Fermented seeds of Pentaclethra macrophylla mitigate against memory deficit and restored altered enzymatic activity in the brain of streptozotocin-diabetic rats.

Memory deficit has been reported as one of the complications of diabetes. Fermented seeds of Pentaclethra Macrophylla (P. macrophylla) have been used in folklore for the management of metabolic diseases. The research aims to evaluate the impact of diets with the inclusion of the fermented seed of P. macrophylla on memory deficit in diabetic rats and its underlying mechanisms. Before the induction, the rats were subjected to training sessions. Thereafter, streptozotocin (50 mg/kg body weight) was administered to the trained rats via intraperitoneal (i.p). 72 hours after, the rats blood glucose level was checked, rats with blood glucose level greater than 250 mg/dl were selected for the memory index evaluation study. The induced rats were randomly distributed into groups: Normal rats (group 1), untreated diabetic rat (Group 2), acarbose treated diabetic rats (group 3); diabetic rats placed on diet supplemented with fermented seed of P. macrophylla (10 & 20% inclusion) were allotted to group 4 & 5. Then, evaluation of memory retention capacity was performed on the day 14 of the experiment. Thereafter, experimental rats were sacrificed, tissue of interest (brain) was excised, homogenized and homogenates were used for biochemical analysis. The cholinergic, angiotensin-1-converting enzyme (ACE), arginase activity and biomarkers for oxidative stress were significantly altered in untreated diabetic rats when compared with non-diabetes rats. Also, the memory capacity of the diabetic rats was significantly reduced when compared with the non-diabetes rats. Meanwhile, diabetic rats placed on diet with fermented seeds of P. macrophylla (10 & 20% inclusion) exhibited significantly higher memory capacity, lower activity of cholinergic, ACE, arginase activity in relation to untreated diabetic rats while the antioxidant status of the brain was enhanced. Nevertheless, fermented seeds of P. macrophylla ameliorated memory deficit in STZ induced diabetes rats. This gave credence to P. macrophylla nutraceutical potential as claimed in folk medicine.

Mitigation of Memory Impairment with Fermented Fucoidan and λ-Carrageenan Supplementation through Modulating the Gut Microbiota and Their Metagenome Function in Hippocampal Amyloid-ß Infused Rats.

Attenuating acetylcholinesterase and insulin/insulin-like growth factor-1 signaling in the hippocampus is associated with Alzheimer's disease (AD) development. Fucoidan and carrageenan are brown and red algae, respectively, with potent antibacterial, anti-inflammatory, antioxidant and antiviral activities. This study examined how low-molecular-weight (MW) and high-MW fucoidan and λ-carrageenan would improve memory impairment in Alzheimer's disease-induced rats caused by an infusion of toxic amyloid-ß(Aß). Fucoidan and λ-carrageenan were dissected into low-MW by Luteolibacter algae and Pseudoalteromonas carrageenovora. Rats receiving an Aß(25-35) infusion in the CA1 region of the hippocampus were fed dextrin (AD-Con), 1% high-MW fucoidan (AD-F-H), 1% low-MW fucoidan (AD-F-L), 1% high-MW λ-carrageenan (AD-C-H), and 1% low-MW λ-carrageenan (AD-C-L) for six weeks. Rats to receive saline infusion (Normal-Con) had an AD-Con diet. The AD-F-L group showed an improved memory function, which manifested as an enhanced Y-maze spontaneous alternation test, water maze, and passive avoidance tests, similar to the Normal-Con group. AD-F-L also potentiated hippocampal insulin signaling and increased the expression of ciliary neurotrophic factor (CNTF) and brain-derived neurotrophic factor (BDNF) in the hippocampus. AD-C-L improved the memory function mainly by increasing the BDNF content. AD-F-H and AD-C-H did not improve the memory function. Compared to AD-Con, the ascending order of AD-C-H, AD-F-H, AD-C-L, and AD-F-L increased insulin signaling by enhancing the pSTAT3®pAkt®pGSK-3ß pathway. AD-F-L improved glucose tolerance the most. Compared to AD-CON, the AD-F-L treatment increased the serum acetate concentrations and compensated for the defect of cerebral glucose metabolism. AD-Con increased Clostridium, Terrisporobacter and Sporofaciens compared to Normal-Con, and AD-F-L and AD-C-L increased Akkermentia. In conclusion, AD-F-L and AD-C-L alleviated the memory function in the rats with induced AD symptoms by modulating.

Formulated Chinese medicine Shaoyao Gancao Tang reduces NLRP1 and NLRP3 in Alzheimer's disease cell and mouse models for neuroprotection and cognitive improvement.

Amyloid ß (Aß) plays a major role in the neurodegeneration of Alzheimer's disease (AD). The accumulation of misfolded Aß causes oxidative stress and inflammatory damage leading to apoptotic cell death. Traditional Chinese herbal medicine (CHM) has been widely used in treating neurodegenerative diseases by reducing oxidative stress and neuroinflammation. We examined the neuroprotective effect of formulated CHM Shaoyao Gancao Tang (SG-Tang, made of Paeonia lactiflora and Glycyrrhiza uralensis at 1:1 ratio) in AD cell and mouse models. In Aß-GFP SH-SY5Y cells, SG-Tang reduced Aß aggregation and reactive oxygen species (ROS) production, as well as improved neurite outgrowth. When the Aß-GFP-expressing cells were stimulated with conditioned medium from interferon (IFN)-γ-activated HMC3 microglia, SG-Tang suppressed expressions of inducible nitric oxide synthase (iNOS), NLR family pyrin domain containing 1 (NLRP1) and 3 (NLRP3), tumor necrosis factor (TNF)-α, interleukin (IL)-1ß and IL-6, attenuated caspase-1 activity and ROS production, and promoted neurite outgrowth. In streptozocin-induced hyperglycemic APP/PS1/Tau triple transgenic (3×Tg-AD) mice, SG-Tang also reduced expressions of NLRP1, NLRP3, Aß and Tau in hippocampus and cortex, as well as improved working and spatial memories in Y maze and Morris water maze. Collectively, our results demonstrate the potential of SG-Tang in treating AD by moderating neuroinflammation.

[Non-aphasic misnaming: a case report and literature review].

A 71-year-old, right-handed woman was admitted to our hospital due to a sudden difficulty with conversation. On admission, she was alert, but had a euphoric mood, disorientation, and a disturbance of recent memory. Her speech was fluent. Her repetition and auditory word cognition were excellent, but she had a slight difficulty with naming visual objects. She frequently showed word-finding difficulty and irrelevant paraphasia during free conversation and a word fluency task. Her irrelevant paraphasia was observed more frequently when she was asked to explain her outbreak of anger at the hospital, i.e., it was situation-dependent. She also had anosognosia. MRI showed an infarct in the territory of the left tuberothalamic artery. Single-photon emission computed tomography revealed low-uptake lesions in the left thalamus and orbital frontal, medial frontal, and medial temporal lobes. The patient was diagnosed with non-aphasic misnaming. The clinical characteristics of patients with non-aphasic misnaming in the literature were reviewed. All of the patients with non-aphasic misnaming had word-finding difficulty and irrelevant paraphasia. Additionally, they had either emotional disturbance or anosognosia.

Chronic nanocurcumin treatment ameliorates pain-related behavior, improves spatial memory, and reduces hippocampal levels of IL-1ß and TNFα in the chronic constriction injury model of neuropathic pain.

BACKGROUND: Memory deficit is a common cognitive comorbid in patients with neuropathic pain that need better treatment. Recent research revealed that nanocurcumin has an antinociceptive action and a protective effect against memory disorders, suggesting its possible effectiveness for the treatment of neuropathic pain and its comorbidity. METHODS: Adult male albino Wistar rats (n = 32) were randomly divided into four experimental groups: CCI+ nanocurcumin, CCI + vehicle, sham + nanocurcumin, and sham + vehicle. Neuropathic pain induced by a chronic constriction injury of the sciatic nerve. Nanocurcumin or vehicle was injected intraperitoneally for 10 days. Behavioral assessment achieved to evaluate pain threshold in the von Frey test and radiant heat test, also spatial learning and memory examined by the Morris water maze (MWM) test. To explore the possible relation, IL-1ß, and TNF-α levels of the hippocampus measured by enzyme-linked immunosorbent assay (ELISA). RESULTS: Our data showed that CCI caused neuropathic pain-related behaviors and spatial learning and memory disorders in rats. Chronic treatment with nanocurcumin significantly increased pain threshold (P < 0.001; F = 27.63, F = 20.58), improved spatial memory (P < 0.01; F = 47.37), and decreased the hippocampal levels of IL-1ß (P < 0.001; F = 33.57) and TNF-α (P < 0.01; F = 7.25) in CCI rats. CONCLUSION: Chronic nanocurcumin can ameliorate pain-related behavior, improve spatial learning and memory deficits, and is associated with the reduction of IL-1ß and TNF-α levels in the hippocampus in CCI rats. Nanocurcumin may be potentially providing a therapeutic alternative for the treatment of neuropathic pain and its memory impairment comorbidity.

A new mouse line with reduced GluA2 Q/R site RNA editing exhibits loss of dendritic spines, hippocampal CA1-neuron loss, learning and memory impairments and NMDA receptor-independent seizure vulnerability.

Calcium (Ca2+)-permeable AMPA receptors may, in certain circumstances, contribute to normal synaptic plasticity or to neurodegeneration. AMPA receptors are Ca2+-permeable if they lack the GluA2 subunit or if GluA2 is unedited at a single nucleic acid, known as the Q/R site. In this study, we examined mice engineered with a point mutation in the intronic editing complementary sequence (ECS) of the GluA2 gene, Gria2. Mice heterozygous for the ECS mutation (named GluA2+/ECS(G)) had a ~ 20% reduction in GluA2 RNA editing at the Q/R site. We conducted an initial phenotypic analysis of these mice, finding altered current-voltage relations (confirming expression of Ca2+-permeable AMPA receptors at the synapse). Anatomically, we observed a loss of hippocampal CA1 neurons, altered dendritic morphology and reductions in CA1 pyramidal cell spine density. Behaviourally, GluA2+/ECS(G) mice exhibited reduced motor coordination, and learning and memory impairments. Notably, the mice also exhibited both NMDA receptor-independent long-term potentiation (LTP) and vulnerability to NMDA receptor-independent seizures. These NMDA receptor-independent seizures were rescued by the Ca2+-permeable AMPA receptor antagonist IEM-1460. In summary, unedited GluA2(Q) may have the potential to drive NMDA receptor-independent processes in brain function and disease. Our study provides an initial characterisation of a new mouse model for studying the role of unedited GluA2(Q) in synaptic and dendritic spine plasticity in disorders where unedited GluA2(Q), synapse loss, neurodegeneration, behavioural impairments and/or seizures are observed, such as ischemia, seizures and epilepsy, Huntington's disease, amyotrophic lateral sclerosis, astrocytoma, cocaine seeking behaviour and Alzheimer's disease.

Effect of 9 - PAHSA on cognitive dysfunction in diabetic mice and its possible mechanism.

Diabetes mellitus (DM) is currently a major global health problem, which is associated with the development of cognitive dysfunction. However, although numerous clinical drugs for hyperglycemia have been used at present, safer and more effective therapeutic intervention strategies for diabetic cognitive impairments are still a huge challenge. Recently, several studies have indicated that a novel class of branched palmitic acid esters of hydroxyl stearic acids (PAHSAs) may have anti-diabetes and anti-inflammatory effects in insulin-resistant mice. Herein, whether the 9-PAHSA that one of the PAHSAs can attenuates DM-associated cognitive impairment in a mouse model of type 2 diabetes has been investigated. Our results showed that 9-PAHSA mildly prevented deficits of spatial working memory in Y-maze test while reversed the preference bias toward novel mice in Social choice test. Furthermore, the effect of REST on cognitive impairment of diabetes was explored for the first time. It was found that the expression of REST in diabetic mice increased, and the expression of target protein BDNF (Brain-derived neurotrophic factor) was decreased. After administration of 9-PAHSA, the situation was reversed. In summary, we conclude that exogenous supplement of 9-PAHSA can improve DM-related cognitive impairment to some extent, and the protective effect may be associated with decreased REST/NRSF (repressor element-1 silencing transcription factor/neuron-restrictive silence factor) and upregulated BDNF expression in frontal cortex.

Effect of Hyperbaric Oxygen on Neurologic Sequelae and All-Cause Mortality in Patients with Carbon Monoxide Poisoning: A Meta-Analysis of Randomized Controlled Trials.

BACKGROUND Hyperbaric oxygen (HBO) is used in patients with carbon monoxide (CO) poisoning to prevent the occurrence of delayed neurological sequelae. However, inconsistent results were obtained regarding the treatment effects of HBO. Therefore, the current meta-analysis was conducted based on published randomized controlled trials (RCTs) to determine the effect of HBO on neurologic sequelae and all-cause mortality in patients with CO poisoning. MATERIAL AND METHODS Electronic databases MedLine, EmBase, and the Cochrane Library were searched for relevant RCTs from inception to March 1, 2019. The pooled relative risks (RRs) and weighted mean differences (WMDs) with corresponding 95% confidence intervals (CIs) were calculated to evaluate the outcomes by using a random-effects model. Sensitivity, subgroup, and publication bias analyses were also conducted. RESULTS Seven RCTs, including 9 cohorts and a total of 2023 patients with CO poisoning, were enrolled in this study. The summary results revealed that HBO showed an association with lower risk of memory impairment compared to patients receiving normobaric oxygen (NBO), whereas 2 sessions of HBO showed an association with higher risk of memory impairment compared to those who received 1 session of HBO. Moreover, HBO was associated with increased neuropsychologic scores of block design and trail making when compared with NBO. No other significant differences regarding the treatment effects of HBO were observed. CONCLUSIONS These results indicate that HBO therapy significantly reduces the risk of memory impairment compared to NBO, but 2 sessions of HBO might not be better for memory impairment than 1 session of HBO.

Study on the Multitarget Synergistic Effects of Kai-Xin-San against Alzheimer's Disease Based on Systems Biology.

Kai-Xin-San (KXS), a classical Chinese traditional prescription, was widely applied in the treatment of Alzheimer's disease (AD), while its functional mechanisms still remain unclear. By using systems biology approaches at animal, cellular, and molecular levels, the improvement of KXS on cognitive impairment was achieved by inhibiting abnormal acetylcholinesterase. The function on the nerve skeleton was performed by regulating the Tau phosphorylation pathway. Its antioxidant, anti-inflammatory, and antiapoptotic effects by modulating the aberrant upregulation of ROS, proinflammatory factors, and apoptosis-related proteins in the brain were studied to reveal the synergistic therapeutic efficacy of KXS. Then, formula dismantling in vitro indicated that ginseng was the principal herb, whereas three other herbs served adjuvant roles to achieve the best effect. After that, the in vivo analysis of components into plasma and brain of AD rats showed that 8 of 23 components in blood and 4 of 10 components in brain were from ginseng, respectively, further verifying the principal status of ginseng and the synergistic effects of the formula. Thus, the anti-AD effects of KXS were achieved by multitargets and multichannels. The systems biology approaches presented here provide a novel way in traditional herbal medicine research.

Zika Virus Infection in Hypothalamus Causes Hormone Deficiencies and Leads to Irreversible Growth Delay and Memory Impairment in Mice.

Zika virus (ZIKV) can cause microcephaly in the fetus. However, its effects on body growth and the development of children with postnatal ZIKV infection are largely unknown. To examine this, we intraperitoneally challenged mouse pups with ZIKV. Infection causes an irreversible growth delay and deficits in spatial learning and memory, with growth-relevant hormones significantly reduced during infection. These effects are associated with ZIKV RNA expression in the hypothalamus, blood, and brain but not in the pituitary and thyroid. Infection is also associated with hypothalamic inflammation, and ZIKV antigen is detectable in neuroendocrine cells producing thyrotropin-releasing hormone. Moreover, early administration of growth hormone could significantly improve growth delay. Our results demonstrate that ZIKV can infect the hypothalamus, causing multi-hormone deficiencies and delayed growth and development in a mouse model. Therefore, prospective multidisciplinary follow-up of ZIKV-infected children may be necessary to understand potential effects of this virus on childhood development.

The effects of safranal, a constitute of saffron, and metformin on spatial learning and memory impairments in type-1 diabetic rats: behavioral and hippocampal histopathological and biochemical evaluations.

Safranal is one of saffron constituents and has antioxidant and neuroprotective properties. Metformin is used as an anti-diabetic drug. This study was planned to investigate the separate and combined treatment effects of safranal and metformin on diabetes-induced learning and memory impairments by behavioral and hippocampal histopathological and biochemical evaluations. Diabetes was induced by intraperitoneal injection of streptozotocin (STZ), treatments with safranal (0.025, 0.1 and 0.4 mg/kg), metformin (50 and 200 mg/kg), and a combination of low doses of this chemicals were initiated after confirmation of diabetes and continued for 37 days. Blood glucose concentration was measured before and on days 15, 25 and 35 after injection of streptozotocin. Learning and memory tested using Morris Water Maze (MWM) on days 40-45 and on day 45 hippocampal specimens were collected for determination of malodialdehyde (MDA), tumor necrosis factor-alpha (TNF-α) and Caspase-3 levels and superoxide dismutase (SOD) activity. The hippocampus was also designed for light microscopy evaluation. Hyperglycemia, spatial learning and memory impairments, hippocampal neuron loss, increase of hippocampal MDA, TNF-α and caspase-3 levels and decrease of SOD activity were observed in diabetic rats. Safranal (0.1 and 0.4 mg/kg), metformin (200 mg/kg) and safranal (0.025 mg/kg) with metformin (50 mg/kg) improved the above-mentioned behavioral, histopathological and biochemical changes. Safranal and metformin and their combination improved learning and memory impairments in STZ-induced diabetic rats. Antioxidant, anti-inflammatory and antiapoptotic mechanisms might be involved. It is recommended that safranal be considered for diabetes management.

HO-1 dependent antioxidant effects of ethyl acetate fraction from Physalis alkekengi fruit ameliorates scopolamine-induced cognitive impairments.

Physalis alkekengi var. francheti is an indigenous herb well known for its anti-inflammatory, sedative, antipyretic, and expectorant properties. However, the information regarding the impacts of P. alkekengi fruits (PAF) in modulation of oxidative stress and learning memory are still unknown. This study therefore evaluated the antioxidant properties of ethyl acetate (EA) fraction of PAF and its impacts on learning and memory. The antioxidant activities of PAF were evaluated in LPS-induced BV2 microglial cells. The potent EA fraction then investigated and confirmed for its involvement of HO-1 pathway using hemin (HO-1 inducer) and ZnPP (HO-1 inhibitor) through Western blotting, DCFH-DA, and/or Griess assay. The involvements of PI3K/Akt, MEK, and p38 MAPK also investigated. Furthermore, we applied EA fraction to the animals at 100 and 200 mg/kg doses to check if the extract could improve scopolamine-induced memory deficits in passive avoidance and elevated plus maze tests. Our results demonstrated that the fractions from PAF significantly inhibited the generation of intracellular reactive oxygen species (ROS) induced by LPS in concentration-dependent manners. In comparison to other fractions, the EA fraction exhibited potent effect in suppressing intracellular ROS generation. Besides, EA fraction also induced the expression of HO-1 in time- and concentration-dependent manners. ZnPP significantly reversed the suppressive effect of EA fraction on LPS-induced ROS generation and NO production, which confirm the involvement of HO-1 signaling in EA-fraction-mediated antioxidant activities. Consistently, blocking of PI3K/Akt, MEK, and p38 MAPK pathways by PAF-EA suppressed the production of intracellular ROS, indicating their potential participation. In addition, one of the major constituents of EA fraction, luteolin-7-O-ß-D-glucoside, also demonstrated HO-1-dependent antioxidant effects in BV2 cells. Further, the EA fraction significantly (p < 0.05) improves scopolamine-induced memory deficits in mice. Taken together, our findings highlight the antioxidant effects of EA fraction of PAF which may be beneficial in treatment of different neurodegenerative diseases associated with free radicals.

The role of rosemary extract in degeneration of hippocampal neurons induced by kainic acid in the rat: A behavioral and histochemical approach.

Systemic Kainic Acid (KA) administration has been used to induce experimental temporal lobe epilepsy in rats. The aim of this study was to evaluate the neuroprotective effect of rosemary extract (RE, 40% Carnosic acid) against KA-induced neurotoxicity in hippocampus and impaired learning and memory. Animals received a single dose of KA (9.5 mg/kg) intraperitoneally (i.p.) (KA group) and were observed for 2 h and were scored from 0 (for normal, no convulsion) to 5 (for continuous generalized limbic seizures). RE (100 mg/kg, orally) was administered daily for 23 days, starting a week before KA injection (KA+RE group). Neuronal degeneration in hippocampus was demonstrated by using Fluoro-Jade B immunofluorescence. The number of pyramidal cells in hippocampus was evaluated by Nissl staining. Also, the Morris Water Maze and Shuttle box have been used to assess spatial memory and passive avoidance learning, respectively. Our results revealed that, after treatment with RE, neuronal loss in CA1 decreased significantly in the animals in KA+RE group. The Morris water navigation task results revealed that spatial memory impairment decreased in the animals in KA+RE group. Furthermore, results in Shuttle box test showed that passive avoidance learning impairment significantly, upgraded in the animals in KA+RE group. These results suggest that RE may improve the spatial and working memory deficits and also neuronal degeneration induced by toxicity of KA in the rat hippocampus, due to its antioxidant activities.

Natural Dietary Supplementation of Anthocyanins via PI3K/Akt/Nrf2/HO-1 Pathways Mitigate Oxidative Stress, Neurodegeneration, and Memory Impairment in a Mouse Model of Alzheimer's Disease.

Well-established studies have shown an elevated level of reactive oxygen species (ROS) that induces oxidative stress in the Alzheimer's disease (AD) patient's brain and an animal model of AD. Herein, we investigated the underlying anti-oxidant neuroprotective mechanism of natural dietary supplementation of anthocyanins extracted from Korean black beans in the amyloid precursor protein/presenilin-1 (APP/PS1) mouse model of AD. Both in vivo (APP/PS1 mice) and in vitro (mouse hippocampal HT22 cells) results demonstrated that anthocyanins regulate the phosphorylated-phosphatidylinositol 3-kinase-Akt-glycogen synthase kinase 3 beta (p-PI3K/Akt/GSK3ß) pathways and consequently attenuate amyloid beta oligomer (AßO)-induced elevations in ROS level and oxidative stress via stimulating the master endogenous anti-oxidant system of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (Nrf2/HO-1) pathways and prevent apoptosis and neurodegeneration by suppressing the apoptotic and neurodegenerative markers such as activation of caspase-3 and PARP-1 expression as well as the TUNEL and Fluoro-Jade B-positive neuronal cells in the APP/PS1 mice. In vitro ApoTox-Glo™ Triplex assay results also showed that anthocyanins act as a potent anti-oxidant neuroprotective agent and reduce AßO-induced neurotoxicity in the HT22 cells via PI3K/Akt/Nrf2 signaling. Importantly, anthocyanins improve memory-related pre- and postsynaptic protein markers and memory functions in the APP/PS1 mice. In conclusion, our data suggested that consumption and supplementation of natural-derived anti-oxidant neuroprotective agent such as anthocyanins may be beneficial and suggest new dietary-supplement strategies for intervention in and prevention of progressive neurodegenerative diseases, such as AD.

Bilateral Thalamic Edema from Coexisting Choroid Plexus Arteriovenous Malformation and Sinus Thrombosis: Case Report.

Bilateral thalamic dysfunction secondary to venous congestion may result from either venous sinus thrombosis or high flow arteriovenous malformations or a combination of both. We present a case of bilateral thalamic edema resulting from concomitant choroid plexus arteriovenous malformation (AVM) and straight sinus thrombosis and describe our treatment approach. The patient presented with several weeks of progressive confusion and memory deficits. Magnetic resonance imaging and venography (MRI/ MRV) showed bilateral thalamic T2 hyperintensities and straight sinus thrombosis. Subsequent cerebral angiography revealed a choroid plexus AVM within the right lateral ventricle. The patient underwent surgical resection of the AVM resulting in postoperative resolution of bilateral thalamic edema on MRI and improvement of his confusion and memory deficits. This case demonstrates a rare example of reversible bilateral thalamic edema secondary to venous hypertension from both an AVM and sinus occlusion after appropriate treatment of the AVM.

Paeoniflorin improves regional cerebral blood flow and suppresses inflammatory factors in the hippocampus of rats with vascular dementia.

OBJECTIVE: To explore the delayed neuroprotection induced by paeoniflorin (PF), the principal component of Paeoniae radix prescribed in Chinese medicine, and its underlying mechanisms in rats subjected to vascular dementia (VD). METHODS: A rat model of VD was induced by bilateral common carotid arteries occlusion (BCCAO). Low-dose or high-dose PF (20 or 40 mg/kg once per day) was administrated for 28 days after VD. The behavioral analysis of rat was measured by water morris. Regional cerebral blood volume (rCBV), regional cerebral blood flflow (rCBF) and mean transit time (MTT) were measured in the bilateral hippocampus by perfusion-weighted imaging (PWI). The levels of interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α) were measured by commercially available enzyme-linked immunosorbent assay kits. Protein levels were evaluated by western blot analysis. mRNA levels were evaluated by real time-polymerase chain reaction. Western blotting was used to estimate p65 translocation. RESULTS: The behavioral analysis showed that PF could decrease the escape latency time (P<0.05), and increase the residence time of the original platform quadrant and the across platform frequency in water maze in VD rats (P<0.05). Likewise, PF remarkably promoted the rCBV (P<0.05), rCBF and decreased per minute MTT (P<0.05) in hippocampus of VD rats. Furthermore, PF decreased the release of IL-1ß, IL-6 and TNF-α as well as inhibited the mRNA expression of IL-1ß, IL-6 and TNF-α in the hippocampus of VD rats (P<0.05 or P<0.01). PF also could decrease the protein expressions of inducible nitric oxide synthase and cyclooxygenase-2 in the hippocampus of VD rats (P<0.05 or P<0.01). In addition, PF signifificantly inhibited the nuclear factor κB (NF-κB) pathway in the hippocampus of VD rats. CONCLUSIONS: PF signifificantly attenuates cognitive impairment, improves hippocampus perfusion and inhibits inflflammatory response in VD rats. In addition, the anti-inflflammatory effects of PF might be due to inhibiting the NF-κB pathway. PF may be a potential clinical application in improving VD.

Oxytocin is implicated in social memory deficits induced by early sensory deprivation in mice.

Early-life sensory input plays a crucial role in brain development. Although deprivation of orofacial sensory input at perinatal stages disrupts the establishment of the barrel cortex and relevant callosal connections, its long-term effect on adult behavior remains elusive. In this study, we investigated the behavioral phenotypes in adult mice with unilateral transection of the infraorbital nerve (ION) at postnatal day 3 (P3). Although ION-transected mice had normal locomotor activity, motor coordination, olfaction, anxiety-like behaviors, novel object memory, preference for social novelty and sociability, they presented deficits in social memory and spatial memory compared with control mice. In addition, the social memory deficit was associated with reduced oxytocin (OXT) levels in the hypothalamus and could be partially restored by intranasal administration of OXT. Thus, early sensory deprivation does result in behavioral alterations in mice, some of which may be associated with the disruption of oxytocin signaling.

Anthriscus nemorosa essential oil inhalation prevents memory impairment, anxiety and depression in scopolamine-treated rats.

Anthriscus nemorosa (Bieb.) Sprengel is used for medicinal purposes in traditional medicine around the world, including Turkey. Ethnobotanical studies suggest that Anthriscus essential oil could improve memory in Alzheimer's disease. The current study was hypothesized to investigate the beneficial effects of inhaled Anthriscus nemorosa essential oil on memory, anxiety and depression in scopolamine-treated rats. Anthriscus nemorosa essential oil was administered by inhalation in the doses of 1% and 3% for 21 continuous days and scopolamine (0.7mg/kg) was injected intraperitoneally 30min before the behavioral testing. Y-maze and radial arm-maze tests were used for assessing memory processes. Also, the anxiety and depressive responses were studied by elevated plus-maze and forced swimming tests. As expected, the scopolamine alone-treated rats exhibited the following: decrease the percentage of the spontaneous alternation in Y-maze test, increase the number of working and reference memory errors in radial arm-maze test, decrease of the exploratory activity, the percentage of the time spent and the number of entries in the open arm within elevated plus-maze test and decrease of swimming time and increase of immobility time within forced swimming test. However, dual scopolamine and Anthriscus nemorosa essential oil-treated rats showed significant improvement of memory formation and exhibited anxiolytic- and antidepressant-like effects in scopolamine-treated rats. These results suggest that Anthriscus nemorosa essential oil inhalation can prevent scopolamine-induced memory impairment, anxiety and depression.

AP39, a Mitochondria-Targeted Hydrogen Sulfide Donor, Supports Cellular Bioenergetics and Protects against Alzheimer's Disease by Preserving Mitochondrial Function in APP/PS1 Mice and Neurons.

Increasing evidence suggests that mitochondrial functions are altered in AD and play an important role in AD pathogenesis. It has been established that H2S homeostasis is balanced in AD. The emerging mitochondrial roles of H2S include antioxidation, antiapoptosis, and the modulation of cellular bioenergetics. Here, using primary neurons from the well-characterized APP/PS1 transgenic mouse model, we studied the effects of AP39 (a newly synthesized mitochondrially targeted H2S donor) on mitochondrial function. AP39 increased intracellular H2S levels, mainly in mitochondrial regions. AP39 exerted dose-dependent effects on mitochondrial activity in APP/PS1 neurons, including increased cellular bioenergy metabolism and cell viability at low concentrations (25-100 nM) and decreased energy production and cell viability at a high concentration (250 nM). Furthermore, AP39 (100 nM) increased ATP levels, protected mitochondrial DNA, and decreased ROS generation. AP39 regulated mitochondrial dynamics, shifting from fission toward fusion. After 6 weeks, AP39 administration to APP/PS1 mice significantly ameliorated their spatial memory deficits in the Morris water maze and NORT and reduced Aß deposition in their brains. Additionally, AP39 inhibited brain atrophy in APP/PS1 mice. Based on these results, AP39 was proposed as a promising drug candidate for AD treatment, and its anti-AD mechanism may involve protection against mitochondrial damage.

Rifampicin is a candidate preventive medicine against amyloid-ß and tau oligomers.

Amyloid-ß, tau, and α-synuclein, or more specifically their soluble oligomers, are the aetiologic molecules in Alzheimer's disease, tauopathies, and α-synucleinopathies, respectively. These proteins have been shown to interact to accelerate each other's pathology. Clinical studies of amyloid-ß-targeting therapies in Alzheimer's disease have revealed that the treatments after disease onset have little benefit on patient cognition. These findings prompted us to explore a preventive medicine which is orally available, has few adverse effects, and is effective at reducing neurotoxic oligomers with a broad spectrum. We initially tested five candidate compounds: rifampicin, curcumin, epigallocatechin-3-gallate, myricetin, and scyllo-inositol, in cells expressing amyloid precursor protein (APP) with the Osaka (E693Δ) mutation, which promotes amyloid-ß oligomerization. Among these compounds, rifampicin, a well-known antibiotic, showed the strongest activities against the accumulation and toxicity (i.e. cytochrome c release from mitochondria) of intracellular amyloid-ß oligomers. Under cell-free conditions, rifampicin inhibited oligomer formation of amyloid-ß, tau, and α-synuclein, indicating its broad spectrum. The inhibitory effects of rifampicin against amyloid-ß and tau oligomers were evaluated in APPOSK mice (amyloid-ß oligomer model), Tg2576 mice (Alzheimer's disease model), and tau609 mice (tauopathy model). When orally administered to 17-month-old APPOSK mice at 0.5 and 1 mg/day for 1 month, rifampicin reduced the accumulation of amyloid-ß oligomers as well as tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent manner. In the Morris water maze, rifampicin at 1 mg/day improved memory of the mice to a level similar to that in non-transgenic littermates. Rifampicin also inhibited cytochrome c release from the mitochondria and caspase 3 activation in the hippocampus. In 13-month-old Tg2576 mice, oral rifampicin at 0.5 mg/day for 1 month decreased amyloid-ß oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation, but not amyloid deposition. Rifampicin treatment to 14-15-month-old tau609 mice at 0.5 and 1 mg/day for 1 month also reduced tau oligomer accumulation, tau hyperphosphorylation, synapse loss, and microglial activation in a dose-dependent fashion, and improved the memory almost completely at 1 mg/day. In addition, rifampicin decreased the level of p62/sequestosome-1 in the brain without affecting the increased levels of LC3 (microtubule-associated protein light chain 3) conversion, suggesting the restoration of autophagy-lysosomal function. Considering its prescribed dose and safety in humans, these results indicate that rifampicin could be a promising, ready-to-use medicine for the prevention of Alzheimer's disease and other neurodegenerative diseases.