Lutein-Zeaxanthin Extract (XanMax® 2002) Attenuates Oxidative Stress, Neuroinflammation, and Memory Deficits in H2O2-Exposed Neuro-2a Cells and Scopolamine-Induced Mice.

Microglial overactivation promotes the production of various second messengers and inflammatory markers in brain tissue, resulting in neuroinflammation and neurodegeneration, which may lead to cognitive decline. The cyclic nucleotides are one of the important second messengers involved in the regulation of neurogenesis, synaptic plasticity, and cognition. The levels of these cyclic nucleotides are maintained by phosphodiesterase enzyme isoforms, particularly PDE4B, in the brain. An imbalance between PDE4B levels and cyclic nucleotides may lead to aggravating neuroinflammation. Lipopolysaccharides (LPS) were administered intraperitoneally on alternate days for 7 days at a dose of 500 μg/kg in mice, which triggered systemic inflammation. This may lead to the activation of glial cells and may activate oxidative stress and neuroinflammatory markers in brain tissue. Furthermore, oral administration of roflumilast (0.1, 0.2, and 0.4 mg/kg) in this model ameliorated oxidative stress markers, neuroinflammation and improved neurobehavioral parameters in these animals. The detrimental effect of LPS increased oxidative stress, AChE enzyme levels, and decreased catalase levels in brain tissues, along with memory impairment in animals. Moreover, it also enhanced the activity and expression of the PDE4B enzyme, resulting in a decline in cyclic nucleotide levels. Furthermore, treatment with roflumilast improved the cognitive decline, decreased AChE enzyme level, and increased the catalase enzyme level. Roflumilast also reduced the PDE4B expression in a dose-dependent manner, which LPS up-regulated. Roflumilast has shown an anti-neuroinflammatory effect and reversed the cognitive decline in LPS-induced mice model.

Behavioral and molecular effects of intrahippocampal infusion of auraptene, resveratrol, and curcumin on H-89-induced deficits on spatial memory acquisition and retention in Morris water maze.

Stroke is the third most common cause of death and the primary cause of morbidity in the United Kingdom. It can be associated with deterioration in both sensorimotor and cognitive skills. Proximal occlusion of the middle cerebral artery (MCAO) in rodents is a widely used model of experimental cerebral ischaemia, which has been used to investigate the effect of stroke on cognition in spatial learning, such as the watermaze. However, findings to-date have been varied, depending on when testing was started after MCAO and the duration of training and testing, raising doubts about the utility of MCAO in rodents to study memory deficits. The present study was designed to discriminate between sensorimotor and spatial memory to establish whether MCAO has a significant influence on both the acquisition and retention of spatial memory. Female Lister Hooded rats (n=10) underwent MCAO. The artery was electrocoagulated from the origin of the lenticulostriate arteries to the inferior cerebral vein and then transected to ensure complete occlusion. Sham animals (n=9) underwent the same procedure except the artery was not occluded or transected and a group of naive, unoperated animals (n=8) was included. Training in the watermaze commenced 10 days after MCAO with 3 days of training to a visible escape platform of varying positions from different start positions. The animals were then trained to find a hidden escape platform at a fixed location (spatial reference memory). The start position was varied and the first trial every day was a probe trial where no platform was present for the first 60 seconds. For acquisition, animals were trained until they spent at least 50% of the probe trial in the quadrant where the platform was normally placed (target quadrant) for 3 consecutive days. The retention of memory was tested 1, 7 and 28 days after this criterion was reached. MCAO induced a consistent infarct involving both cortex and caudate which by 28 days was represented by ipsilateral tissue loss of 32.1 2.8 % of the contralateral hemisphere (mean S.E.M). The watermaze results revealed no deficit in acquisition or retention of memory in MCAO animals compared to sham and naive animals. There was no difference in the average number of days to reach acquisition criterion (Graph 1), and no difference in the proportion of time spent in the target quadrant during the retention tests (Graph 2). Data are presented as mean S.E.M. In conclusion, this study, designed to differentiate between spatial memory and sensorimotor deficits, revealed no evidence for deficits in memory acquisition or retention following MCAO. (See Figure 1).

BackgroundMultiple sclerosis (MS), an autoimmune‐neurodegenerative disease, exhibits features of neurovascular inflammation including endothelial activation and shedding of microparticles (MPs). While the brain lacks ‘classical’ lymphatics, we previously reported expression of venous‐lymphatic endothelial markers (LYVE‐1, podoplanin, prox‐1, VEGFR‐3, VEGF‐C, VEGF‐D) in both brain tissue and sera, with altered expression of these proteins in MS. Based on differential expression of these markers in brain tissue, we propose that these markers may originate within brain microvascular endothelium and undergo changes in disease which can be analyzed diagnostically.ObjectivesTo validate the neurolymphatic biomarker matrix as a novel, non‐invasive and cost‐effective tool for diagnosing MS and discriminating MS subtypes.MethodsNeurolymphatic biomarker expression was determined in human cerebral microvascular endothelial cells (hCMECs) following 24–48 hours of TNF‐α (20 ng/ml) exposure +/− IFN‐γ (1000 U/ml) using western blotting. MPs from these cells were visualized using scanning electron microscopy. Human sera were analyzed by flow cytometry, western and dot blotting to characterize relative partitioning of neurolymphatic biomarkers in MP.ResultshCMECs released MPs that contain lymphatic and junctional markers as well as caveolin‐1. Plasma MPs were seen to liberate soluble (non‐particulate) neurolymphatic biomarkers upon storage, indicating that serum represents a more stable MP‐derived pool of these markers. MP flow analysis of intracellular actin revealed that permeabilization destabilizes phosphatidylserine‐Annexin V interaction which is used to designate MP identity, suggesting that flow cytometry of MPs may require more judicious interpretation. All neurolymphatic markers so far tested were able to distinguish MS from healthy control serum samples; FOXC2 expression can further distinguish subtypes of MS: RRMS from SPMS.ConclusionLymphatic biomarkers in plasma and sera are expressed by brain microvascular endothelial cells and exhibit changes in expression in response to inflammatory stimuli (cytokines). Such alterations parallel transfer of these markers into caveolin‐1 ‐enriched microparticles, which represent a circulating ‘snapshot’ of the vascular surface that can be analyzed by several immune approaches, particularly following storage‐dependent solubilization of these biomarkers.Support or Funding InformationSupported by the Annette Funicello Research Fund for Neurological Diseases and the Malcolm Feist Predoctoral Fellowship from Center for Cardiovascular Diseases and Sciences, LSU Health Sciences Center‐ShreveportThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CaMKII Activation in the Entorhinal Cortex Disrupts Previously Encoded Spatial Memory

Evaluation of antiepileptic effect of S-adenosyl methionine and its role in memory impairment in pentylenetetrazole-induced kindling model in rats.

Age-related cognitive impairments are associated with differentially expressed genes (DEGs) linked to defined neural systems; however, studies examining multiple regions of the hippocampus fail to find links between behavior and transcription in the dentate gyrus (DG). We hypothesized that use of a task requiring intact DG function would emphasize molecular signals in the DG associated with a decline in performance. We used a water maze beacon discrimination task to characterize young and middle-age male F344 rats, followed by a spatial reference memory probe trial test. Middle-age rats showed increased variability in discriminating two identical beacons. Use of an allocentric strategy and formation of a spatial reference memory were not different between age groups; however, older animals compensated for impaired beacon discrimination through greater reliance on spatial reference memory. mRNA sequencing of hippocampal subregions indicated DEGs in the DG of middle-age rats, linked to synaptic function and neurogenesis, correlated with beacon discrimination performance, suggesting that senescence of the DG underlies the impairment. Few genes correlated with spatial memory across age groups, with a greater number in region CA1. Age-related CA1 DEGs, correlated with spatial memory, were linked to regulation of neural activity. These results indicate that the beacon task is sensitive to impairment in middle age, and distinct gene profiles are observed in neural circuits that underlie beacon discrimination performance and allocentric memory. The use of different strategies in older animals and associated transcriptional profiles could provide an animal model for examining cognitive reserve and neural compensation of aging.SIGNIFICANCE STATEMENT Hippocampal subregions are thought to differentially contribute to memory. We took advantage of age-related variability in performance on a water maze beacon task and next-generation sequencing to test the hypothesis that aging of the dentate gyrus is linked to impaired beacon discrimination and compensatory use of allocentric memory. The dentate gyrus expressed synaptic function and neurogenesis genes correlated with beacon discrimination in middle-age animals. Spatial reference memory was associated with CA1 transcriptional correlates linked to regulation of neural activity and use of an allocentric strategy. This is the first study examining transcriptomes of multiple hippocampal subregions to link age-related impairments associated with discrimination of feature overlap and alternate response strategies to gene expression in specific hippocampal subregions.

Improvement of spatial learning and memory, cortical gyrification patterns and brain oxidative stress markers in diabetic rats treated with Ficus deltoidea leaf extract and vitexin

AimThis work aims to investigate the possible radio-adaptive mechanisms induced by low-dose (LD) whole-body γ-irradiation alone or combined with alpha-lipoic acid (ALA) administration in modulating high-dose (HD) head irradiation–induced brain injury in rats.Materials and MethodsRats were irradiated with LD (.25 Gy) 24 hours prior HD (20 Gy), and subjected to ALA (100 mg/kg/day) 5 minutes after HD and continued for 10 days. At the end of the experiment, animals were sacrificed and brain samples were dissected for biochemical and histopathological examinations.ResultsHD irradiation-induced brain injury as manifested by elevation of oxidative stress, DNA damage, apoptotic, and inflammatory markers in brain tissue. Histological examination of brain sections showed marked alterations. However, LD alone or combined with ALA ameliorated the changes induced by HD.ConclusionUnder the present experimental conditions, LD whole-body irradiation exhibited neuroprotective activity against detrimental effects of a subsequent HD head irradiation. This effect might be due to the adaptive response induced by LD that activated the anti-oxidative, anti-apoptotic, and anti-inflammatory mechanisms in the affected animals making them able to cope with the subsequent high-dose exposure. However, the combined LD exposure and ALA supplementation produced a further modulating effect in the HD-irradiated rats.

Efficacy of electroacupuncture stimulating Shenmen (HT7), Baihui (GV20), Sanyinjiao (SP6) on spatial learning and memory deficits in rats with insomnia induced by para-chlorophenylalanine: a single acupoint combined acupoints.

Mercury is a highly poisonous heavy metal abundantly found in the environment in its inorganic form. Although evidence have been provided about the possible role of inorganic mercury in the pathology of Alzheimer's disease (AD), its effect on cognitive and mitochondrial functions have not yet been completely understood. Thus, the purpose of the present study was to examine the effects of the chronic exposure to mercuric chloride (0.4, 0.8 and 1.6 mg kg-1 per day for 3 weeks) through drinking water (by gavage) on spatial learning and memory and hippocampal mitochondrial function in beta-amyloid treated rats (1 μg per μL per side, intrahippocampally). The acquisition and retention of spatial memory were evaluated by the Morris water maze (MWM) test. Several parameters of hippocampal mitochondrial function were also measured. The results indicated that mercury impaired spatial learning and memory as well as aggravated Aβ-induced memory impairments in a concentration-dependent manner. Furthermore, mercury exposure resulted in a significant increase in ROS generation, MMP collapse, mitochondrial swelling, glutathione oxidation, lipid peroxidation, and outer membrane damage. In addition, a reduced cytochrome c oxidase (complex IV) activity and elevated ADP/ATP ratio in the rats' hippocampus was also observed. The findings of the current study revealed that chronic mercury exposure led to mitochondrial dysfunction, which resulted in spatial memory impairments. The results also showed that mercury can exacerbate the toxic effects of Aβ on spatial memory and hippocampal mitochondrial function.

Objective: It is known that the acetylcholinergic afferents of the neocortex from subcortical areas participate in learning and memory. Autopsy studies in cases of Alzheimer’s disease (AD) have shown that most of the neurons of nucleus basalis magnocellularis (NBM) are atrophic or decreased in number. In this study, we searched for whether or not it was possible to improve the impaired learning and memory functions with foetal neural tissue transplantation in an experimental model of AD. Method: A total of thirty seven young adult male Wistar albino rats were served as experimental subjects. NBM on the right side was destroyed by the injection of kainic acid stereotactically so as to make a model of AD. The grafts were obtained from 14-16 day foetuses of the same genus. After the tissue with cholinergic neurons dissected from ventral forebrain and tissue with non-cholinergic neurons dissected from telencephalic vesicle, cell suspensions were prepared and injected stereotactically to the ipsilateral frontal cortex. Spatial learning and memory functions were tested by Morris’ water maze tasks. Results: Spatial learning and memory functions in rats were impaired by unilateral lesions of nucleus basalis magnocellularis. The impairment observed during the early period partially improved by the time. It was observed that this amelioration was accelerated with both cholinergic and non-cholinergic foetal neural tissue implantation. Conclusion: In our study, improvement of spatial learning and memory impairment with both cholinergic and non-cholinergic foetal neural tissue implantation can be explained by re-establishment of impaired connections via proliferation of limited number of surviving cholinergic neurons creating new synapses, as a result of upregulation of endogenous neural stem cells and activation of trophic mechanisms by implantation, rather than creation of functional synapses between the graft and the recipient tissue.

Objective(s) Diabetes mellitus is associated with disturbances of learning and memory and cognitive functioning. Aegle marmelos Corr. from Rutaceae family is widely used in Iranian folk medicine for the treatment of diabetes mellitus. Considering the beneficial antidiabetic and antioxidant potential of A. marmelos, this study was conducted to evaluate the effect of oral administration of A. marmelos on learning and spatial memory in diabetic rats using Morris water maze test. Materials and Methods Considering the beneficial antidiabetic potential of A. marmelos, this study was conducted to evaluate the effect of chronic oral administration of A. marmelos as cognitive enhancer, on learning and spatial memory in diabetic rats using Morris water maze test. Male Wistar rats were randomly divided into normal-control, diabetic-control, and A. marmelos-treated diabetic groups (100, 250 and 500 mg/kg, p.o.). Animals were treated for 4 weeks by A. marmelos or normal saline. Diabetes was induced by a single dose i.p. injection of streptozotocin (45 mg/kg). In each group of animals, spatial learning and memory parameters were analyzed. Results Clear impairment of spatial learning and memory was observed in diabetic group versus normal-control group. A. marmelos showed dose dependent improvement in spatial learning and memory parameters that swimming time (Escape Latency) in normal-control and A. marmelos-treated diabetic animals rats was significantly (P< 0.01) lower than diabetic-control, while swimming speed was significantly (P< 0.05) higher. Conclusion The study demonstrated that A. marmelos has significant protective affect against diabetes-induced spatial learning and memory deficits. This effect could be attributed to hypoglycemic, hypolipidemic and antioxidant activity of A. marmelos.

Estrogen enhances the retention of spatial reference memory in the open field tower task, but disrupts the expression of spatial memory following a novel start position

Central FGF21 production regulates memory but not peripheral metabolism.