Late-stage rescue of visually guided behavior in the context of a significantly remodeled retinitis pigmentosa mouse model.

Patients with progressive neurodegenerative disorder retinitis pigmentosa (RP) are diagnosed in the midst of ongoing retinal degeneration and remodeling. Here, we used a Pde6b-deficient RP gene therapy mouse model to test whether treatment at late disease stages can halt photoreceptor degeneration and degradative remodeling, while sustaining constructive remodeling and restoring function. We demonstrated that when fewer than 13% of rods remain, our genetic rescue halts photoreceptor degeneration, electroretinography (ERG) functional decline and inner retinal remodeling. In addition, in a water maze test, the performance of mice treated at 16 weeks of age or earlier was indistinguishable from wild type. In contrast, no efficacy was apparent in mice treated at 24 weeks of age, suggesting the photoreceptors had reached a point of no return. Further, remodeling in the retinal pigment epithelium (RPE) and retinal vasculature was not halted at 16 or 24 weeks of age, although there appeared to be some slowing of blood vessel degradation. These data suggest a novel working model in which restoration of clinically significant visual function requires only modest threshold numbers of resilient photoreceptors, halting of destructive remodeling and sustained constructive remodeling. These novel findings define the potential and limitations of RP treatment and suggest possible nonphotoreceptor targets for gene therapy optimization.

Estradiol effects on spatial memory in women.

To examine the role of estradiol in hippocampal-dependent spatial memory in women, 86 female undergraduates were tested in a virtual Morris water task (VMWT), a virtual radial arm maze (VRAM), and a mental rotation task (MRT) within a single daily session. The VMWT and RAM were also administered 24 h later to examine the effects of estradiol on memory consolidation. Women on oral contraceptives (OCs) or those who were naturally cycling and exhibited low estradiol (LE) or high estradiol (HE), as determined by salivary assays, were included. At the start of day two, the HE group showed superior spatial reference memory on the VMWT relative to the LE group, as evidenced by significantly shorter distances navigating to the hidden platform. The LE group also had the poorest probe trial performance at the start of day two compared to both other groups. There were no group differences in performance on the RAM or MRT. These results provide support for estradiol's role in the consolidation of spatial reference memory in women, and emphasize the differential sensitivities of various virtual memory tasks in assessing spatial memory function in women.

Magnolol attenuates the locomotor impairment, cognitive deficit, and neuroinflammation in Alzheimer's disease mice with brain insulin resistance via up-regulating miR-200c.

In this study, we aimed to investigate the effect of Magnolol on Alzheimer's disease (AD). After the model of streptozotocin-induced AD mice with brain insulin resistance was established, the mice were treated with Magnolol or miR-200c antagomiR. The abilities of ambulations, rearings, discrimination, spatial learning, and memory were evaluated by open-field test (OFT), novel object recognition (NOR), and morris water maze (MWM) tests. The levels of malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP), and miR-200c in the mice hippocampus were evaluated by enzyme-linked immunosorbent assay, Western blot, or Quantitative real-time Polymerase Chain Reaction. In AD mice model, streptozotocin induced the locomotor impairment and cognitive deficit, up-regulated levels of MDA, TNF-α, IL-6, and CRP, while down-regulated levels of GSH, SOD, and miR-200c. Magnolol increased the rearings numbers and discrimination index of AD mice in OFT and NOR tests. Magnolol increased the number of entries in the target quadrant and time spent in the target quadrant and decreased the escape latency of AD mice in the MWM test. Magnolol also down-regulated the levels of MDA, TNF-α, IL-6, and CRP, and up-regulated the levels of GSH, SOD, and miR-200c in the hippocampus tissues of AD mice. However, miR-200c antagomiR did the opposite and further offset the effects of the Magnolol on AD mice. Magnolol attenuated the locomotor impairment, cognitive deficit, and neuroinflammatory in AD mice with brain insulin resistance via up-regulating miR-200c.

Evaluation of neurotoxicity and long-term function and behavior following intrathecal 1 % 2-chloroprocaine in juvenile rats.

Spinally-administered local anesthetics provide effective perioperative anesthesia and/or analgesia for children of all ages. New preparations and drugs require preclinical safety testing in developmental models. We evaluated age-dependent efficacy and safety following 1 % preservative-free 2-chloroprocaine (2-CP) in juvenile Sprague-Dawley rats. Percutaneous lumbar intrathecal 2-CP was administered at postnatal day (P)7, 14 or 21. Mechanical withdrawal threshold pre- and post-injection evaluated the degree and duration of sensory block, compared to intrathecal saline and naive controls. Tissue analyses one- or seven-days following injection included histopathology of spinal cord, cauda equina and brain sections, and quantification of neuronal apoptosis and glial reactivity in lumbar spinal cord. Following intrathecal 2-CP or saline at P7, outcomes assessed between P30 and P72 included: spinal reflex sensitivity (hindlimb thermal latency, mechanical threshold); social approach (novel rat versus object); locomotor activity and anxiety (open field with brightly-lit center); exploratory behavior (rearings, holepoking); sensorimotor gating (acoustic startle, prepulse inhibition); and learning (Morris Water Maze). Maximum tolerated doses of intrathecal 2-CP varied with age (1.0 µL/g at P7, 0.75 µL/g at P14, 0.5 µL/g at P21) and produced motor and sensory block for 10-15 min. Tissue analyses found no significant differences across intrathecal 2-CP, saline or naïve groups. Adult behavioral measures showed expected sex-dependent differences, that did not differ between 2-CP and saline groups. Single maximum tolerated in vivo doses of intrathecal 2-CP produced reversible spinal anesthesia in juvenile rodents without detectable evidence of developmental neurotoxicity. Current results cannot be extrapolated to repeated dosing or prolonged infusion.

Rosinidin Attenuates Lipopolysaccharide-Induced Memory Impairment in Rats: Possible Mechanisms of Action Include Antioxidant and Anti-Inflammatory Effects.

The investigation aimed to evaluate the favourable effects of rosinidin in lipopolysaccharide (LPS)-induced learning and memory impairment in rats. Adult Wistar rats (150-200 g) were segregated equally into four different groups and treated as below: Group 1 (normal) and Group 2 (LPS control) were administered orally with 3 mL of 0.5% SCMC (vehicle); Group 3 and Group 4 were test groups and orally administered with rosinidin lower dose (10 mg/kg) and higher dose 20 mg/kg. Daily, 1 h post-offer mentioned treatments, Group 1 animals were injected with normal saline (i.p.) and groups 2-4 were treated with 1 mg/kg/day of LPS. This treatment schedule was followed daily for 7 days. During the treatment, schedule rats were evaluated for spontaneous locomotor activity, memory, and learning abilities. The biochemical assessment was carried out of acetylcholine esterase (AChE), endogenous antioxidants (GSH, SOD, GPx, and catalase), oxidative stress marker MDA, neuroinflammatory markers (IL-6, IL-1ß, TNF-α, and NF-κB), and BDNF. LPS-induced reduced spontaneous locomotor activity and memory impairment in the animals. Moreover, LPS reduced GSH, SOD, GPx, and catalase levels; altered activities of AChE; elevated levels of MDA, IL-6, IL-1ß, TNF-α, and NF-κB; and attenuated the levels of BDNF in brain tissue. Administration of rosinidin to LPS-treated animals significantly reduced LPS-induced neurobehavioral impairments, oxidative stress, neuroinflammatory markers, and reversed the Ach enzyme activities and BDNF levels towards normal. Results demonstrated that rosinidin attenuates the effects of LPS on learning memory in rats.

Silver Nanoparticles Conjugate Attenuates Highly Active Antiretroviral Therapy-Induced Hippocampal Nissl Substance and Cognitive Deficits in Diabetic Rats.

BACKGROUND: The application of nanomedicine to antiretroviral drug delivery holds promise in reducing the comorbidities related to long-term systemic exposure to highly active antiretroviral therapy (HAART). However, the safety of drugs loaded with silver nanoparticles has been debatable. This study is aimed at evaluating the effects of HAART-loaded silver nanoparticles (HAART-AgNPs) on the behavioural assessment, biochemical indices, morphological, and morphometric of the hippocampus in diabetic Sprague-Dawley rats. METHODS: Conjugated HAART-AgNPs were characterized using FTIR spectroscopy, UV spectrophotometer, HR-TEM, SEM, and EDX for absorbance peaks, size and morphology, and elemental components. Forty-eight male SD rats (250 ± 13 g) were divided into nondiabetic and diabetic groups. Each group was subdivided into (n = 8) A (nondiabetic+vehicle), B (nondiabetic+HAART), C (nondiabetic+HAART-AgNPs), D (diabetic+vehicle), E (diabetic+HAART), and F (diabetic+HAART-AgNPs). Morris water maze, Y-maze test, and weekly blood glucose levels were carried out. Following the last dose of 8-week treatment, the rats were anaesthetized and euthanized. Brain tissues were carefully removed and postfixed for Nissl staining histology. RESULTS: 1.5 M concentration of HAART-AgNPs showed nanoparticle size 20.3 nm with spherical shape. HAART-AgNPs revealed 16.89% of silver and other elemental components of HAART. The diabetic control rats showed a significant increase in blood glucose, reduced spatial learning, positive hippocampal Nissl-stained cells, and a significant decrease in GSH and SOD levels. However, administration of HAART-AgNPs to diabetic rats significantly reduced blood glucose level, improved spatial learning, biochemical indices, and enhanced memory compared to diabetic control. Interestingly, diabetic HAART-AgNP-treated rats showed a significantly improved memory, increased GSH, SOD, and number of positive Nissl-stained neurons compared to diabetic-treated HAART only. CONCLUSION: Administration of HAART to diabetic rats aggravates the complications of diabetes and promotes neurotoxic effects on the experimental rats, while HAART-loaded silver nanoparticle (HAART-AgNP) alleviates diabetes-induced neurotoxicity.

Protective effect of quercetin against the metabolic dysfunction of glucose and lipids and its associated learning and memory impairments in NAFLD rats.

BACKGROUND: Quercetin (QUE) is a flavonol reported with anti-inflammatory and antioxidant activities, and previous results from the group of this study have demonstrated its neuroprotective effect against lipopolysaccharide-induced neuropsychiatric injuries. However, little is known about its potential effect on neuropsychiatric injuries induced or accompanied by metabolic dysfunction of glucose and lipids. METHODS: A nonalcoholic fatty liver disease (NAFLD) rat model was induced via a high-fat diet (HFD), and glucolipid parameters and liver function were measured. Behavioral performance was observed via the open field test (OFT) and the Morris water maze (MWM). The plasma levels of triggering receptor expressed on myeloid cells-1 (TREM1) and TREM2 were measured via enzyme-linked immunosorbent assay (ELISA). The protein expression levels of Synapsin-1 (Syn-1), Synaptatogmin-1 (Syt-1), TREM1 and TREM2 in the hippocampus were detected using western blotting. Morphological changes in the liver and hippocampus were detected by HE and Oil red or silver staining. RESULTS: Compared with the control rats, HFD-induced NAFLD model rats presented significant metabolic dysfunction, hepatocyte steatosis, and impaired learning and memory ability, as indicated by the increased plasma concentrations of total cholesterol (TC) and triglyceride (TG), the impaired glucose tolerance, the accumulated fat droplets and balloon-like changes in the liver, and the increased escaping latency but decreased duration in the target quadrant in the Morris water maze. All these changes were reversed in QUE-treated rats. Moreover, apart from improving the morphological injuries in the hippocampus, treatment with QUE could increase the decreased plasma concentration and hippocampal protein expression of TREM1 in NAFLD rats and increase the decreased expression of Syn-1 and Syt-1 in the hippocampus. CONCLUSIONS: These results suggested the therapeutic potential of QUE against NAFLD-associated impairment of learning and memory, and the mechanism might involve regulating the metabolic dysfunction of glucose and lipids and balancing the protein expression of synaptic plasticity markers and TREM1/2 in the hippocampus.

Sirt3-mediated mitochondrial dysfunction is involved in fluoride-induced cognitive deficits.

Excessive fluoride is capable of inducing cognitive deficits, but the mechanisms remain elusive. This study aimed to investigate the effects and underlying mechanisms of fluoride on mitochondrial dysfunction and neurobiological alterations, as well as cognitive impairment. C57BL/6 mice were orally administered 25, 50, and 100 mg/L NaF for 90 days. Cultured human neuroblastoma SH-SY5Y cells were exposed to NaF (110 mg/L) for 24 h in the presence or absence of Sirt3 overexpression. The results demonstrated that chronic exposure to high fluoride induced cognitive deficits and neural/synaptic injury in mice. Fluoride reduced mitochondrial antioxidant enzyme activities and elevated SOD2 acetylation by downregulating Sirt3 expression in the brains of mice and NaF-treated SH-SY5Y cells. Moreover, fluoride lowered mtDNA transcription and induced mitochondrial dysfunction along with increased FoxO3A acetylation in the brains of mice and NaF-treated SH-SY5Y cells. Subsequent experiments revealed that overexpression of Sirt3 significantly attenuated the adverse effects of fluoride on radical scavenging capabilities and mtDNA transcription, as well as mitochondrial function in SH-SY5Y cells. These results suggest that chronic long-term fluoride exposure evokes neural/synaptic injury and cognitive impairment through mitochondrial dysfunction and its associated oxidative stress, which is, at least partly, mediated by Sirt3 inhibition in the mouse brain.

Safflower leaf ameliorates cognitive impairment through moderating excessive astrocyte activation in APP/PS1 mice.

In addition to beta-amyloid (Aß) plaques and neurofibrillary tangles, Alzheimer's disease (AD) is typically triggered or accompanied by abnormal inflammation, oxidative stress and astrocyte activation. Safflower (Carthamus tinctorius L.) leaf, featuring functional ingredients, is a commonly consumed leafy vegetable. Whether and how dietary safflower leaf powder (SLP) ameliorates cognitive function in an AD mouse model has remained minimally explored. Therefore, we orally administered SLP to APP/PS1 transgenic mice to explore the neuroprotective effects of SLP in preventing AD progression. We found that SLP markedly improved cognitive impairment in APP/PS1 mice, as indicated by the water maze test. We further demonstrated that SLP treatment ameliorated inflammation, oxidative stress and excessive astrocyte activation. Further investigation indicated that SLP decreased the Aß burden in APP/PS1 mice by mediating excessive astrocyte activation. Our study suggests that safflower leaf is possibly a promising, cognitively beneficial food for preventing and alleviating AD-related dementia.

B Vitamins Supplementation Can Improve Cognitive Functions and May Relate to the Enhancement of Transketolase Activity in A Rat Model of Cognitive Impairment Associated with High-fat Diets.

OBJECTIVE: To determine whether B vitamin treatment was sufficient to reduce cognitive impairment associated with high-fat diets in rats and to modulate transketolase (TK) expression and activity. METHODS: To test this, we separated 50 rats into five groups that were either fed a standard chow diet (controls) or a high-fat diet (experimental groups H0, H1, H2, and H3). H0 group animals received no additional dietary supplementation, while H1 group animals were administered 100 mg/kg body weight (BW) thiamine, 100 mg/kg BW riboflavin, and 250 mg/kg BW niacin each day, and group H2 animals received daily doses of 100 mg/kg BW pyridoxine, 100 mg/kg BW cobalamin, and 5 mg/kg BW folate. Animals in the H3 group received the B vitamin regimens administered to both H1 and H2 each day. RESULTS: Over time, group H0 exhibited greater increases in BW and fat mass relative to other groups. When spatial and memory capabilities in these animals were evaluated via conditioned taste aversion (CTA) and Morris Water Maze (MWM), we found B vitamin treatment was associated with significant improvements relative to untreated H0 controls. Similarly, B vitamin supplementation was associated with elevated TK expression in erythrocytes and hypothalamus of treated animals relative to those in H0 (P<0.05). CONCLUSION: Together, these findings suggest B vitamin can modulate hypothalamic TK activity to reduce the severity of cognitive deficits in a rat model of obesity. As such, B vitamin supplementation may be a beneficial method for reducing cognitive dysfunction in clinical settings associated with high-fat diets.

An overview of the behavioral, neurobiological and morphological effects of topiramate in rats exposed to chronic unpredictable mild stress.

The environmental psychological stress causes depressive disorders. Stress causes many neurobiological, neurodegenerative changes in brain. Topiramate (TPM) is used in the treatment of epilepsy and psychiatric diseases. However, there are conflicting findings that TPM disrupts cognitive functions. We aimed to investigate the effects of TPM on depression, anxiety, learning and memory as well as neurobiological, morphological changes in rats exposed to chronic unpredictable mild stress (CUMS). After CUMS was formed by random application of nine mild stressors for 45 days, TPM (at doses of 0.1, 1, 10, 100 mg/kg) was administered for 21 days. Sucrose preference, locomotor activity, forced swimming, elevated plus maze and Morris water maze tests were performed. Corticosterone, BDNF (Brain-derived neurotrophic factor) and glutamate levels and volumes of hippocampus were evaluated. Body weights of the rats were measured. Immobilization time increased in CUMS, CUMS + TPM0.1 in forced swimming test and time spent in platform quadrant increased in Control + TPM1, CUMS, CUMS + TPM0.1, CUMS + TPM1 in Morris water maze test. Control + TPM1 decreased distance to platform in Morris water maze while CUMS + TPM100 increased. Learning is impaired in CUMS + TPM100 while it is improved in Control + TPM1. BDNF levels increased in CUMS and glutamate levels increased in CUMS, CUMS + TPM10. Body weight decreased in CUMS, CUMS + TPM0.1, CUMS + TPM1, CUMS + TPM100. Hippocampus volumes increased in CUMS. In conclusion, CUMS improved cognition and this finding was supported by the increase of BDNF levels and volume of hippocampus. TPM 1 mg/kg improved cognition in non-stressed rats. TPM 0.1 and 1 mg/kg improved while TPM 100 mg/kg impaired memory in rats exposed to stress.

Aluminum impairs cognitive function by activating DDX3X-NLRP3-mediated pyroptosis signaling pathway.

INTRODUCTION: Aluminum is a kind of chemical contaminants in food which can induce neurotoxicity. Aluminum exposure is closely related to neurodegenerative diseases (ND), in which neuroinflammation might involve. However, the molecular mechanism of aluminum-induced neuroinflammation through pyroptosis is not fully clarified yet. MATERIAL AND METHODS: The mice model of subacute exposure to aluminum chloride (AlCl3) was established. BV2 microglia cells was treated with AlCl3 in vitro. Resveratrol (Rsv) was adopted as intervention agent. RESULTS: Our results showed that aluminum induced cognitive impairment, destroying blood brain barrier (BBB), and causing nerve injury in mice. Meanwhile, aluminum could stimulate nucleotide oligomerization domain-like receptor family pyrin domain containing protein 3 (NLRP3) inflammasome assembly and activate caspase-1 (CASP1), inducing gasdermin D (GSDMD)-mediated pyroptosis signaling, releasing cytokines IL-1ß and IL-18, further promoting the activation of glial cells to magnify neuroinflammatory response. Moreover, DEAD-box helicase 3 X-linked (DDX3X) and stress granule RasGAP SH3-domain-binding protein 1 (G3BP1) both participated in neuroinflammation induced by aluminum. When co-treated with Rsv, these injuries were alleviated to some extent. CONCLUSION: Aluminum exposure could induce nerve cell pyroptosis and neuroinflammation by DDX3X-NLRP3 inflammasome signaling pathway, which could be rescued via Rsv activating sirtuin 1 (SIRT1).

Protective effect and mechanism of docosahexaenoic acid on the cognitive function in female APP/PS1 mice.

Docosahexaenoic acid (DHA) has been studied for many years owing to its protective effect on the decline in brain function. DHA intake reduces the risk of Alzheimer's disease (AD) and decreases amyloid deposition; however, the underlying molecular mechanism has not been completed elucidated. In this study, the effect of DHA on the cognitive function of amyloid precursor protein (APP)/PS1 in wild-type mice and its related mechanism were investigated. Results from the Morris water maze test showed that DHA improved learning and memory function in mice. Moreover, DHA reduced neuronal damage in mice brains, as determined using Nissl staining. Unsaturated fatty acid levels in the brain of mice increased (p < 0.01) after DHA administration and saturated fatty acid levels decreased (p < 0.01). The deposition of amyloid-beta (Aß) plaques and tau protein neurofibrillary tangles was significantly inhibited. The mechanism of action of DHA was attributed to the upregulation of the expression of ß-secretase (BACE)2, which competed with BACE1 to cleave APP, thus decreasing the production of extracellular Aß fragments (p < 0.01). The expression level of insulin-degrading enzyme was not significantly different. The expression of N-methyl-D-aspartate receptors was further downregulated and the phosphorylation of glycogen synthase kinase-3ß and tau protein was inhibited (p < 0.01). These data indicated that DHA could protect cognitive function in mice by reducing Aß plaque formation and decreasing tau phosphorylation levels.

rhFGF20 promotes angiogenesis and vascular repair following traumatic brain injury by regulating Wnt/ß-catenin pathway.

The pathology of cerebrovascular disorders takes an important role in traumatic brain injury (TBI) by increasing intracranial pressure. Fibroblast growth factor 20 (FGF20) is a brain-derived neurotrophic factor, that has been shown to play an important role in the survival of dopaminergic neurons and the treatment of Parkinson's disease (PD). However, little is known about the role of FGF20 in the treatment of TBI and its underlying mechanism. The purpose of this study was to evaluate the protective effect of recombinant human FGF20 (rhFGF20) on protecting cerebral blood vessels after TBI. In this study, we indicated that rhFGF20 could reduce brain edema, Evans blue penetration and upregulated the expression of blood-brain barrier (BBB)-related tight junction (TJ) proteins, exerting a protective effect on the BBB in vivo after TBI. In the TBI repair phase, rhFGF20 promoted angiogenesis, neurological and cognitive function recovery. In tumor necrosis factor-α (TNF-α)-induced human brain microvascular endothelial cells (hCMEC/D3), an in vitro BBB disruption model, rhFGF20 reversed the impairment in cell migration and tube formation induced by TNF-α. Moreover, in both the TBI mouse model and the in vitro model, rhFGF20 increased the expression of ß-catenin and GSK3ß, which are the two key regulators in the Wnt/ß-catenin signaling pathway. In addition, the Wnt/ß-catenin inhibitor IWR-1-endo significantly reversed the effects of rhFGF20. These results indicate that rhFGF20 may prevent vascular repair and angiogenesis through the Wnt/ß-catenin pathway.

Loganin substantially ameliorates molecular deficits, pathologies and cognitive impairment in a mouse model of Alzheimer's disease.

Alzheimer's disease (AD) is the most common age-related neurodegenerative disease threatening the health of the elderly, but the available therapeutic and preventive drugs remain suboptimal. Loganin, an iridoid glycoside extracted from Cornus officinalis, is reported to have anti-inflammatory and memory-enhancing properties. This study is aimed to explore the influence of loganin on cognitive function in 3xTg-AD mice and the underlying mechanism associated with its neuroprotection. According to the results of behavioral tests, we found that administration of loganin could significantly alleviate anxiety behavior and improve memory deficits of 3xTg-AD mice. Furthermore, immunohistochemical analysis displayed that there were decreased Aß deposition in the hippocampus and cortex of 3xTg-AD mice treated with loganin compared with the control mice. Importantly, the Aß-related pathological change was mainly involved in altering APP expression and processing. And loganin was also found to reduce the levels of phosphorylated tau (i.e. pTauS396 and pTauS262) in 3xTg-AD mice. By performing 2D-DIGE combined with MALDI-TOF-MS/MS, we revealed 28 differentially expressed proteins in the 3xTg-AD mice treated with loganin compared with the control mice. Notably, 10 proteins largely involved in energy metabolism, synaptic proteins, inflammatory response, and ATP binding were simultaneously detected in 3xTg-AD mice compared to WT mice. The abnormal changes of energy metabolism (PAGM1 and ENO1), synaptic proteins (SYN2 and Cplx2), inflammatory response (1433Z) were verified by western blot. Overall, our study suggested that loganin could be used as a feasible candidate drug to ameliorate molecular deficits, pathologies and cognitive impairment for prevention and treatment of AD.

Effects and mechanisms of probucol on aging-related hippocampus-dependent cognitive impairment.

BACKGROUND: In the present study, we aimed to investigate the effects of probucol on aging-related hippocampus-dependent cognitive impairment and explore the potential mechanisms. METHODS: D-galactose (100 mg/kg, once daily for 6 weeks) was subcutaneously injected to induce aging in mice. Then the mice were administered with probucol or vehicle once a day for 2 weeks. The hippocampus-related cognition was evaluated with Morris water maze test, novel object recognition test, and contextual fear conditioning test. Moreover, synaptic plasticity was assessed, and RNA-sequencing was applied to further explore the molecular mechanisms. RESULTS: Aging mice induced by D-galactose showed conspicuous learning and memory impairment, which was significantly ameliorated by probucol. Meanwhile, probucol enhanced the spine density and dendritic branches, improved long-term potentiation, and increased the expression of PSD95 of aging mice. Probucol regulated 70 differentially expressed genes compared to D-galactose group, of which 38 genes were upregulated and 32 genes were downregulated. At last, RNA-sequencing results were verified by quantitative reverse transcription-polymerase chain reaction. CONCLUSIONS: Probucol improved learning and memory in aging mice through enhancing synaptic plasticity and regulating gene expression, indicating the potential application of probucol to prevent and treat aging-related disorders.

Catalytically active gold clusters with atomic precision for noninvasive early intervention of neurotrauma.

BACKGROUND: Neurotrauma is a worldwide public health problem which can be divided into primary and secondary damge. The primary damge is caused by external forces and triggers the overproduction of peroxides and superoxides, leading to long-lasting secondary damage including oxidative stress, wound infection and immunological reactions. The emerging catalysts have shown great potential in the treatment of brain injury and neurogenic inflammation, but are limited to biosafety issues and delivery efficiency. RESULTS: Herein, we proposed the noninvasive delivery route to brain trauma by employing highly active gold clusters with enzyme-like activity to achieve the early intervention. The decomposition rate to H2O2 of the ultrasmall gold clusters is 10 times that of glassy carbon (GC) electrodes, indicating excellent catalytic activity. The gold clusters can relieve the oxidative stress and decrease the excessive O2·- and H2O2 both in vitro and in vivo. Besides, gold clusters can accelerate the wound healing of brain trauma and alleviate inflammation via inhibiting the activation of astrocytes and microglia through noninvasive adminstration. decrease the peroxide and superoxide of brain tissue. CONCLUSIONS: Present work shows noninvasive treatment is a promising route for early intervention of brain trauma.

Effects of dexmedetomidine on postoperative cognitive function of sleep deprivation rats based on changes in inflammatory response.

We aimed to assess the effects of dexmedetomidine (DEX) on postoperative cognitive function of sleep deprivation (SD) rats based on changes in inflammatory response. Male rats were randomly divided into blank control (C), SD, DEX, and SD+DEX groups. The SD model was established through intraperitoneal injection of DEX. The escape latency was detected through Morris water maze test daily, and the mechanical withdrawal threshold and thermal withdrawal latency were detected for 8 d. The content of malondialdehyde (MDA) and activity of superoxide dismutase (SOD) in hippocampus homogenate were determined, and the morphological changes in neurons were detected through Nissl staining. The concentration of interleukin-1ß (IL-1ß), tumor necrosis factor-α (TNF-α), and IL-6 in the hippocampus was detected by enzyme-linked immunosorbent assay, and the Rac1/protein kinase B (AKT)/nuclear factor-κB (NF-κB) expressions were detected by Western blotting. The changes in immunofluorescence localization of NF-κB were observed by confocal microscopy. Compared with SD group, the escape latency was shortened, original platform-crossing times increased, MDA content declined, SOD activity rose, neurons were arranged orderly and number of Nissl bodies increased in the hippocampal CA1 region, levels of IL-1ß, TNF-α, and IL-6 in the hippocampus decreased, Rac1/AKT/NF-κB expressions were down-regulated, and proportion of NF-κB entering the nucleus declined in SD+DEX group (P < 0.05). DEX can effectively alleviate postoperative hippocampal inflammation and improve cognitive function of SD rats. The ability of DEX to relieve oxidative stress of hippocampal neurons, restore damaged cells, and reduce hippocampal inflammation in SD rats may be related to the Rac1/AKT/NF-κB pathway.

Sulforaphane inhibits the production of Aß partially through the activation of Nrf2-regulated oxidative stress.

Sulforaphane (SFN), a potent nuclear factor erythroid 2-related factor 2 (Nrf2) activator, presents a potential role in improving Alzheimer's disease (AD)-specific symptoms. However, the regulation mechanism of SFN in AD is poorly understood. Here, we established AD models both in vitro and in vivo. Animal behaviors were tested by the Morris water maze test. The pathology of the hippocampus and the content of Aß were detected. SFN (40 mg kg-1) decreased the escape latency (24.96 ± 7.43 s) and increased the target-zone frequency (3.19 ± 1.19) in rats. SFN improved the pathological morphology and the number of neurons in the hippocampus. Additionally, SFN significantly upregulated the contents of thioredoxin and glutathione as well as the activities of antioxidant enzymes, along with the expression of the Nrf2 protein. Conversely, SFN lowered the Aß content and ROS level in N2a/APP cells. After silencing the Nrf2 by SiRNA, the inhibitory effects of SFN on ROS and Aß production were partially weakened. In conclusion, the improvement of AD by SFN was closely related with Nrf2 activation.

PARP inhibitor PJ34 ameliorates cognitive impairments induced by transient cerebral ischemia/reperfusion through its anti-inflammatory effects in a rat model.

Cerebral ischemia is a major health threat to humankind around the world, and the reperfusion methods may provoke irreversible damages to brain tissues, causing impairment of neurological function. The goal of this study is to investigate the potential neurological protective effect of PJ34, a well-characterized poly (ADP-ribose) polymerase 1 (PARP-1) inhibitor, on cerebral ischemia-reperfusion (I/R)-induced injury of the rat model. The cerebral I/R rats were received (3, 6, or 12 mg/kg) injections of PJ34 or saline at 24 h, 6 h before middle cerebral artery occlusion (MCAO) and 1 h, 24 h, and 48 h after MCAO. All rats were subject to the neurological behavior tests by open field test and Morris water maze test. The expression of pro-inflammatory cytokines, Cyclooxygenase 2 (COX-2) and inducible nitric oxide synthase (iNOS) in cerebral tissues was also determined. Our results demonstrated that the administration of PJ34 dose-dependently ameliorated cerebral I/R-induced injury and improved neurological performance of cerebral I/R rats. We also revealed that PJ34 treatment effectively reduced COX2, iNOS, and pro-inflammatory cytokine levels in the I/R-induced injury tissues. Our finding further supports that inhibition of PARP-1 activity is beneficial for reducing post-I/R-induced brain damage via targeting inflammatory response.