Platform Quadrant Research Articles

Neurological effects of subchronic exposure to dioctyl phthalate (DOP), lead, and arsenic, individual and mixtures, in immature mice.

Dioctyl phthalate (DOP) (200, 500, and 1000 mg kg-1 bw, i.g.), Pb (Ac)2 (50 mg L-1, p.o.), and NaAsO2 (10 mg L-1, p.o.) were administered individually and as mixtures to weanling male mice for 8 weeks. It was observed that Pb, As, and DOP exposure could significantly inhibit the growth and development of mice. Compared with the Pb, As, and Pb + As groups, the activities of iNOS and TNOS were significantly increased, the levels of AChE and SOD were significantly decreased, and the level of MDA was significantly increased in the Pb + DOP-H, As + DOP-H, and Pb + As + DOP-H groups. The factorial analysis shows that the iNOS, TNOS, and AChE present synergistic effects on Pb, As, and DOP. A significant increase of escape latency and a significant decrease of original platform quadrant stops were observed between Pb + As + DOP-H and Pb + As groups. The factorial analysis shows that there was a synergistic effect on Pb, As, and DOP. Compared with that of the control group, the expression levels of caspase-3 and Bax expression in Pb + As, DOP-H, Pb + DOP-H, As + DOP-H, and Pb + As + DOP-H groups were significantly increased in the hippocampus. The expression levels of Bcl-2 expression decreased significantly and the Bax/Bcl-2 ratio increased significantly. Pathological alterations on the hippocampus were found in exposed groups. This result shows that combined exposure of Pb, As, and DOP could induce neurotoxicity, of which possible mechanism is hippocampal neuronal apoptosis. Graphical abstract This study shows that there were three components with eigenvalues greater than 1, which together explained 89.40% of total variance. The first component (PC1) showed high loadings on B-SOD, L-SOD, B-MDA, L-MDA, K-MDA, iNOS, tNOS, and AChE and accounted for 46.55% of the total variance after Varimax rotation. PC2 accounted for 23.81% of the total variance with high loadings on B-As, L-As, K-As, and K-SOD, whereas PC3 showed high loadings on B-Pb, L-Pb, and K-Pb and accounted for 19.04% of the total variance.

Directional cues and landmark configurations: The effect of rotating one set of landmarks relative to another.

In this article we addressed the question whether rats can use distal landmarks as directional cues that are used in combination with other proximal landmark configurations. The animals were trained with an A, B, C, and D landmark configuration in the Morris pool, where B and C are the near (to platform) landmarks and A and D the far ones. We also added another more distal "directional" cue Z (a white strip attached to the black curtain surrounding the pool). Experiment 1a shows a robust detrimental effect on the time spent by the rats swimming in the platform quadrant when the location of all landmarks was "Inverted" (rotated by 180 degrees) with respect to Z. A similar detrimental effect was found when, after the inversion manipulation, the locations of the near and far landmarks were "Flipped" (B swapped with C and A with D). Rats in both Inverted and Flipped tests spent more time in the Z quadrant compared to the platform quadrant (BC). Experiment 1b provided evidence distinguishing between alternative explanations of how the directional cue Z acts in combination with the other landmarks. The results from both experiments show that Z operates differently to the standard landmarks. It can function as a beacon in its own right. It can also combine with the other landmarks to produce a high level of search performance, in a way that we hypothesize to be distinct from that described by the configural analysis often applied to multiple landmarks. (PsycINFO Database Record (c) 2019 APA, all rights reserved).

The seed of Litchi chinensis fraction ameliorates hippocampal neuronal injury in an Aβ25-35-induced Alzheimer’s disease rat model via the AKT/GSK-3β pathway

Context The seed of Litchi chinensis Sonn., a famous traditional Chinese medicine, was recently reported to enhance cognitive function by inhibiting neuronal apoptosis in rats. Objective We determined whether the seed of Litchi chinensis fraction (SLF) can ameliorate hippocampal neuronal injury via the AKT/GSK-3β pathway. Materials and methods We established Alzheimer’s disease (AD) model by infusing Aβ25-35 into the lateral ventricle of Sprague–Dawley (SD) rats and randomly divided into five groups (n = 10): sham, donepezil and SLF (120, 240 and 480 mg/kg/d). Rats were treated by intragastric administration for 28 consecutive days. Spatial learning and memory were evaluated with Morris water maze, while protein expression of AKT, GSK-3β and tau in the hippocampal neurons was measured by Western blotting and immunohistochemistry. Results On the fifth day, escape latency of the AD model group was 45.78 ± 2.52 s and that of the sham operative group was 15.98 ± 2.32 s. SLF could improve cognitive functions by increasing the number of rats that crossed the platform (p < 0.01), and their platform quadrant dwell time (p < 0.05). The protein expression level of AKT was upregulated (p < 0.001), while that of GSK-3β and tau (p < 0.01) was remarkably downregulated in the hippocampal CA1 area. Discussion and conclusions To our knowledge, the present study is the first to show that SLF may exert neuroprotective effect in AD rats via the AKT/GSK-3β signalling pathway, thereby serving as evidence for the potential utility of SLF as an effective drug against AD.

Abnormal brain activity in rats with sustained hypobaric hypoxia exposure: a resting-state functional magnetic resonance imaging study.

Background:Hypobaric hypoxia (HH) exposure at high altitudes can result in a decline in cognitive function, which may have a serious impact on the daily life of people who migrate to high altitudes. However, the specific HH-induced changes in brain function remain unclear. This study explored changes in brain activity in rats exposed to a sustained HH environment using functional magnetic resonance imaging (fMRI).Methods:Healthy male rats (8 weeks old) were randomly divided into a model group and a control group. A rat model of cognitive impairment induced by sustained HH exposure was established. The control and model groups completed training and testing in the Morris water maze (MWM). A two-sample t-test for between-group difference comparisons was performed. Repeated measures analyses of variance for within-group comparisons were performed and post-hoc comparisons were made using the Tukey test. Between-group differences in spontaneous brain activity were assessed using a voxel-wise analysis of resting-state fMRI (rs-fMRI), combined with analyses of the fractional amplitude of low frequency fluctuations (fALFF) in statistical parametric mapping.Results:In the MWM test, the escape latencies of the model group were significantly longer compared with those of the control group (control group vs. model group, day 1: 21.6 ± 3.3 s vs. 40.5 ± 3.4 s, t = –11.282; day 2: 13.5 ± 2.2 s vs. 28.7 ± 5.3 s, t = –7.492; day 3: 10.5 ± 2.8 s vs. 22.6 ± 6.1 s, t = –5.099; day 4: 9.7 ± 2.5 s vs. 18.6 ± 5.2 s, t = –4.363; day 5: 8.8 ± 2.7 s vs. 16.7 ± 5.0 s, t = –3.932; all P < 0.001). Within both groups, the escape latency at day 5 was significantly shorter than those at other time points (control group: F = 57.317, P < 0.001; model group: F = 50.718, P < 0.001). There was no within-group difference in average swimming speed (control group, F = 1.162, P = 0.956; model group, F = 0.091, P = 0.880). Within the model group, the time spent within the original platform quadrant was significantly shorter (control group vs. model group: 36.1 ± 5.7 s vs. 17.8 ± 4.3 s, t = 7.249, P < 0.001) and the frequency of crossing the original platform quadrant was significantly reduced (control group vs. model group: 6.4 ± 1.9 s vs. 2.0 ± 0.8 s, t = 6.037, P < 0.001) compared with the control group. In the rs-fMRI study, compared with the control group, rats in the model group showed widespread reductions in fALFF values throughout the brain.Conclusions:The abnormalities in spontaneous brain activity indicated by the fALFF measurements may reflect changes in brain function after HH exposure. This widespread abnormal brain activity may help to explain and to provide new insights into the mechanism underlying the impairment of brain function under sustained exposure to high altitudes.

Effect of Hydrogen-Rich Water on Radiation-Induced Cognitive Dysfunction in Rats.

The goal of this work was to determine whether hydrogen-rich water (HRW) could attenuate radiation-induced cognitive dysfunction in rats and to explore the underlying mechanisms. Rats received 30 Gy whole-brain irradiation using a 6-MeV electron beam. Either purified water or HRW (0.8-0.9 ppm) was administrated at 10 min prior to irradiation, as well as a daily HRW treatment after irradiation for 30 consecutive days. The Morris water maze was used to test spatial memory in the rats. The concentration of glutathione (GSH), malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG) and the super-oxidedismutase (SOD) activity in cerebral cortex, as well as brain-derived neurotrophic factor (BDNF) level in serum, were measured. Immunofluorescence staining was adopted to detect proliferating cells. The expression of BDNF-TrkB pathway-related genes and proteins were detected using qRT-PCR and Western blot. Models of cognitive dysfunction were successfully established using a 30 Gy dose of ionizing radiation. Compared to the radiation treated group, the radiation-HRW treated group showed significantly decreased escape latency (P < 0.05), but increased retention time, swimming distance of original platform quadrant (P < 0.05) and number of platform crossings (P < 0.05). Furthermore, the SOD, GSH (P < 0.05) and BDNF (P < 0.05) levels in the radiation-HRW treated group were higher compared to the radiation treated group. The MDA and 8-OHdG levels (P < 0.05) were decreased in the radiation-HRW treated group when compared to the radiation treated group. Additionally, treatment with HRW increased the number of BrdU+NeuN+ cells in the radiation treated group. The mRNA and protein levels of BDNF and TrkB (P < 0.05) in radiation-HRW treated group was higher than that in the radiation treated group. Collectively, our study indicates that HRW has a protective effect on radiation-induced cognitive dysfunction, and that the possible mechanisms mainly involve anti-oxidative and anti-inflammatory reactions, and its protection of newborn neurons by regulating the BDNF-TrkB signaling pathway.

Deferiprone ameliorates memory impairment in Scopolamine-treated rats: The impact of its iron-chelating effect on β-amyloid disposition

Alzheimer’s disease (AD) is a neurodegenerative disease characterized by cognitive and memory problems. Scopolamine (SCOP) is a natural anticholinergic drug that was proven to cause memory impairment in rats. Chelating agents are potential neuroprotective and memory enhancing agents as they can trap iron that enters in pathological deposition of β-amyloid (Aβ) which is a hallmark in AD and memory disorders. This study investigated the potential neuroprotective and memory enhancing effects of the iron chelating drug, Deferiprone. Three doses (5, 10, and 20 mg/kg) were administered to rats treated with SCOP (1.14 mg/kg/day). Systemic administration of SCOP for seven days caused memory impairment which manifested as decreased time spent in platform quadrant in Morris water maze test, decreased retention latencies in passive avoidance test, and increased acetylcholinesterase (AChE) activity, Aβ, and free iron deposition. It was observed that pretreatment with Deferiprone increased platform quadrant time in Morris water maze and increased retention latencies in the passive avoidance test. It also attenuated the increase in AChE activity and decreased Aβ and iron deposition. Overall, Deferiprone (10 mg/kg) was determined as the most effective dose. Therefore, this study suggests neuroprotective and memory enhancing effects for Deferiprone in SCOP-treated rats which might be attributed to its iron chelating action and anti-oxidative effect.

Role of NR2B in sevoflurane anesthesia-induced cognitive dysfunction in aged rats

Objective To evaluate the role of 2B-containing NMDA receptors (NR2B) in sevoflurane anesthesia-induced cognitive dysfunction in aged rats. Methods Thirty-two healthy male Sprague-Dawley rats, aged 18 months, weighing 570-630 g, were divided into 4 groups (n=8 each) using a random number table method: control group (group C), sevoflurane anesthesia group (group S), sevoflurane anesthesia plus NR2B specific inhibitor Ro 25-6981 group (group S+ RO) and Ro 25-6981 group (group RO). S and S+ RO groups inhaled 3% sevoflurane for 4 h. Ro 25-6981 1 mg/kg was intraperitoneally injected at 15 min before inhaling sevoflurane in group S+ RO.Morris water maze test was performed at 2 days after the end of anesthesia to assess cognitive function.The rats were then sacrificed, and hippocampal tissues were obtained for determination of the expression and phosphorylation of ERK1/2 by Western blot. Results Compared with group C, the escape latency was significantly prolonged, the frequency of crossing the original platform was reduced, the time of staying at the original platform quadrant was shortened, and the phosphorylation of ERK1/2 was decreased in group S (P 0.05). Compared with group S, the escape latency was significantly shortened, the frequency of crossing the original platform was increased, the time of staying at the original platform quadrant was prolonged, and the phosphorylation of ERK1/2 was increased in group S+ RO(P 0.05). Conclusion The mechanism by which sevoflurane anesthesia induces cognitive dysfunction is related to up-regulating the expression of NR2B and inhibiting the activity of ERK1/2 in aged rats. Key words: Receptors, N-methyl-D-aspartate; Anesthetics, inhalation; Cognition disorders; Aged

The dual orexinergic receptor antagonist DORA-22 improves the sleep disruption and memory impairment produced by a rodent insomnia model.

Insomnia-related sleep disruption can contribute to impaired learning and memory. Treatment of insomnia should ideally improve the sleep profile while minimally affecting mnemonic function, yet many hypnotic drugs (e.g. benzodiazepines) are known to impair memory. Here, we used a rat model of insomnia to determine whether the novel hypnotic drug DORA-22, a dual orexin receptor antagonist, improves mild stress-induced insomnia with minimal effect on memory. Animals were first trained to remember the location of a hidden platform (acquisition) in the Morris Water Maze and then administered DORA-22 (10, 30, or 100 mg/kg doses) or vehicle control. Animals were then subjected to a rodent insomnia model involving two exposures to dirty cages over a 6-hr time period (at time points 0 and 3 hr), followed immediately by a probe trial in which memory of the water maze platform location was evaluated. DORA-22 treatment improved the insomnia-related sleep disruption-wake was attenuated and NREM sleep was normalized. REM sleep amounts were enhanced compared with vehicle treatment for one dose (30 mg/kg). In the first hour of insomnia model exposure, DORA-22 promoted the number and average duration of NREM sleep spindles, which have been previously proposed to play a role in memory consolidation (all doses). Water maze measures revealed probe trial performance improvement for select doses of DORA-22, including increased time spent in the platform quadrant (10 and 30 mg/kg) and time spent in platform location and number of platform crossings (10 mg/kg only). In conclusion, DORA-22 treatment improved insomnia-related sleep disruption and memory consolidation deficits.

Effects of Euterpe oleracea to Enhance Learning and Memory in a Conditioned Nicotinic and Muscarinic Receptor Response Paradigm by Modulation of Cholinergic Mechanisms in Rats.

Euterpe oleracea (EO) includes a large number of polyphenolic compounds such as phenolics, flavonoids, and anthocyanins that have antioxidant activities. E. oleracea was suggested to ease the oxidative stress and inflammation in brain cells. Our aim was to analyze the effects of E. oleracea on learning and memory. Seventy-two (250 ± 25 g) male Wistar albino rats were used for this study. The groups consisted of control, EO100 mg/kg, EO300 mg/kg, scopolamine 1.5 mg/kg, mecamylamine 7.5 mg/kg, combinations of scopolamine with EO100 mg/kg, EO300 mg/kg, and rivastigmine 1.5 mg/kg; and mecamylamine combined with EO100 mg/kg. Before the start of the study, E. oleracea doses were provided once a day for a period of 15 days and for a 6-day experimental period. Thirty minutes after intraperitoneal scopolamine and mecamylamine injections, gastrogavage was applied to each group. Ninety minutes after the drug treatments, locomotor activity and Morris water maze tests were performed. Rats were killed and each hippocampus was used for the quantification of acetylcholine (Ach). Statistical analyses were calculated using one-way and two-way analyses of variance (ANOVA), and a value of P < .05 was considered significant. In groups EO100 mg/kg and EO300 mg/kg the results did not show any significant changes on learning and memory compared with the control group. Mecamylamine and scopolamine enhanced the latency for the escape platform, and decreased the time spent in escape platform quadrant when the memory tests were applied in reference to the control value of P < .05. Scopolamine and mecamylamine combinations of EO100 mg/kg, EO300 mg/kg, and rivastigmine were proven to improve the memory. There was significant difference between the first and fifth days of the learning tests in all the groups, but no significant difference occurred between the groups. Ach levels in hippocampi supported all memory tests. We suggest that E. oleracea made no alterations on learning and memory, but still improved nicotinic and muscarinic receptor-mediated and impaired memory just as rivastigmine.

Effect of Piper betel leaf extract on learning and memory in Aluminium chloride induced Alzheimer’s disease in Wistar rats

Alzheimer's disease is a common neurological disorder affecting a significant proportion of the elderly population.There are only a few drugs which can be used safely to treat it. We sought to investigate for the first time Piper betel leaf, a postmeal mouth freshener for its potential use in Alzheimer's disease. Five groups of male Wistar rats with six rats in each group aged 10-12 weeks were used. The control group received the distilled water, aluminium chloride (AlCl3) group was treated with AlCl3, the standard group was treated with rivastigmine with AlCl3, and the two test groups received piper betel leaf extract (PBE) at doses of 400mg/kg and 500mg/kg body weight with AlCl3. AlCl3 was administered orally for 42 days in all the treated groups. Memory and learning were evaluated by Morris water maze test and Passive avoidance test.The results of the Morris water maze test showed reduced mean escape latency period in all the groups on trial day three (P≤0.05) and on trial day four (P ≤0.01) compared to AlCl3 group. The retention of spatial memory by probe trial showed that PBE and rivastigmine treated group spent more time in the target (platform) quadrant when compared to AlCl3 group (P≤0.01). The passive avoidance test showed a significant increase in step through latency in standard and test groups compared to the AlCl3 treated group. The weight of the rats treated with AlCl3 and PBE was reduced at the end of the treatment period while increased in standard and control group. The study shows the beneficial effects of Piper betel leaves in Alzheimer’s disease by significantly improving the learning and memory functions in rats.

Role of JNK Signaling Pathway in Dexmedetomidine Post-Conditioning-Induced Reduction of the Inflammatory Response and Autophagy Effect of Focal Cerebral Ischemia Reperfusion Injury in Rats.

To investigate the effect of dexmedetomidine post-conditioning on the inflammatory response and autophagy effect of focal cerebral ischemia reperfusion injury in rats, and further to study its potential mechanisms. Water maze was conducted to evaluate spatial learning and memory ability of middle cerebral artery occlusion (MCAO) rats. TTC staining was used to observe the area of cerebral infarction. The expressions of inflammatory factors in serum were detected by ELISA. TUNEL assay, HE staining, and transmission electron microscopy were used to detect the apoptosis of neurons, neuro-cytopathic changes, and the formation of auto-phagosome in hippocampus CA1 region, respectively. The mRNA and protein expression of Beclin-1, Caspase-3, and light chain 3 (LC3) were detected by qRT-PCR and Western blot. Moreover, the activity of C-Jun N-terminal kinase (JNK) pathway was detected by Western blot. The escape latency (EL); cerebral infarction area ratio; positive apoptosis; neuron pathological changes; auto-phagosome numbers; inflammatory factor contents; mRNA and protein expressions of Beclin-1, Caspase-3 and LC3II/I; and the phosphorylation level of JNK were decreased, while the times across platform and the times stayed in the quadrant of the original platform were increased after dexmedetomidine treatment. However, the protective effect of dexmedetomidine on brain injury in MCAO rats was reversed by JNK pathway activator. Dexmedetomidine post-conditioning could improve learning and memory dysfunction caused by MCAO in rats and reduce the inflammatory response and autophagy effect. The mechanism may be related to inhibition of JNK pathway activation.

Polyethylene glycol-conjugated human adrenomedullin as a possible treatment for vascular dementia

Adrenomedullin (AM) is a multifunctional bioactive peptide. Recent studies have shown that AM has protective effects against ischemic brain damage. We recently prepared a long-acting human AM derivative that was conjugated with a 60 kDa polyethylene glycol (PEG-AM), which had an effect similar to that of native AM. In this study, we examined the effect of PEG-AM on four-vessel occlusion model rats, which exhibit vascular dementia. From day 10 to day 14 after surgery, the learning and memory abilities of the rats were examined using a Morris water maze. The rats were treated with a single subcutaneous injection of 1.0 or 10.0 nmol/kg of PEG-AM. PEG-AM treatment reduced the escape latency in the hidden platform test. Furthermore, the treatment increased the time spent in the platform quadrant in the probe test. The data showed that PEG-AM injection prevented memory loss and learning disorders in dose-dependent manner. On day 14, the immunoreactive AM concentration in plasma was 9.749 ± 2.167 pM in the high-dose group (10.0 nmol/kg) and 0.334 ± 0.073 pM in the low-dose group (1.0 nmol/kg). However, even in the low-dose group, a significant effect was observed in both tests.The present data indicate that PEG-AM is a possible therapeutic agent for the treatment of ischemic brain injury or vascular dementia.

Effects of hypoxic-induced bone marrow mesenchymal stem cells on motor and cognitive function in rats with craniocerebral trauma

Objective To explore the effects of hypoxic-induced bone marrow mesenchymal stem cells (BMSCs) on motor and cognitive function in rats with craniocerebral trauma. Methods 18 adult Wistar rats were randomly divided into 3 groups, Group A, Group B, Group C and another 6 normal rats were taken as the normal control group. The Morris water maze test was performed on 21, 23 and 25 days after injection of BMSCs or dulbeeeo modified eagle medium (DMEM) solution, including the location-based navigation test and the spatial search test. Hematoxylin (HE) staining was performed on the hippocampus tissue after the experiment. Western blotting was used to detect the expression of apoptotic marker protein. Results The incubation period of rats in the four groups showed a decreasing trend with time (F=22.460, P 0.05). The space search experiment shows that the number of crossing in the group C and the swimming time in the platform quadrant were higher than those in the group A and B, but lower than the control group (F=198.670, P<0.01; F=4.615, P<0.05). The observation results of hematoxylin and eosin (HE) staining showed that there was a decrease in the number of nucleus parenchyma neurons in the hippocampal area in group A. There were significant differences in group B and C compared to group A. Westernblotting results indicated that group C had better anti-apoptotic effect than group B [(0.51±0.13) vs. (0.86±0.21), t=3.471, P<0.05]. PCR results indicated that group C had better anti-apoptotic effect than group B [(0.41±0.08) vs. (0.78±0.13), t=5.937, P<0.01]. Conclusion BMSCs induced by hypoxic conditions have better effects on motor and cognitive function in rats with craniocerebral trauma than normal oxygen induction. Key words: Bone marrow mesenchymal stem cells; Craniocerebral injury; Rat; Low oxygen

Nigella sativa oil protected the hippocampus against Acetyl cholinesterase and oxidative dysfunctions-driven impaired working memory in rats

Oxidative damages in organophosphates poisoning is associated with neuro-cognitive deficits. This study investigates the protective effect of Nigella sativa oil (NSO) in mitigating dichlorvos (DDVP) induced oxidative damage and neuro-cognitive impairment in rats. Thirty-two rats were randomly divided into four groups, exposed to 1 ml/kg of normal saline, 8.8 mg/kg of DDVP, DDVP + 1 ml/kg of NSO and NSO respectively for 14 consecutive days. Body weights were recorded at day 1 and 15 of the experiment, the rats were exposed to 3 trials each on the 11, 12 and 13th days in the Morris water maze, and subsequently latency to hidden platform and time in the platform quadrant were recorded as measures of long term memory (LTM), short term memory (STM) and reference memory on the 14th day. The rats were euthanized on the 15th day, the brains excised and the hippocampi of five brains in each group were removed, homogenized to analyze for total reactive oxygen species (ROS), nitrous oxide (NO) levels and acetylcholinesterase (AChE) activities, while the other three were processed for histology and Ki67 immunohistochemistry. DDVP exposure caused a significant increase in hippocampal NO and ROS levels, with reductions in AChE activities and Ki67 protein expression. This was associated with delayed escape latency and reduced time in platform quadrant. NSO intervention prevented outburst in ROS and NO, preserved the neurogenic cells and improved neuro-cognitive indices. We thus conclude that stabilizing oxidative and neurogenic functions are vital to protect against DDVP hippocampal insults.

Dibutyryl cAMP Enhances Cognitive Functions in Diabetic Rats by Increasing the Hippocampal Neurogenesis

Dibutyryl cyclic adenosine monophosphate (dBcAMP) is a cell‐permeable synthetic analog of cyclic adenosine monophosphate (cAMP) known to acts as an intracellular second messenger for neurotransmitters and hormones. dBcAMP enhances differentiation and survival of neurons from neuronal stem cells, differentiation of mesenchymal stromal cell into neurons and stimulates the differentiation of astrocytes and contribute to neuroprotection in neural tissue injury.Diabetes, a chronic metabolic disease has adverse effects on adult hippocampal neurogenesis and cognitive function. Even though, dBcAMP is used as a therapeutic agent in some disease models, it has not been used in diabetes. Present experiment was aimed to study the effects of dBcAMP on learning and memory and adult neurogenesis, in streptozotocin model of diabetic rats. Diabetes was induced in male Wistar rats (3 months old) by injecting streptozotocin (ip, 50mg/kg) into the peritoneal cavity. After confirming the diabetic condition (hyperglycemia) in these rats after 48hrs of STZ injection, they were grouped into diabetic (DI) and diabetic+dBcAMP (DI+dBcAMP groups. Age matched normal rats served as control group (C). DI+dBcAMP group were treated with dBcAMP (ip,10mg/kg) intraperitoneally for 10 days and C and DI groups were be treated with PBS for the same duration. After treatment, animals in all groups were subjected to learning and memory test in Morris water maze from day21 to day27 of the experiment to assess the cognitive function. After the behavioral test rats (n=6 in all groups) were sacrificed on day 30. Fresh hippocampal tissue were collected for ELISA (for BDNF, brain derived neurotrophic factor), and Western blot (for doublecortin, DCX) analysis. Rats (n=6 in all groups), were be perfused with 4% paraformaldehyde and hippocampi were collected for immunostaining (DCX). Number of DCX positive neurons were quantified in the hippocampal dentate gyrus. Data were analyzed by One/Two –way ANOVA, followed by Bonferroni's multiple comparison test. Results showed a significant memory deficit (decreased time spent and distance traveled in platform quadrant) in DI rats compared to C (p&lt;0.001, One way ANOVA), and memory was significantly increased in DI+ dBcAMP compared to DI group (p&lt;0.001). Analysis of number of DCX positive neurons in the dentate gyrus (neurogenesis) showed a significant decrease in neurogenesis in DI group compared to C group (p&lt;0.001, One‐way ANOVA) and it was significantly increased in DI+dBcAMP (p&lt;0.001, One‐way ANOVA). Western blot analysis for DCX showed significant increase in DI+ dBcAMP group (p&lt;0.01) and hence confirmed the DCX positive neuron count data. Analysis of BDNF levels in the hippocampus of the DI+dBcAMP was found to be significantly increased compared to DI group (p&lt;0.01). We conclude that dBcAMP enhances cognitive functions in diabetic rats by increasing the Hippocampal BDNF levels and hence enhanced neurogenesis. Thus dBcAMP may be a potential molecule to be considered in treatment of diabetic patients to prevent the cognitive deterioration.Support or Funding InformationCollege of Graduate Studies and Research Sector, Kuwait UniversityThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Effects of leptin on brain injury and long-term cognitive function in rats undergoing orthotopic liver transplantation

Objective To evaluate the effects of leptin on brain injury and long-term cognitive function in rats undergoing orthotopic liver transplantation. Methods Ninety clean-grade male Sprague-Dawley rats, aged 3 months, weighing 200-250 g, were divided into 3 groups by a random number table method: sham operation group(S group), liver ischemia-reperfusion(I/R) group(I/R group) and leptin group(L group), with 18 rats in each group.Orthotopic liver transplantation was performed to establish the model of liver I/R injury in I/R and L groups.Leptin 1 mg/kg was intraperitoneally injected at the onset of ischemia in L group, and the equal volume of normal saline was given instead of leptin in S and I/R groups.Twelve rats in each group were sacrificed at 3 days after operation, and brains were removed for examination of the pathological changes in hippocampal CA1 region(with a light microscope) and for determination of apoptosis in hippocampal neurons(by TUNEL assay) and expression of aquaporin 4(AQP4) and protein kinase C(PKC) in the hippocampus(by Western blot). The apoptosis rate was calculated.The remaining 6 rats in each group underwent a Morris water maze test at 30 days after surgery to evaluate long-term cognitive function. Results Compared with S group, the apoptosis rate of hippocampal neurons was significantly increased, the expression of AQP4 and PKC was up-regulated, the escape latency was prolonged, and the time of staying at the platform quadrant was shortened in I/R and L groups(P<0.05). Compared with I/R group, the apoptosis rate of hippocampal neurons was significantly decreased, the expression of AQP4 and PKC was down-regulated, the escape latency was shortened, and the time of staying at the platform quadrant was prolonged in L group(P<0.05). Conclusion Leptin can reduce the brain damage in rats undergoing orthotopic liver transplantation, the mechanism may be related to down-regulating the expression of PKC and AQP4, and leptin can also improve long-term cognitive function after orthotopic liver transplantation in rats. Key words: Leptin; Liver transplantation; Reperfusion injury; Cognition disorders

Acupuncture plus moxibustion intervention improves learning-memory ability by suppressing hippocampal JAK2/STAT3 signaling in Alzheimer's rats

To investigate the effect of acupuncture plus moxibustion on learning-memory ability and expression of hippocampal Janus kinase-2 (JAK2)/signal transducer and activator of transcription-3 (STAT3)/suppressors of cytokine signaling-3 (SOCS3) signaling in Alzheimer's Disease (AD) rats, so as to reveal their mechanisms underlying improvement of AD. A total of 60 SD rats were randomly divided into four groups：normal control, sham-operation, model and acupuncture-moxibustion (Acu-moxi, n＝15 in each group) groups. The AD model was established by microinjection of β-amyloid 1-42(Aβ1-42，5 µL)into the bilateral hippocampus. Seven days after modeling, Acu-moxi intervention was given. After insertion of acupuncture needles into "Baihui" (GV20) and bilateral "Shenshu" (BL23) and manipulating them for a while, the needles were then retained for 15 min, when, the mild moxibustion was performed at the same time. The treatment was conducted once daily, 5 times a week for consecutive 4 weeks. After the treatment, Morris water maze test was used to detect the animals' learning-memory ability. Immunohistochemistry and Western blot were respectively used to detect the number of positive cells and protein expression levels of JAK2, STAT3 and SOCS3 in the hippocampus tissue. Following modeling and compared with the normal control and sham-operation groups, the average escape latency was significantly prolonged (P<0.01), and the number of the original platform crossing and the residence time in the platform quadrant were significantly shortened in the model group (P<0.01). The numbers of hippocampal JAK2- and STAT3-positive cells and expression levels of hippocampal JAK2 and STAT3 proteins were significantly increased (P<0.01), and the number of hippocampal SOCS3-positive cells as well as the expression of SOCS3 protein significantly decreased in the model group relevant to the normal control and sham-operation groups (P<0.01). After the intervention, the average escape latency was significantly shortened (P< 0.01), and the number of the original platform crossing and the residence time in the platform quadrant were significantly increased in the Acu-moxi group (P<0.01), and the expression levels of JAK2 and STAT3 were significantly down-regulated and that of SOCS3 was considerably up-regulated in the Acu-moxi group relevant to the model group (P<0.01)．. Acu-moxi intervention can improve the learning-memory ability in AD rats, which is associated with its functions in inhibiting hippocampal JAK2/STAT3 signaling and up-regulating SOCS3 (a negative feedback factor) protein level.

Adolescent fluoxetine history impairs spatial memory in adult male, but not female, C57BL/6 mice

BackgroundEpidemiological reports indicate that mood-related disorders are common in the adolescent population. The prevalence of juvenile major depressive disorder has resulted in a parallel increase in the prescription rates of fluoxetine (FLX) within this age group. Although such treatment can last for years, little is known about the enduring consequences of adolescent antidepressant exposure on memory-related performance. MethodsWe exposed separate groups of adolescent (postnatal day [PD] 35) male and female C57BL/6 mice to FLX (20 mg/kg) for 15 consecutive days (PD35-49). Three weeks after FLX exposure (PD70), we assessed learning and memory performance on a single-day training object novelty recognition test, or a spatial memory task on the Morris water maze (MWM). ResultsWe found that FLX pretreatment did not influence performance on either the object novelty recognition task or the MWM, 24 h after training. Conversely, 48 h post spatial-training on the MWM, FLX pretreated male mice spent significantly less time on the quadrant of the missing platform during a standard probe trial. No differences in MWM performance were observed in the adult female mice pretreated with FLX. LimitationsA limitation of this study is that normal adolescent mice (i.e., non-stressed) were evaluated for memory-related behavior three weeks after antidepressant exposure. Thus, it is possible that FLX pre-exposure in combination with animal models for the study of depression may yield different results. ConclusionTogether, these results demonstrate enduring spatial memory-related deficiencies after pre-exposure to FLX during adolescence in male, but not female, C57BL/6 mice.

Manual Acupuncture Regulates Behavior and Cerebral Blood Flow in the SAMP8 Mouse Model of Alzheimer's Disease.

Background: A growing body of evidence has demonstrated that cerebrovascular function abnormality plays a key role in occurrence and worsening of Alzheimer’s disease (AD). Reduction of cerebral blood flow (CBF) is a sensitive marker to early perfusion deficiencies in AD. As one of the most important therapies in complementary and alternative medicine, manual acupuncture (MA) has been used in the treatment of AD. However, the moderating effect of MA on CBF remains largely unknown.Objective: To investigate the effect of MA on the behavior and CBF of SAMP8 mice.Methods: SAMP8 mice were randomly divided into the AD, MA, and medicine (M) groups, with SAMR1 mice used as the normal control (N) group. Mice in the M group were treated with donepezil hydrochloride at 0.65 μg/g. In the MA group, MA was applied at Baihui (GV20) and Yintang (GV29) for 20 min. The above treatments were administered once a day for 15 consecutive days. The Morris water maze and arterial spin labeling MRI were used to assess spatial learning and memory in behavior and CBF respectively.Results: Compared with the AD group, both MA and donepezil significantly decreased the escape latency (p < 0.01), while also elevating platform crossover number and the percentage of time and swimming distance in the platform quadrant (p < 0.01 or p < 0.05). The remarkable improvement in escape latency in the MA group appeared earlier than the M group, and no significant statistical significance was observed between the N and MA group with the exception of days 5 and 10. The CBF in the prefrontal lobe and hippocampus in the MA group was substantially higher than in the AD group (p < 0.05) with the exception of the right prefrontal lobe, with similar effects of donepezil.Conclusion: Manual acupuncture can effectively improve the spatial learning, relearning and memory abilities of SAMP8 mice. The increase in CBF in the prefrontal lobe and hippocampus could be an important mechanism for the beneficial cognitive effects of MA in AD.

The effects and mechanisms of the action of galangin on spatial memory in rats.

Galangin, a flavonoid compound with acetylcholinesterase inhibitory activity, may improve cognitive functions by enhancing cholinergic transmission. We aimed to investigate the effects of galangin on spatial memory impairment in rats. The effects of galangin (50 and 100 mg/kg) and reference anti-dementia drug donepezil (1mg/kg) administrations were examined on memory impairment induced by the muscarinic cholinergic receptor antagonist scopolamine or the nicotinic cholinergic receptor antagonist mecamylamine in the Morris water maze (MWM) test. Hippocampal acetylcholine concentrations were also determined. Galangin 50 and 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in scopolamine-treated rats. Galangin 100 mg/kg significantly decreased the mean distance to platform and increased the time spent in the escape platform quadrant in mecamylamine-treated rats. The effects of galangin in the MWM were comparable with donepezil. Scopolamine and mecamylamine decreased acetylcholine concentrations, whereas galangin both alone and with mecamylamine or scopolamine administration increased acetylcholine concentrations. Galangin improved memory impairment comparable to donepezil and nicotinic and muscarinic receptors may be involved in this effect. Galangin may be considered as a promising flavonoid in the prevention and treatment of memory impairment in Alzheimer's disease and other dementias (Fig. 7,Ref. 37).