Brain Dopamine Concentrations Research Articles

A Single Electrode Organic Neuromorphic Device for Dopamine Sensing in Vivo

AbstractOrganic Electronic platforms for biosensing are being demonstrated at a fast pace, especially in healthcare applications where the use of organic (semi‐)conductive materials leads to devices that efficiently interface living matter. Nevertheless, interesting properties of organic (semi‐)conductors are usually neglected in the development of (bio‐)sensors. Among these, the non‐linear response when operated under dynamic biasing conditions (i.e., with pulsed driving voltages), thus mimicking synaptic plasticity phenomena, offers promising and largely unexplored possibilities for bio‐sensing. The artificial synaptic response's figures of merit reflect the composition of the surrounding environment and, ultimately, the ion concentration and dynamics at the organic (semi‐)conductor/electrolyte interface. Therefore, new sensing strategies that rely on the effect of target analytes on the short‐term plasticity response of Organic Neuromorphic Devices are being demonstrated. This work presents the development of a label‐free Single Electrode Neuromorphic Device (SEND) specifically designed for in vivo real‐time mapping of dopamine concentration. The device response is investigated as a function of the driving frequency, resulting in the determination of the optimal operational configuration for minimally invasive neuromorphic devices. It exhibits stable multi‐parametric response in complex fluids, in brain's mechanical models and in vivo, enabling monitoring of local variations of dopamine concentration in the rat brain.

Modulation of tenofovir by probenecid: Impact on drug, interleukin-1β, and dopamine concentration in the prefrontal cortex and cerebellum

The blood–brain barrier’s limited permeability to tenofovir restricts its ability to clear HIV from the brain. Probenecid acting as an adjuvant increases tenofovir concentrations in plasma and the kidneys thereby enhancing its therapeutic effect. However, the probenecid effect on brain tenofovir concentration and possible adverse effects remains poorly understood. We investigated the effect of probenecid co-administered tenofovir on tenofovir brain concentration, interleukin-1β (IL-1β) and dopamine concentration in the prefrontal cortex (PFC) and the cerebellum. Ninety-six male BALB/c mice were divided into four groups viz: a control group, Tenofovir disoproxil fumarate (TDF) treated, probenecid treated, and TDF + probenecid treated. We orally administered a single dose of TDF (5 mg/kg), and probenecid (8.3 mg/kg), and sacrificed six mice per group after 1 h, 4 h, and 6 h post-treatment to collect plasma, PFC, and cerebellar tissue. Co-administered tenofovir increased tenofovir concentration, peaking at 6 h with the cerebellum having the highest concentration. This suggests that probenecid enhanced the entry of tenofovir into the brain. Tenofovir alone increased IL-1β concentration at all intervals post-administration, while probenecid alone had no impact on IL-1β concentration. Co-administered tenofovir also increased IL-1β concentration. Probenecid’s limited impact on IL-1β concentration following co-administration suggests that its anti-inflammatory properties may require more than 6 h to have an effect. Furthermore, neither tenofovir nor probenecid affected dopamine concentration. In conclusion, probenecid enhances the concentration and retention of tenofovir in the brain, making it a possible pharmacokinetic enhancer. However, its anti-inflammatory effects may require a longer duration to fully manifest.

3 The impact of early-life cecal microbiota transplantation on injurious behaviors in egg-laying chickens

Abstract Injurious behaviors in laying hens are a critical issue facing the poultry egg industry. Recent studies have shown that the gut microbiota influences host brain function and behavioral characteristics in humans and various animals. In laying hens, it has been reported that injurious behaviors (such as aggression, feather pecking and cannibalism) are associated with dysregulation of the microbiota-gut-brain axis. To further interrogate the role of the microbiota-gut-brain axis on bird behavior, we used two inbred layer chicken lines, 63 and 72 (line 72 displays more aggressive behavior), and transferred pooled cecal contents from either line to day of hatch chicks. Cecal microbiota transplantation (CMT) from each line was conducted once daily, by gavage, from d 1 to 10, then boosted once weekly from wk 3 to 5. We hypothesized that the cecal microbiota composition and animal behavior in recipient birds would be similar to that of their donor animals because of the microbiota-gut-brain axis. Microbial communities were compared using 16S rRNA gene amplicon sequencing, behavior was recorded in home cages as well as in paired aggression tests, and physiological measurements were taken from brain tissue and blood to measure levels of neurotransmitters and immune function. When examining the differences in the donor birds, hypothalamic serotonin and tryptophan concentrations were greater for line 63 compared with line 72 birds (P < 0.05). Plasma corticosterone, heterophil/lymphocyte ratios, and central norepinephrine concentrations were less for line 63 birds (P < 0.05). Cecal microbial diversity was not statistically different between the lines, but many bacterial taxa were differentially abundant between the two lines. After cecal transplantation, 63-CMT (recipient) birds displayed less aggressive behavior with a greater hypothalamic serotonergic activity at wk 5, similar to donor birds. Correspondingly, two amplicon sequence variants (ASVs) belonging to Lachnospiraceae and one Ruminococcaceae UCG-005 ASV were positively correlated with the concentrations of brain tryptophan and serotonin, respectively. Along with greater aggression, 72-CMT birds seemed to have greater physical growth traits (increased body weight, ileal villus/crypt; P ≤ 0.05), but decreased concentrations of brain norepinephrine and dopamine, and the greatest ileal serotonin turnover in the ileum at wk 5 (P < 0.05). ASVs belonging to Mollicutes RF39 and GCA-900066225 in 72-CMT birds were negatively correlated with the brain 5-hydroxyindoleacetic acid (5-HIAA) at wk 5, and one Bacteroides ASV was negatively correlated with plasma serotonin at wk 16. Meanwhile, 63-CMT birds potentially had better gut health and immune function (greater concentrations of ileal mucosal secretory IgA, plasma IL-10; P < 0.05). These results suggest linkages among serotonergic activity, stress response, innate immunity, and gut microbiota populations and that CMT could be a novel strategy for reducing aggressive behavior through regulating signaling along the microbiota-gut-brain axis.

Novel Phytosomal Formulation of Emblica officinalis Extracts with Its In Vivo Nootropic Potential in Rats: Optimization and Development by Box-Behnken Design

Purpose. The present study aimed to improve the aqueous solubility, permeability, bioavailability, and nootropic potential of standardized Emblica officinalis extract (EOE) by developing a novel phytosomal formulation. Method. Emblica officinalis extract-loaded phytosomes (EOPs) were prepared using solvent evaporation. The EOP was prepared at different molar ratios of extract and phospholipid. Herein, the effects of phospholipid extract ratio (A), temperature (B), and reaction time (C) were systematically investigated on entrapment efficiency using Box-Behnken design. In vitro and in vivo characterizations of the optimized formulation were performed. Results. Optimized EOP formulation (89.90 ± 0.24 μg/ml) exhibited improved aqueous solubility than plain EOE (11.85 ± 0.25 μg/ml). The optimized formulation’s particle size and Zeta potential were 198.4 ± 0.20 nm and −39.0 ± 0.40 mv. DSC and XRD studies confirmed the partial amorphization of EOE in phytosomes. Optimized formulation exhibited 69.82 ± 0.17% of EOE release at 12 h and followed zero-order release kinetics. Moreover, the phytosomal formulation of EOE exhibited its rationality with an improvement of bioavailability by 2.7 folds compared with pure EOE. Compared to EOE, EOP showed significantly (p<0.05 lower escape and transfer latencies on both days in MWMT and EPMT, indicating more effective memory-enhancing activity. Furthermore, EOP-treated rats exhibited improved acetylcholine (Ach) levels than EOE. Brain tissue concentrations measured following EOP oral administration (1.06 ± 0.04 μg/ml) were substantially greater (p<0.05) than those following EOE (0.32 ± 0.07 μg/ml). The brain dopamine and serotonin concentration were found to be higher (16.27 ± 1.209 and 43.28 ± 1.550 ng/ml) in the EOP-treated group as compared to the pure extract-treated group (10.40 ± 1.185 and 32.79 ± 1.738 ng/ml). Conclusion. Improvement of aqueous solubility, permeability, dissolution, bioavailability, and narrower particle size distribution could facilitate enhancement in the nootropic potential of EOE phytosomal formulation.

Effects of cannabidiol in post-stroke mood disorders in neonatal rats.

Neonatal rats can manifest post-stroke mood disorders (PSMD) following middle cerebral artery occlusion (MCAO). We investigated whether cannabidiol (CBD) neuroprotection, previously demonstrated in neonatal rats after MCAO, includes prevention of PSMD development. Seven-day-old Wistar rats (P7) underwent MCAO and received either vehicle or 5 mg/kg CBD treatment. Brain damage was quantified by MRI, and neurobehavioral and histological (TUNEL) studies were performed at P14 and P37. PSMD were assessed using the tail suspension test, forced swimming test, and open field tests. The dopaminergic system was evaluated by quantifying dopaminergic neurons (TH+) in the Ventral Tegmental Area (VTA), measuring brain dopamine (DA) concentration and DA transporter expression, and assessing the expression and function D2 receptors (D2R) through [35S]GTPγS binding. Animals without MCAO served as controls. CBD reduced MCAO-induced brain damage and improved motor performance. At P14, MCAO induced depressive-like behavior, characterized by reduced TH+ cell population and DA levels, which CBD did not prevent. However, CBD ameliorated hyperactivity observed at P37, preventing increased DA concentration by restoring D2R function. These findings confirm the development of PSMD following MCAO in neonatal rats and highlight CBD as a neuroprotective agent capable of long-term functional normalization of the dopaminergic system post-MCAO. MCAO in neonatal rats led to post-stroke mood disorders consisting in a depression-like picture in the medium term evolving towards long-term hyperactivity, associated with an alteration of the dopaminergic system. The administration of CBD after MCAO did not prevent the development of depressive-like behavior, but reduced long-term hyperactivity, normalizing dopamine receptor function. These data point to the importance of considering the development of depression-like symptoms after neonatal stroke, a well-known complication after stroke in adults. Our work confirms the interest of CBD as a possible treatment for neonatal stroke.

Koumine supplementation positively affects growth, circadian rhythms, and stress levels in Cyprinus carpio

This study evaluated the effects of koumine on growth performance, brain transcriptional response, expression of genes associated with circadian rhythms, and physiological stress indicators in carp (5.21 ± 0.05 g). Fish were fed four different koumine levels (0, 0.2, 2, and 20 mg/kg) of diet (crude protein 29.71%, crude lipid 3.68%) for 10 weeks in a RAS (26.0–28.0 ℃, pH 7.3–7.5, and DO 5.5–6.1 mg/L). Each type of feed was administered to three replicate tanks (50 L, 12 cycles per day), each containing 30 fish, with feeding occurring twice daily. The results showed that koumine supplementation improved the growth performance of carp. Significant enrichment of circadian rhythm, memory, and behavior-related pathways in the brain of the koumine-supplemented group of fish. The circadian rhythm positive feedback-related genes MKP5, ATP1A, ATP2A, and CRY2 were significantly upregulated (P < 0.05), and the negative feedback-related genes REV-ERBA were significantly downregulated (P < 0.05) in the koumine supplementation group. The fish in the koumine group showed a significant increase in brain dopamine concentrations (P < 0.05) and a significant decrease in 5-hydroxytryptamine concentrations (P < 0.05). Overall, our study showed that koumine supplementation improved growth performance and reduced stress levels during rearing of carp, which may be related to the regulation of expression of circadian rhythm-related pathways.

Bee venom (Apis mellifera L.) rescues zinc oxide nanoparticles induced neurobehavioral and neurotoxic impact via controlling neurofilament and GAP-43 in rat brain

This study investigated the possible beneficial role of the bee venom (BV, Apis mellifera L.) against zinc oxide nanoparticles (ZNPs)-induced neurobehavioral and neurotoxic impacts in rats. Fifty male Sprague Dawley rats were alienated into five groups. Three groups were intraperitoneally injected distilled water (C 28D group), ZNPs (100 mg/kg b.wt) (ZNPs group), or ZNPs (100 mg/kg.wt) and BV (1 mg/ kg.bwt) (ZNPs + BV group) for 28 days. One group was intraperitoneally injected with 1 mL of distilled water for 56 days (C 56D group). The last group was intraperitoneally injected with ZNPs for 28 days, then BV for another 28 days at the same earlier doses and duration (ZNPs/BV group). Depression, anxiety, locomotor activity, spatial learning, and memory were evaluated using the forced swimming test, elevated plus maze, open field test, and Morris water maze test, respectively. The brain contents of dopamine, serotonin, total antioxidant capacity (TAC), malondialdehyde (MDA), and Zn were estimated. The histopathological changes and immunoexpressions of neurofilament and GAP-43 protein in the brain tissues were followed. The results displayed that BV significantly decreased the ZNPs-induced depression, anxiety, memory impairment, and spatial learning disorders. Moreover, the ZNPs-induced increment in serotonin and dopamine levels and Zn content was significantly suppressed by BV. Besides, BV significantly restored the depleted TAC but minimized the augmented MDA brain content associated with ZNPs exposure. Likewise, the neurodegenerative changes induced by ZNPs were significantly abolished by BV. Also, the increased neurofilament and GAP-43 immunoexpression due to ZNPs exposure were alleviated with BV. Of note, BV achieved better results in the ZNPs + BV group than in the ZNPs/BV group. Conclusively, these results demonstrated that BV could be employed as a biologically effective therapy to mitigate the neurotoxic and neurobehavioral effects of ZNPs, particularly when used during ZNPs exposure.

Behavioral and neurological effects of Vrk1 deficiency in zebrafish

Vaccinia-related kinase 1 (VRK1) is a serine/threonine kinase, for which mutations have been reported cause to neurodegenerative diseases, including spinal muscular atrophy, characterized by microcephaly, motor dysfunction, and impaired cognitive function, in humans. Partial Vrk1 knockdown in mice has been associated with microcephaly and impaired motor function. However, the pathophysiological relationship between VRK1 and neurodegenerative disorders and the precise mechanism of VRK1-related microcephaly and motor function deficits have not been fully investigated. To address this, in this study, we established vrk1-deficient (vrk1−/−) zebrafish and found that they show mild microcephaly and impaired motor function with a low brain dopamine content. Furthermore, vrk1−/− zebrafish exhibited decreased cell proliferation, defects in nuclear envelope formation, and heterochromatin formation in the brain. To our knowledge, this is the first report demonstrating the important role of VRK1 in microcephaly and motor dysfunction in vivo using vrk1−/− zebrafish. These findings contribute to elucidating the pathophysiological mechanisms underlying VRK1-mediated neurodegenerative diseases associated with microcephaly.

Optimizing zebrafish rearing-Effects of fish density and environmental enrichment.

Despite its popularity in research, there is very little scientifically validated knowledge about the best practices on zebrafish (Danio rerio) husbandry, which has led to several facilities having their own husbandry protocols. This study was performed to expand knowledge on the effects of enrichment and fish density on the welfare of zebrafish, with hopes of providing a scientific basis for future recommendations and legislations. Zebrafish were reared at three different stocking densities, (1, 3 or 6 fish/L), in tanks with or without environmental enrichment. Agonistic behavior was observed twice a week for 9 weeks directly in the housing tanks. Aspects of welfare is known to be reflected in neuroendocrine stress responses. Thus, cortisol secretion in response to lowering the water level was analyzed for each group. In addition, we assessed cortisol secretion in response to confinement and risk-taking behavior (boldness) using the novel tank diving test for individual fish. At termination of the experiment fish were subjected to stress by transfer to a novel environment and brain tissue was sampled for analysis of brain monoaminergic activity. Fish kept at the lowest density (1 fish/L) showed a significantly higher level of aggression than fish kept at 3 or 6 fish/L. Moreover, fish kept at this low density showed significantly higher cortisol secretion on a group level than fish kept at the higher stocking densities, when subjected to lowering of the water level. Keeping fish at 1 fish/L also had effects on brain monoamines, these fish showing higher brain dopamine concentrations but lower dopamine turnover than fish kept at higher densities. Neither stocking density or enrichment had any clear effects on the behavior of individual fish in the novel tank diving test. However, fish kept at high densities showed lower and more variable growth rates than fish kept at 1 fish/L. Taken together these results suggest that zebrafish should not be kept at a density of 1 fish/L. The optimal stocking density is likely to be in the range of 3-6 fish/L.

Analysis of Phenolic Acids and Flavonoids in Rabbiteye Blueberry Leaves by UPLC-MS/MS and Preparation of Nanoemulsions and Extracts for Improving Antiaging Effects in Mice.

Rabbiteye blueberry leaves, a waste produced after harvest of blueberry, are rich in polyphenols. This study aims to analyze phenolic acids and flavonoids in blueberry leaves by UPLC-MS/MS and prepare nanoemulsions for determining anti-aging activity in mice. Overall, 30% ethanol was the most suitable extraction solvent for total phenolic acids and total flavonoids. A total of four phenolic acids and four flavonoids were separated within seven minutes for further identification and quantitation by UPLC-MS/MS in selective reaction monitoring (SRM) mode, with 3-O-caffeoylquinic acid being present in the highest amount (6474.2 μg/g), followed by quercetin-3-O-galactoside (1943.9 μg/g), quercetin-3-O-rutinoside (1036.6 μg/g), quercetin-3-O-glucoside (867.2 μg/g), 5-O-caffeoylquinic acid (815.8 μg/g), kaempferol-3-O-glucoside (309.7 μg/g), 3,5-dicaffeoylquinic acid (195.3 μg/g), and 4,5-dicaffeoylquinic acid (60.8 μg/g). The blueberry nanoemulsion was prepared by using an appropriate ratio of soybean oil, Tween 80, glycerol, ethanol, and water at 1.2%, 8%, 2%, 2%, and 86.8%, respectively, and mixing with dried blueberry extract, with the mean particle size and zeta potential being 16 nm and -54 mV, respectively. A high stability was observed during storage of nanoemulsion for 90 days at 4 °C and heated at 100 °C for 2 h. An animal study revealed that this nanoemulsion could elevate dopamine content in mice brain as well as superoxide dismutase, glutathione peroxidase, and catalase activities in mice liver while reducing the contents of malondialdehyde and protein carbonyl in mice brains. Collectively, the high-dose nanoemulsion possessed the highest efficiency in improving mice aging with a promising potential for development into a health food.

The Role of the Dopamine System in Post-Stroke Mood Disorders in Newborn Rats.

Post-stroke mood disorders (PSMD) affect disease prognosis in adults. Adult rodent models underlie the importance of the dopamine (DA) system in PSMD pathophysiology. There are no studies on PSMD after neonatal stroke. We induced neonatal stroke in 7-day-old (P7) rats by temporal left middle cerebral artery occlusion (MCAO). Performance in the tail suspension test (TST) at P14 and the forced swimming test (FST) and open field test (OFT) at P37 were studied to assess PSMD. DA neuron density in the ventral tegmental area, brain DA concentration and DA transporter (DAT) expression as well as D2 receptor (D2R) expression and G-protein functional coupling were also studied. MCAO animals revealed depressive-like symptoms at P14 associated with decreased DA concentration and reduced DA neuron population and DAT expression. At P37, MCAO rats showed hyperactive behavior associated with increased DA concentration, normalization of DA neuron density and decreased DAT expression. MCAO did not modify D2R expression but reduced D2R functionality at P37. MCAO-induced depressive-like symptoms were reversed by the DA reuptake inhibitor GBR-12909. In conclusion, MCAO in newborn rats induced depressive-like symptoms and hyperactive behavior in the medium and long term, respectively, that were associated with alterations in the DA system.

The Ubiquitin Proteasome System as a Therapeutic Area in Parkinson's Disease.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder. There are no available therapeutics that slow or halt the progressive loss of dopamine-producing neurons, which underlies the primary clinical symptoms. Currently approved PD drugs can provide symptomatic relief by increasing brain dopamine content or activity; however, the alleviation is temporary, and the effectiveness diminishes with the inevitable progression of neurodegeneration. Discovery and development of disease-modifying neuroprotective therapies has been hampered by insufficient understanding of the root cause of PD-related neurodegeneration. The etiology of PD involves a combination of genetic and environmental factors. Although a single cause has yet to emerge, genetic, cell biological and neuropathological evidence implicates mitochondrial dysfunction and protein aggregation. Postmortem PD brains show pathognomonic Lewy body intraneuronal inclusions composed of aggregated α-synuclein, indicative of failure to degrade misfolded protein. Mutations in the genes that code for α-synuclein, as well as the E3 ubiquitin ligase Parkin, cause rare inherited forms of PD. While many ubiquitin ligases label proteins with ubiquitin chains to mark proteins for degradation by the proteasome, Parkin has been shown to mark dysfunctional mitochondria for degradation by mitophagy. The ubiquitin proteasome system participates in several aspects of the cell's response to mitochondrial damage, affording numerous therapeutic opportunities to augment mitophagy and potentially stop PD progression. This review examines the role and therapeutic potential of such UPS modulators, exemplified by both ubiquitinating and deubiquitinating enzymes.

Effects of mitophagy on aerobic exercise intervention for depression in rats

Objective: This experiment was designed to observe the effects of aerobic exercise on depressive behavior in rats induced by chronic unpredictable mild stress (CUMS), and to explore the possible mechanism by detecting the proteins related to mitochondrial autophagy. Methods: SD rats were randomly divided into three groups: blank control group (C, n=12), depression model group (D, n=12) and post-depression exercise group (D+E, n=12). Group D and D+E were modeled with CUMS for 28 days, and group D+E underwent aerobic exercise intervention for 4 weeks after model establishment. Then the behavior of rats was evaluated. The concentrations of whole brain dopamine and norepinephrine were determined by ELISA kits. The morphology and structure of mitochondria in the frontal lobe were observed with the transmission electron microscope (TEM). Mitochondrial autophagy lysosomes were localized by immunofluorescence colocalization. The expressions of LC3 and P62 proteins in the frontal lobe were measured with Western Blotting. The relative content of mitochondrial DNA was detected using Real-time PCR. Results: ①Compared with group C, the sucrose preference ratio in group D was decreased significantly(P＜0.01); Compared with group D, the sucrose preference ratio in group D+E was increased significantly (P＜0.01). ②In the open field experiment, compared with group C, group D had a significant decrease in activity, average speed and total distance (P＜0.05); Compared with group D, the average rate of activity in group D+E was significantly higher (P＜0.05). ③ELISA results showed that the levels of whole brain dopamine and norepinephrine were significantly lower in group D rats than those in group C (P＜0.05). ④Under transmission electron microscopy, compared with group C, group D had different degrees of mitochondrial swelling, decreased crest density, and intermembrane space dilation.; Compared with group D, a significant increase in mitochondrial autophagosomes and autophagic lysosomes was observed in neurons in group D+E. Increased co-localization of mitochondria with lysosomes in the D+E group could be observed under fluorescence microscopy. ⑤Compared with group C, the expression of P62 was increased significantly(P＜0.05), and LC3II/LC3I ratio was decreased significantly (P＜0.05) in group D; Compared with group D, LC3II/LC3I ratio was significantly higher in group D+E than that in group D (P＜0.05). ⑥Compared with group C, the relative number of mitochondrial DNA in the frontal lobe of group D was increased significantly (P＜0.05). Conclusion: Aerobic exercise has a significant improvement effect on depression induced by CUMS in rats, and its mechanism may be related to the upregulation of the level of linear autophagy.

Lifetime exposure to benzophenone-3 at an environmentally relevant concentration leads to female–biased social behavior and cognition deficits in zebrafish

Benzophenone-3 (BP3) is an organic UV filter widely used in the commercial formulations of various personal care products. It has been detected ubiquitously in the environment and human tissues. Recently, BP3–induced neurotoxicity has been identified as the main health risk to humans and aquatic organisms. However, most research has been focused on embryonic development, and few studies explore chronic lifetime exposure. In the present study, we evaluated the neurotoxicity of lifetime exposure to an environmentally relevant concentration of BP3 in zebrafish. Our findings revealed that continuous BP3 exposure at 10 μg/L (0.04 μM) from 6 h post fertilization (hpf) to adulthood at 5 months led to female–biased social behavioral deficits and learning and memory impairment. These neurobehavioral effects were characterized by decreased prosocial activities in the social preference test and mirror biting assay, and reduced learning and memory in a T–maze test. Furthermore, these effects were accompanied by female–specific decreases in brain weight and brain dopamine concentration, female–biased decrease of neurogenesis in the telencephalon as well as female–specific increases in apoptotic cells and expression levels of genes and proteins related to the apoptosis pathway in the brain. Our results suggest that BP3–induced social behavior and learning/memory deficits are correlated to the cell loss in the telencephalon region of the zebrafish brain.

Dynamics of Dopamine and Other Monoamines Content in Rat Brain after Single Low-Dose Carbon Nuclei Irradiation

Space radiation, presented primarily by high-charge and -energy particles (HZEs), has a substantial impact on the central nervous system (CNS) of astronauts. This impact, surprisingly, has not only negative but also positive effects on CNS functions. Despite the fact that the mechanisms of this effect have not yet been elucidated, several studies indicate a key role for monoaminergic networks underlying these effects. Here, we investigated the effects of acute irradiation with 450 MeV/n carbon (12C) nuclei at a dose of 0.14 Gy on Wistar rats; a state of anxiety was accessed using a light–dark box, spatial memory in a Morris water maze, and the dynamics of monoamine metabolism in several brain morphological structures using HPLC. No behavioral changes were observed. Irradiation led to the immediate suppression of dopamine turnover in the prefrontal cortex, hypothalamus, and striatum, while a decrease in the level of norepinephrine was detected in the amygdala. However, these effects were transient. The deferred effect of dopamine turnover increase was found in the hippocampus. These data underscore the ability of even low-dose 12C irradiation to affect monoaminergic networks. However, this impact is transient and is not accompanied by behavioral alterations.

Oral administration of phenylalanine molecularly imprinted polymer (MIP) benefits PKU mouse model.

Phenylketonuria (PKU) is a rare genetic disorder caused by a defect in the metabolism of phenylalanine (Phe). Currently, the most commonly used treatment for PKU is dietary Phe restriction. Problems associated with Phe restricted diets include lack of universal availability, high treatment costs, and reduced adherence to continued treatment with age and finally the development of psychological and neurological problems in a significant proportion of patients despite early start of treatment. One possible approach to decreasing blood Phe level, is inhibition of GI tract absorption of this amino acid. We had previously shown that a Phe selective molecularly imprinted polymer was able to bind Phe in the GI tract and attenuate its plasma concentration. In this work, we used different orally administered Phe selective molecularly imprinted polymer doses in a PKU mouse model to further study the effects of this treatment on biochemical profile and cognitive function in test animals. Treatments started 21 days postnatally. After 3 weeks, brain and plasma amino acid profiles and brain monoaminergic neurotransmitter concentrations were measured. Behavioral profile was also evaluated. Treatment with 2% and 5% Phe selective molecularly imprinted polymer significantly reduced levels of blood Phe in PKU model animals (46% and 48% respectively) meanwhile levels of other amino acids remained unchanged. Brain dopamine concentrations in hippocampus was effectively restored by supplementation of Phe selective molecularly imprinted polymer. Finally, polymer treatment improved locomotor dysfunction in PKU model animals. Our data suggest that the Phe selective molecularly imprinted polymer can be a new candidate for treatment of PKU patients. Take home message: Orally administered Phenylalanine Selective Molecularly Imprinted Polymer is able to inhibit absorption of phenylalanine from the GI tract and may offer a new treatment, in conjunction with dietary restriction, for PKU patients.

Wuzi Yanzong pill attenuates MPTP-induced Parkinson’s Disease via PI3K/Akt signaling pathway

Wuzi Yanzong Pill (WYP) was found to play a protective role on nerve cells and neurological diseases, however the molecular mechanism is unclear. To understand the molecular mechanisms that underly the neuroprotective effect of WYP on dopaminergic neurons in Parkinson's disease (PD). PD mouse model was induced by the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Gait and hanging tests were used to assess motor behavioral function. Immunofluorescence assay was used to determine TH-positive neurons in substantia nigra (SN). Apoptosis, dopamine and neurotrophic factors as well as expression of PI3K/Akt pathway were detected by TUNEL staining, ELISA and western blotting, respectively. First, it was observed that WYP intervention improved abnormal motor function in MPTP-induced PD model, alleviated the loss of TH+ neurons in SN, and increased dopamine content in brain, revealing a potential protective effect. Second, network pharmacology was used to analyze the possible targets and pathways of WYP action in the treatment of PD. A total of 126 active components related to PD were screened in WYP, and the related core targets included ALB, GAPDH, Akt1, TP53, IL6 and TNF. Particularly, the effect of WYP on PD may be medicate through PI3K/Akt signaling pathway and apoptotic regulation. The WYP treated PD mice had higher expression of p-PI3K, p-Akt and Bcl-2 but lower expression of Bax and cleaved caspase-3 than the non-WYP treated PD mice. Secretion of brain-derived neurotrophic factor (BDNF) and cerebral dopamine neurotrophic factor (CDNF) were also increased in the treated mice. WYP may inhibit apoptosis and increase the secretion of neurotrophic factor via activating PI3K/ Akt signaling pathway, thus protecting the loss of dopamine neurons in MPTP-induced PD mice.

Simultaneous administration of coffee and rasagiline/l-dopa protects against paraquat-induced neurochemical and motor behavior impairments in vivo

BackgroundCaffeine is a natural alkaloid present in a variety of highly consumed popular drinks such as coffee, tea and soft drinks as well as chocolate. Its consumption elicits beneficiary psychostimulant that has been linked to a reduced risk of developing Parkinson’s disease (PD). The aim of the present study is to investigate the possible synergistic neuroprotective effects of co-administration of caffeine (CAF) or coffee (COF) with rasagiline (R) or l-dopa against paraquat (PQ)-induced neurochemical and motor behavior impairments in mice.ResultsIn behavioral tests, R + COF increased the locomotor activity in rotarod test compared to l-dopa + COF. l-Dopa combinations decreased the immobility time in FST compared to rasagiline combinations; l-dopa + CAF provided a similar increase in locomotor activity compared to R + CAF. Combination of CAF or COF with l-dopa or rasagiline resulted in a substantial improvement in brain neurotransmitter and antioxidant levels as they significantly increased dopamine and super oxide dismutase but significantly decreased nitric oxide levels as compared to l-dopa or rasagiline, respectively. Furthermore, they also exerted a protective effect against the neurodegenerative histopathological changes induced by PQ.ConclusionsOur findings demonstrated co-administration of COF or CAF, adenosine 2A receptor antagonists, along with l-dopa or rasagiline possesses a new therapeutic strategy for the management of PD neurochemical disturbances and motor behavior impairments through preservation of the brain dopamine and serotonin content, antioxidants level and histological features.

Mitigation of Lead Neurotoxicity by Aqueous Fruit Extract of Adansonia digitata in Adult Wistar Rats

Aim: The current study seeks to explore the neuroprotective benefits of Adansonia digitata against lead induced memory impairment, neurotransmitter/AChE activity imbalance, oxidative stress as well as brain damage.&#x0D; Methodology: Thirty male adult rats weighing 160g-200g were divided randomly into six groups (I-V1) consisting of five (5) rats in each group. Group I served as control and were administered with distilled water (1 ml/kg) only while groups II -VI were treatment groups. Group II were administered 250 mg/kg of Adansonia digitata; group III were administered 30 mg/kg of lead; Group IV were administered 250 mg/kg of Adansonia digitata plus 30 mg/kg of lead; Group V were administered 500 mg/kg of Adansonia digitata plus 30 mg/kg of lead; Group VI were administered 30 mg/kg of lead plus 10 mg/kg of succimer. All administrations were carried out through oral gavage for a period of 28 days.&#x0D; Results: Lead administration caused memory impairment, decreased dopamine concentration and AChE activity in brain, induced oxidative stress resulting in brain damage. Adansonia digitata treatment significantly (P&lt;.001) attenuated memory impairment, modulated dopamine concentration and AChE activity, prevented oxidative stress and ameliorated histopathological changes in the brain of Wistar rats.&#x0D; Conclusion: The result showed that Adansonia digitata ameliorates lead-induced memory impairment in Wistar rats by improving memory index, controlling dopamine concentration and AChE activity, preventing oxidative stress and neuronal degeneration.

Correlations of blood and brain biochemistry in phenylketonuria: Results from the Pah-enu2 PKU mouse

BackgroundIn phenylketonuria (PKU), treatment monitoring is based on frequent blood phenylalanine (Phe) measurements, as this is the predictor of neurocognitive and behavioural outcome by reflecting brain Phe concentrations and brain biochemical changes. Despite clinical studies describing the relevance of blood Phe to outcome in PKU patients, blood Phe does not explain the variance in neurocognitive and behavioural outcome completely. MethodsIn a PKU mouse model we investigated 1) the relationship between plasma Phe and brain biochemistry (Brain Phe and monoaminergic neurotransmitter concentrations), and 2) whether blood non-Phe Large Neutral Amino Acids (LNAA) would be of additional value to blood Phe concentrations to explain brain biochemistry. To this purpose, we assessed blood amino acid concentrations and brain Phe as well as monoaminergic neurotransmitter levels in in 114 Pah-Enu2 mice on both B6 and BTBR backgrounds using (multiple) linear regression analyses. ResultsPlasma Phe concentrations were strongly correlated to brain Phe concentrations, significantly negatively correlated to brain serotonin and norepinephrine concentrations and only weakly correlated to brain dopamine concentrations. From all blood markers, Phe showed the strongest correlation to brain biochemistry in PKU mice. Including non-Phe LNAA concentrations to the multiple regression model, in addition to plasma Phe, did not help explain brain biochemistry. ConclusionThis study showed that blood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters. Take-home messageBlood Phe is still the best amino acid predictor of brain biochemistry in PKU. Nevertheless, neurocognitive and behavioural outcome cannot fully be explained by blood or brain Phe concentrations, necessitating a search for other additional parameters.