learning ability depression due to long-term ultraviolet A eye irradiation.

Long-term ultraviolet A (UVA) eye irradiation decreases memory and learning ability in mice. However, the underlying mechanism is still unclear. In this study, ICR mice were used to study the effects of long-term UVA eye irradiation. The eyes of mice were exposed to UVA from an FL20SBLB-A lamp three times a week for 1 year. Then, we analyzed memory and learning ability in the mice using water maze and step-through passive avoidance tests, and measured the levels of p53, Period2 (Per2), Clock, brain and muscle Arnt-like protein-1 (Bmal1), nicotinamide mononucleotide adenylyltransferase (NMNAT) activity, nicotinamide phosphoribosyltransferase (NAMPT) activity, nicotinamide adenine dinucleotide (NAD+), and sirtuin 1 (Sirt1) in the brains of treated and control animals. The results showed that the p53 level increased significantly following long-term UVA eye irradiation, whereas the levels of Period2, Bmal1, Clock, NMNAT and NAMPT activities, NAD+, and Sirt1 decreased significantly. Furthermore, we found that p53 inhibition ameliorated the UVA eye irradiation-induced depression of memory and learning ability. These results indicate that long-term UVA eye irradiation stimulates p53, inhibits the clock gene, and reduces Sirt1 production in the NAD+ constructional system, resulting in reduced memory and learning ability.

Tripterygium glycoside ameliorates neuroinflammation in a mouse model of Aβ25-35-induced Alzheimer’s disease by inhibiting the phosphorylation of IκBα and p38

ABSTRACT Alzheimer’s disease (AD) is acommon neurodegenerative disease in the aged population. Tripterygium glycoside (TG) has been reported to protect the nervous system. However, the effect of TG on AD is still unknown. We aimed to explore the effect of TG on AD. Thirty-two C57BL/6J mice were randomly selected and assigned to the normal control, AD model, AD+donepezil, and AD+TG groups. PC12 cells were assigned to the normal control, AD cell model, and AD+TG groups. The alterations in spatial memory and learning abilities of mice were measured by Morris water maze. Neuronal damage in mice was detected using Nissl staining. The expression levels of Aβ25-35, p-Tau, and CD11b in brain tissues were detected using immunohistochemistry. The expression levels of IL-1β, TNF-α, NO, p-P38, P38, p-IκBα, Caspase1, COX2, and iNOS were measured using ELISAs, qRT–PCR, and western blotting.TG significantly improved the spatial memory and learning abilities of AD mice. Compared toAD model group, significantly lower expression levels of Aβ25-35, p-Tau, and CD11b were observed in AD+TG group (p < 0.05). The neuron density significantly increased in AD+TG group (p < 0.05). Significantly lower expression levels of IL-1β, TNF-α, NO, caspase-1, COX2, iNOS, p-IκBα and p-P38 MAPK were detected in AD+TG group (p < 0.05). In summary, TG may exert aneuroprotective effect by suppressing the release of inflammatory factors and microglial activity and inhibiting the phosphorylation of IκBα and p38 MAPK. These findings may improve our understanding of the mechanism of TG intervention in AD.

ROS dependent neurotoxicity, genotoxicity &amp; histopathological alterations triggered by β-cyfluthrin, a synthetic pyrethroid

Abstract Given the widespread use of pyrethroids in home and agriculture, it becomes important to evaluate their potential effects on humans. This study was taken up to gain an insight into the genotoxicity and behavioural toxicity of β-cyfluthrin when administered orally to male Swiss albino mice. Further, the activity of acetyl cholinesterase and antioxidant enzymes was estimated and histopathological examination of brain was performed. It was found that 28 days oral exposure to β-cyfluthrin caused genotoxicity by damaging the DNA as seen by a decline in mitotic index, increase in aberrant cells, tail length and tail intensity. Neuromuscular coordination and learning ability of mice was adversely affected. Concomitantly, a reduction in acetylcholinesterase and antioxidant enzymes occur indicating oxidative stress caused by the pesticide. Histopathological examination of brain revealed structural alterations in the hippocampus region. Thus, it may be concluded that β-cyfluthrin exposure caused neurobehavioural alterations, genotoxicity, oxidative stress and histopathological changes in mice.

DBcAMP Rescues the Neurons From Degeneration in Kainic Acid-Injured Hippocampus, Enhances Neurogenesis, Learning, and Memory.

Dibutyryl cyclic adenosine monophosphate (dBcAMP) is a cell-permeable synthetic analog of cyclic adenosine monophosphate (cAMP). Although the elevation of cAMP levels was reported to promote the functional recovery in spinal cord injury, its role in neurogenesis or functional recovery after hippocampal injury is unknown. The objective of the study was to investigate the effects of dBcAMP on learning, memory, and hippocampal neurogenesis in the excitotoxically lesioned hippocampus. An excitotoxic lesion was induced in the hippocampi of 4-month-old male BALB/c mice by injecting 0.25 μg/μl into the lateral ventricles of both sides. The lesioned mice (L) were divided into L+dBcAMP and L+phosphate-buffered saline (PBS) groups. Sham surgery (S) was done by the injection of 1 μl of sterile saline into the lateral ventricles. The sham surgery mice were divided into S+dBcAMP and S+PBS groups. Mice in the L+dBcAMP and S+dBcAMP groups were treated with dBcAMP for 1 week (i.p., 50 mg/kg), whereas mice in the L+PBS and S+PBS groups were treated with PBS. The mice in all groups were subjected to water maze and passive avoidance tests at the end of the 4th week. Cresyl violet staining and NeuN and doublecortin immunostaining were done to analyze the morphology and neurogenesis. The water maze learning sessions did not show a significant difference in escape latency between the groups, suggesting an unimpaired learning ability of mice in all groups. The L+dBcAMP mice had significantly short entry latency and higher target quadrant time/distance traveled compared to the L+PBS group, suggesting better memory retention. The L+dBcAMP group had a significantly improved memory retention compared to the L+PBS mice during the passive avoidance test. Morphological studies showed significantly greater adult neurons and increased hippocampal neurogenesis in the hippocampus of mice in the L+dBcAMP group compared to those in the L+PBS group. There was no significant difference between the S+dBcAMP and S+PBS groups in the water maze/passive avoidance tests and the number of neurons. In conclusion, dBcAMP protects the hippocampal neuron from degeneration and enhances hippocampal neurogenesis, learning, and memory.

Long-term UVA exposure to the eye compromises memory and learning ability in mice via corticotropin-releasing hormone type 2 receptor.

Long-term eye exposure to ultraviolet (UV)A can effect memory and learning ability. However, the underlying mechanism behind these effects remain unknown. In this study, we used HR-1 mice to study effects of long-term UVA eye irradiation. The eyes or dorsal skin of the mice were exposed to UVA at the dose of 110kj/m2 using an FL20SBLB-A lamp three times a week over 12 months. We measured the levels of reactive oxygen species, corticotropin-releasing hormone (CRH), urocortin 2, and CRH type 2 receptor (CRHR-2) in the brain of treated and control animals. Their memory and learning ability following exposure to UVA was analyzed by the standard water maze test. Our results showed that the levels of reactive oxygen species, CRH, urocortin 2, and CRHR-2 increased significantly following long-term UVA irradiation, and the effects were more pronounced in animals subjected to eye irradiation than those subjected to dorsal skin irradiation. Furthermore, the UVA exposure led to an increase in the levels of β-amyloid and microglia in the brain. These results indicated that UVA eye irradiation potentially mediated a decline in memory and learning ability via enhancing levels of urocortin 2, microglia, and β-amyloid in the brain.

The Magic of Crystal Structure-Based Inhibitor Optimization: Development of a Butyrylcholinesterase Inhibitor with Picomolar Affinity and in Vivo Activity.

The enzymatic activity of butyrylcholinesterase (BChE) in the brain increases with the progression of Alzheimer's disease, thus classifying BChE as a promising drug target in advanced Alzheimer's disease. We used structure-based drug discovery approaches to develop potent, selective, and reversible human BChE inhibitors. The most potent, compound 3, had a picomolar inhibition constant versus BChE due to strong cation-π interactions, as revealed by the solved crystal structure of its complex with human BChE. Additionally, compound 3 inhibits BChE ex vivo and is noncytotoxic. In vitro pharmacokinetic experiments show that compound 3 is highly protein bound, highly permeable, and metabolically stable. Finally, compound 3 crosses the blood-brain barrier, and it improves memory, cognitive functions, and learning abilities of mice in a scopolamine model of dementia. Compound 3 is thus a promising advanced lead compound for the development of drugs for alleviating symptoms of cholinergic hypofunction in patients with advanced Alzheimer's disease.

Evaluating the Effectiveness of GTM-1, Rapamycin, and Carbamazepine on Autophagy and Alzheimer Disease

BackgroundThis study was proposed to compare the efficacy and safety of GTM-1, Rapamycin (Rap), and Carbamazepine (CBZ) in managing Alzheimer disease (AD). The impact of the above mentioned therapeutic drugs on autophagy was also investigated in our study.Material/MethodsFirstly, 3×Tg AD mice were randomly allocated into 4 groups (each group with 10 mice), in which AD mice were separately treated with dimethylsulfoxide (DMSO, vehicle group), GTM-1 (6 mg/kg), Rap (1 mg/kg), and CBZ (100 mg/kg). Then spatial memory and learning ability of mice was tested using the Morris water maze. Routine blood tests were performed to evaluate the toxicity of these drugs. Amyloid-β42 (Aβ42) concentration was detected by ELISA and immunohistochemistry. Proteins related to autophagy were detected by Western blot.ResultsGTM-1, Rap, and CBZ significantly improved the spatial memory of 3×Tg AD mice compared to that in the vehicle group (all P<0.05). Moreover, this study revealed that CBZ dosage was related to toxicity in mice. All of the above drugs significantly increased the expression of LC3-II and reduced Aβ42 levels in hippocampi of 3×Tg AD mice (all P<0.05). On the other hand, neither GTM-1 nor CBZ had significant influence on the expression of proteins on the mTOR pathway.ConclusionsGTM-1 can alleviate the AD syndrome by activating autophagy in a manner that is dependent on the mTOR pathway and it therefore can be considered as an alternative to Rap.

Evaluation of the Potency of Kinetin on Radiation Induced Behavioural Changes in Swiss Albino Mice.

According to the various independent studies conducted, it is well evident fact that radiation induces oxidative stress in the living system. It is also proved that this oxidative stress will lead to the various behavioural changes such as anxiety and memory impairment. Kinetin is one of the important plant cytokine with anti-aging properties. However, very few studies were conducted to check its potential in ameliorating the behavioural changes induced by the ionizing radiation. This study was aimed to check the potential of kinetin in ameliorating the radiation induced behavioural changes in albino mice. In this study, survival analysis was performed using three different dose of kinetin intervention along with, one radiation control group and one normal control group (n=50). Based on the cumulative survival rate, single effective dose of kinetin was selected and used to evaluate the behavioural changes induced by radiation. The open field apparatus was used to evaluate the anxiety level (n=18, six in each group). Eight armed radial maze was used to evaluate the memory and learning ability in mice model. Survival study results suggest 100 mg/kg body weight of kinetin showed highest cumulative survival rate. Therefore, this dose was selected as an effective drug dose for further study. Analysis also showed 6 Gy whole body electron beam radiation had significantly increased anxiety level, increased duration to complete the task as well as mistakes done during the task. Further, kinetin intervention had significantly ameliorated the same. A 100 mg/kg body weight of kinetin intervention helps in reducing the anxiety and improves the learning ability in mice exposed to electron beam radiation.

Long-term UVA eye irradiation causes decreased learning ability in mice.

Long-term eye radiation with ultraviolet A (UVA) denatures the cells of the cerebral hippocampus. However, the influence on memory and learning ability in mice is not known. HR-1 mice were used. We irradiated the eyes or dorsal skin of the mice with UVA at a dose of 110 kJ/m(2) using an FL20SBLB-A lamp for 6, 12, and 24 months. The mean escape latency in the water maze was significantly increased in the UVA-irradiated mice in comparison with that seen in the controls. In the mice in which UVA eye irradiation was performed for 24 months, the depression of memory and learning ability was remarkable. The acetylcholinesterase activity, choline acetyltransferase activity, and acetylcholine content in the brain in the UVA eye-irradiated mice were significantly less than those observed in the control mice. Furthermore, during UVA eye irradiation, the levels of β-amyloid (Aβ), γ-secretase, which produces Aβ peptide, and advanced glycation end products increased. Moreover, the effects of UVA eye irradiation increased with the duration of irradiation (or aging), and the introduction of glucose into the brain also decreased with UVA eye irradiation. These results indicate that UVA eye irradiation induces a decreased memory and learning ability in mice.