Reduction Of Dopamine Research Articles

Neurotransmitter and metabolic effects of interferon-alpha in association with decreased striatal dopamine in a Non-Human primate model of Cytokine-Induced depression.

Inflammatory stimuli administered to humans and laboratory animals affect mesolimbic and nigrostriatal dopaminergic pathways in association with impaired motivation and motor activity. Alterations in dopaminergic corticostriatal reward and motor circuits have also been observed in depressed patients with increased peripheral inflammatory markers. The effects of peripheral inflammation on dopaminergic pathways and associated neurobiologic mechanisms and consequences have been difficult to measure in patients. Postmortem tissue (n=11) from an established, translationally-relevant non-human primate model of cytokine-induced depressive behavior involving chronic interferon-alpha (IFN-a) administration was utilized herein to explore the molecular mechanisms of peripheral cytokine effects on striatal dopamine. Dopamine (but not serotonin or norepinephrine) was decreased in the nucleus accumbens (NAcc) and putamen of IFN-a-treated animals (p<0.05). IFN-a had no effect on number of striatal neurons or dopamine terminal density, suggesting no overt neurodegenerative changes. RNA sequencing examined in the caudate, putamen, substantia nigra, and prefrontal cortical subregions revealed that while IFN-a nominally up-regulated limited numbers of genes enriching inflammatory signaling pathways in all regions, robust, whole genome-significant effects of IFN-a were observed specifically in putamen. Genes upregulated in the putamen primarily enriched synaptic signaling, glutamate receptor signaling, and inflammatory/metabolic pathways downstream of IFN-a, including MAPK and PI3K/AKT cascades. Conversely, gene transcripts reduced by IFN-a enriched oxidative phosphorylation (OXPHOS), protein translation, and pathways regulated by dopamine receptors. Unsupervised clustering identified a gene co-expression module in the putamen that was associated with both IFN-a treatment and low dopamine levels, which enriched similar inflammatory, metabolic, and synaptic signaling pathways. IFN-a-induced reductions in dopamine further correlated with genes related to excitotoxic glutamate, kynurenine, and altered dopamine receptor signaling (r=0.78-97, p<0.05). These findings provide insight into the immunologic mechanisms and neurobiological consequences of peripheral inflammation effects on dopamine, which may inform novel treatment strategies targeting inflammatory, metabolic or neurotransmitter systems in depressed patients with high inflammation.

Single-Vesicle Electrochemistry in Fresh Brain Slices Enables In Situ Quantification of Vesicular Monoamine.

The quantitative analysis of vesicular neurotransmitters in neurons in situ is paramount for investigating neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease (PD). Unfortunately, a direct approach for monitoring neurotransmitter chemistry in single vesicles in fresh brain tissue has remained inaccessible so far. Here, we introduce an innovative platform of single-vesicle electrochemistry (SVE) in fresh brain tissue, enabling the quantification of neurotransmitters at the single-vesicle level for both soma and varicosity. Utilizing this methodology, we investigated a PD animal model, which demonstrated a significant reduction in both vesicular dopamine (DA) storage and exocytotic release in DA neurons in the substantia nigra. Furthermore, SVE unveiled the heterogeneous nature of chemical neurotransmission among DA neurons across different brain regions. Importantly, this tissue-based SVE approach can be extended to quantify other monoamine neurotransmitters, such as norepinephrine and serotonin, at the single-vesicle level. The introduction of this methodology marks a significant advancement, offering a novel avenue to explore neurological and psychiatric disorders through the lens of neurotransmitter signaling in the mammalian brain. This breakthrough has the potential to deepen our understanding of the underlying mechanisms of these complex disorders and may pave the way for the development of targeted therapeutic interventions.

Effect of short-term dopamine reduction on insulin sensitivity and post-prandial insulin and glucose responses in Standardbred horses

The role of dopamine in the regulation of insulin secretion in horses is poorly understood and requires further investigation. Pituitary pars intermedia dysfunction (PPID) is associated with decreased activity of dopaminergic neurons which normally suppress peptide hormone secretion from the pituitary pars intermedia. A high proportion of horses with PPID also have insulin dysregulation (ID), characterised by post-prandial hyperinsulinaemia and/or tissue insulin resistance, which are risk factors for the development of laminitis. The aim of this study was to investigate the effects of alpha-methyl-para-tyrosine (AMPT), a tyrosine hydroxylase inhibitor that reduces dopamine production, on insulin sensitivity and the post-prandial insulin response to a glucose-containing meal. Six healthy Standardbred horses were enrolled in a placebo-controlled randomised crossover study, in which one dose of AMPT (40 mg/kg BW) or placebo was administered orally, prior to performing an in-feed oral glucose test (OGT) and a frequently sampled intravenous glucose tolerance test (FSIGTT). Dopamine reduction by AMPT was confirmed by an increase in plasma prolactin concentration and the lack of post-prandial increase in plasma dopamine concentration compared to placebo. Post-prandial insulin responses, both peak and AUCi, were increased after AMPT compared to placebo (P=0.048 and P=0.005, respectively), without affecting blood glucose concentrations. However, one dose of AMPT did not appear to affect tissue sensitivity as assessed by the FSIGTT. This study confirmed that dopamine plays a role in the regulation of insulin secretion in horses, as it does in other species, whereby the post-prandial release of dopamine into the circulation may inhibit pancreatic insulin secretion. Further studies are required to evaluate different dosing protocols for AMPT, and to further investigate the links between PPID, ID and laminitis risk in horses.

Physiological and metabolic effects of short-term dopamine reduction in healthy horses using a tyrosine hydroxylase inhibitor (alpha-methyl-para-tyrosine)

Alpha-methyl-para-tyrosine (AMPT) is a reversible inhibitor of tyrosine hydroxylase, the rate-limiting enzyme in catecholamine synthesis. This study aimed to determine whether AMPT could reduce dopamine concentrations in horses. Six healthy adult Standardbred geldings were administered AMPT (40 mg/kg BW, orally) or placebo in a randomised crossover study design. Clinical examination findings were recorded, and blood samples were collected for up to 6 h after administration of AMPT or placebo, for measurement of blood glucose, plasma ACTH and cortisol concentrations, and plasma metabolomic analysis. Plasma prolactin concentration was determined as a proxy index of central dopamine reduction. No adverse clinical effects were detected after oral administration of AMPT, with heart rate, mean arterial pressure and blood glucose concentration not differing between AMPT treatment or placebo. Plasma prolactin concentration peaked 1 h after AMPT administration before returning to baseline at 2 h (for five horses) or 6 h (for one horse). Metabolomic analysis demonstrated a reduction in plasma dopamine (0.72-fold change; P=0.016) 1 h after AMPT treatment. Plasma ACTH and cortisol concentrations were not different between AMPT and placebo over time. A few metabolites associated with ketogenesis were increased, and certain amino acids decreased, at 1 h compared with baseline, for both AMPT treatment and placebo. Therefore, AMPT was effective in reducing both central and circulating dopamine concentrations in healthy horses following a single oral dose. Further pharmacokinetic and pharmacodynamic studies are warranted to optimise the dose and duration of AMPT treatment to achieve longer-term dopamine reduction. Plasma metabolomic findings suggested an interruption to energy flux at the time of sample collection, which may be relevant to nutritional studies in horses and warrants further investigation.

Peripheral dopamine suppression and elevated cystatin C in early diabetic nephropathy in spontaneously diabetic rats.

Intrarenal dopamine plays a protective role against the development of diabetic nephropathy during the early stages of the disease. In streptozotocin-induced diabetic mice with renal-specific catechol-O-methyl transferase knockout, intrarenal dopamine was found to suppress glomerular hyperfiltration, reduce oxidative stress and inflammation, and inhibit fibrosis. However, although dopamine activation in streptozotocin-induced diabetic models has been shown to provide renal protection, the role of dopamine in models of naturally induced diabetes mellitus is still unclear. In the present study, we orally administered 10 mg/kg benserazide, a peripheral decarboxylase inhibitor, to spontaneously diabetic Torii rats daily to investigate the activation of the renal dopaminergic system during the progression of diabetic nephropathy. Our findings show that peripheral dopamine decreased urinary 8-iso-prostaglandin F2α and suppressed increases in plasma cystatin C levels. This study demonstrates that a reduction in peripheral dopamine can exacerbate renal dysfunction, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration, thereby clarifying the pivotal role of endogenous peripheral dopamine in modulating oxidative stress and kidney performance.NEW & NOTEWORTHY By administering a peripheral decarboxylase inhibitor, we revealed that peripheral dopamine inhibits both the increase in urinary 8-iso-prostaglandin F2α, an oxidative stress marker, and the increase in plasma cystatin C, an early renal dysfunction marker, even in the early stages of diabetic nephropathy characterized by glomerular hyperfiltration. By visualizing renal dopamine precursor distribution, we highlighted the role of endogenous renal dopamine in oxidative stress and renal function following the onset of glomerular hyperfiltration.

Neurophysiological markers of motor compensatory mechanisms in early Parkinson's disease.

Compensatory mechanisms in Parkinson's disease are defined as the changes that the brain uses to adapt to neurodegeneration and progressive dopamine reduction. Motor compensation in early Parkinson's disease could, in part, be responsible for a unilateral onset of clinical motor signs despite the presence of bilateral nigrostriatal degeneration. Although several mechanisms have been proposed for compensatory adaptations in Parkinson's disease, the underlying pathophysiology is unclear. Here, we investigate motor compensation in Parkinson's disease by investigating the relationship between clinical signs, dopamine transporter imaging data and neurophysiological measures of the primary motor cortex (M1), using transcranial magnetic stimulation in presymptomatic and symptomatic hemispheres of patients. In this cross-sectional, multicentre study, we screened 82 individuals with Parkinson's disease. Patients were evaluated clinically in their medication OFF state using standardized scales. Sixteen Parkinson's disease patients with bilateral dopamine transporter deficit in the putamina but unilateral symptoms were included. Twenty-eight sex- and age-matched healthy controls were also investigated. In all participants, we tested cortical excitability using single- and paired-pulse techniques, interhemispheric inhibition and cortical plasticity with paired associative stimulation. Data were analysed with ANOVAs, multiple linear regression and logistic regression models. Individual coefficients of motor compensation were defined in patients based on clinical and imaging data, i.e. the motor compensation coefficient. The motor compensation coefficient includes an asymmetry score to balance motor and dopamine transporter data between the two hemispheres, in addition to a hemispheric ratio accounting for the relative mismatch between the magnitude of motor signs and dopaminergic deficit. In patients, corticospinal excitability and plasticity were higher in the presymptomatic compared with the symptomatic M1. Also, interhemispheric inhibition from the presymptomatic to the symptomatic M1 was reduced. Lower putamen binding was associated with higher plasticity and reduced interhemispheric inhibition in the presymptomatic hemisphere. The motor compensation coefficient distinguished the presymptomatic from the symptomatic hemisphere. Finally, in the presymptomatic hemisphere, a higher motor compensation coefficient was associated with lower corticospinal excitability and interhemispheric inhibition and with higher plasticity. In conclusion, the present study suggests that motor compensation involves M1-striatal networks and intercortical connections becoming more effective with progressive loss of dopaminergic terminals in the putamen. The balance between these motor networks seems to be driven by cortical plasticity.

Aversion-induced drug taking and escape behavior involve similar nucleus accumbens core dopamine signaling signatures.

Dopamine release in the nucleus accumbens core (NAcC) has long been associated with the promotion of motivated behavior. However, inhibited dopamine signaling can increase behavior in certain settings, such as during drug self-administration. While aversive environmental stimuli can reduce dopamine, it is unclear whether such stimuli reliably engage this mechanism in different contexts. Here we compared the physiological and behavioral responses to the same aversive stimulus in different designs to determine if there is uniformity in the manner that aversive stimuli are encoded and promote behavior. NAcC dopamine was measured using fiber photometry in male and female rats during cocaine self-administration sessions in which an acutely aversive 90 dB white noise was intermittently presented. In a separate group of rats, aversion-induced changes in dopamine were measured in an escape design in which operant responses terminated aversive white noise. Aversive white noise significantly reduced NAcC dopamine and increased cocaine self-administration in both male and female rats. The same relationship was observed in the escape design, in which white noise reduced dopamine and promoted escape attempts. In both designs, the magnitude of the dopamine reduction predicted behavioral performance. While prior research demonstrated that pharmacologically reduced dopamine signaling can promote intake, this report demonstrates that this physiological mechanism is naturally engaged by aversive environmental stimuli and generalizable to non-drug contexts. These findings illustrate a common physiological signature in response to aversion that may promote both adaptive and maladaptive behavior.

Rethinking Parkinson's disease: could dopamine reduction therapy have clinical utility?

Following reports of low striatal dopamine content in Parkinson’s disease, levodopa was shown to rapidly reverse hypokinesis, establishing the model of disease as one of dopamine deficiency. Dopaminergic therapy became standard of care, yet it failed to reverse the disease, suggesting the understanding of disease was incomplete. The literature suggests the potential for toxicity of dopamine and its metabolites, perhaps more relevant given the recent evidence for elevated cytosolic dopamine levels in the dopaminergic neurons of people with Parkinson’s. To understand the relevance of these data, multiple investigations are reviewed that tested dopamine reduction therapy as an alternative to dopaminergic agents. The data from use of an inhibitor of dopamine synthesis in experimental models suggest that such an approach could reverse disease pathology, which suggests that cytosolic dopamine excess is a primary driver of disease. These data support clinical investigation of dopamine reduction therapy for Parkinson’s disease. Doing so will determine whether these experimental models are predictive and this treatment strategy is worth pursuing further. If clinical data are positive, it could warrant reconsideration of our disease model and treatment strategies, including a shift from dopaminergic to dopamine reduction treatment of the disease.

Fabrication of Au-polydopamine blackspheres-loaded PLLA-(silk fibroin) scaffold with photothermal conversion in NIR-II biowindows for deep nerve regeneration

Near infrared second region (NIR II) is applied in deep tissue imaging and tumor therapy. TRPV1 ion channels in cell membrane are widely distributed in nerve tissue, and opened with thermal stimulation, inducing Ca2+ influx. Gold-polydopamine (PDA) blackspheres (AuPBs) with good NIR II absorption and photothermal conversion were prepared by self-oxidation–reduction of dopamine and chlorauric acid, and then loaded on PLLA-SF parallel films (PSPF), which were then curved into nerve scaffolds (PSPF@AuPBs). After this scaffold implantation in sciatic nerve injury site (a depth of more than 1 cm under the skin), PDA in AuPBs relieved inflammatory response in injury site, leading to higher VEGF expression and new-vessels formation; furthermore, TRPV1 ion channels in Schwann cells (SCs) were periodically opened under NIR II irradiation to achieve effect of Ca2+ influx, activating SCs to highly express BDNF and NGF, and then promoting arrangement and myelination of SCs, nerve regeneration and functional recovery. These results suggested that our fabricated PSPF@AuPBs, as an effective NIR II adsorption platform, could provide a good photothermal conversion therapy to improve deep tissue regeneration.

Immunological Aspects of Depressive Disorder - The Review

Abstract Depression represents a mood disorder and is considered to be one of the most common mental disorders in general. World Health Organization estimates that depression will be the leading cause of disability-adjusted life years, until 2030. Depression is a complex heterogeneous disorder where immune system and its regulation play an important role. Innate and adaptive immunity mechanisms are included, along with processes of immune activation and suppression. The expression of humoral factors of innate immunity, especially pro-inflammatory cytokines, is increased, whereas the intensity of cellular immune mechanisms, primarily T cells and NK cells, are impaired. The influence of pro- inflammatory cytokines on depression is reflected in their effect on certain enzymes and ensuing reduction of neurotransmitters serotonin and dopamine. They also affect the neuroendocrine function in central nervous system, resulting in increase of cortisol levels and inactivation of glucocorticoid receptors in the periphery, which leads to neurodegeneration and decrease in neurotransmitter production. Certain cytokines affect neuroplasticity through the decreasing of concentration of neurotrophic brain factor and induction of brain cell apoptosis. The results are often contradictory talking about mechanisms of adaptive immunity. On one hand, an increased activity of Tlymphocytes is observed, while on the other, there are evidence of spontaneous apoptosis and impaired function of these cellsin depression. In addition, neuroprotective role of autoreactive and regulatory T cells in prevention of depression has also been demonstrated. The aim of this paper is to analyze the current knowledge on the role of immune mechanisms in the pathogenesis of depression.

Parkinson's Disease and Photobiomodulation: Potential for Treatment.

Parkinson's disease is the second most common neurodegenerative disease and is increasing in incidence. The combination of motor and non-motor symptoms makes this a devastating disease for people with Parkinson's disease and their care givers. Parkinson's disease is characterised by mitochondrial dysfunction and neuronal death in the substantia nigra, a reduction in dopamine, accumulation of α-synuclein aggregates and neuroinflammation. The microbiome-gut-brain axis is also important in Parkinson's disease, involved in the spread of inflammation and aggregated α-synuclein. The mainstay of Parkinson's disease treatment is dopamine replacement therapy, which can reduce some of the motor signs. There is a need for additional treatment options to supplement available medications. Photobiomodulation (PBM) is a form of light therapy that has been shown to have multiple clinical benefits due to its enhancement of the mitochondrial electron transport chain and the subsequent increase in mitochondrial membrane potential and ATP production. PBM also modulates cellular signalling and has been shown to reduce inflammation. Clinically, PBM has been used for decades to improve wound healing, treat pain, reduce swelling and heal deep tissues. Pre-clinical experiments have indicated that PBM has the potential to improve the clinical signs of Parkinson's disease and to provide neuroprotection. This effect is seen whether the PBM is directed to the head of the animal or to other parts of the body (remotely). A small number of clinical trials has given weight to the possibility that using PBM can improve both motor and non-motor clinical signs and symptoms of Parkinson's disease and may potentially slow its progression.

Chronic neurotoxicity of Tetrabromobisphenol A: Induction of oxidative stress and damage to neurons in Caenorhabditis elegans

Tetrachlorobisphenol A (TCBPA) has been used as an alternative flame retardant in various fields. However, the long-term effects of TCBPA on the nervous system remain unclear. Thus, Caenorhabditis elegans (L4 larvae) were selected as a model animal to investigate the neurotoxic effects and underlying mechanisms after 10 d of TCBPA exposure. Exposure to TCBPA (0.01–100 μg/L) decreased locomotive behavior in a concentration-dependent manner. In addition, reactive oxygen species (ROS) formation and lipofuscin accumulation were significantly increased, and the expression of sod-3 was upregulated in the exposed nematodes, indicating that TCBPA exposure induced oxidative damage. Furthermore, 100 μg/L TCBPA exposure caused a reduction in dopamine and serotonin levels, and damage in dopaminergic and serotoninergic neurons, which was further confirmed by the downregulated expression of related genes (e.g., dop-1, dop-3, cat-1, and mod-1). Molecular docking analysis demonstrated the potential of TCBPA to bind to the neurotransmitter receptor proteins DOP-1, DOP-3, and MOD-1. These results indicate that chronic exposure to TCBPA induces neurotoxic effects on locomotive behavior, which is associated with oxidative stress and damage to dopaminergic and serotoninergic neurons.

Piezoelectric nanogenerators enabled neuromodulation rescued dopaminergic neuron loss in Parkinson’s disease

Parkinson’s disease (PD) is a neurodegenerative disease with dopaminergic neurons loss, which induces dopamine reduction and body motion disorder. Traditional deep brain stimulation (DBS), which involves the implanting metal electrodes into the subcortical nucleus of the brain, has a huge risk of invasive surgery and low resolution. Here we present that pomegranate-like piezoelectric nanogenerators are able to efficiently transduce ultrasonic wave into electric power generation under ultrasound stimulation, which modulates intracellular calcium signaling and tyrosine hydroxylase levels to activate the neuron activity and process of deep-brain tissue in vitro and in vivo. Strikingly, after one-week nanogenerator-mediated neuromodulation, the damaged dopaminergic neurons in PD-zebrafish and mice were reversed with a decrease in α-synuclein aggregates and an increase in tyrosine hydroxylase for neuronal recovery of PD. The behaviors of PD mice model also have a significant improvement, compared with untreated group. This approach provides a minimally invasive and high precision neurotechnology protect against neuronal death and loss of synapse in PD and other neurodegenerative diseases.

Neurotoxicity of the Cu(OH)2 Nanopesticide through Perturbing Multiple Neurotransmitter Pathways in Developing Zebrafish.

The copper hydroxide [Cu(OH)2] nanopesticide is an emerging agricultural chemical that can negatively impact aquatic organisms. This study evaluated the behavioral changes of zebrafish larvae exposed to the Cu(OH)2 nanopesticide and assessed its potential to induce neurotoxicity. Metabolomic and transcriptomic profiling was also conducted to uncover the molecular mechanisms related to potential neurotoxicity. The Cu(OH)2 nanopesticide at 100 μg/L induced zebrafish hypoactivity, dark avoidance, and response to the light stimulus, suggestive of neurotoxic effects. Altered neurotransmitter-related pathways (serotoninergic, dopaminergic, glutamatergic, GABAergic) and reduction of serotonin (5-HT), dopamine (DA), glutamate (GLU), γ-aminobutyric acid (GABA), and several of their precursors and metabolites were noted following metabolomic and transcriptomic analyses. Differentially expressed genes (DEGs) were associated with the synthesis, transport, receptor binding, and metabolism of 5-HT, DA, GLU, and GABA. Transcripts (or protein levels) related to neurotransmitter receptors for 5-HT, DA, GLU, and GABA and enzymes for the synthesis of GLU and GABA were downregulated. Effects on both the glutamatergic and GABAergic pathways in zebrafish were specific to the nanopesticide and differed from those in fish exposed to copper ions. Taken together, the Cu(OH)2 nanopesticide induced developmental neurotoxicity in zebrafish by inhibiting several neurotransmitter-related pathways. This study presented a model for Cu(OH)2 nanopesticide-induced neurotoxicity in developing zebrafish that can inform ecological risk assessments.

Differential patterns of basal and naloxone-evoked dopamine efflux in the rat dorsal and ventral striatum following prolonged-intermittent exposure to morphine.

Hypodopaminergia in the ventral striatum is a putative neurobiological correlate of withdrawal in opioid-dependent individuals. This perspective stands in contrast to brain imaging studies with chronic opioid users showing that naloxone-enhanced dopamine (DA) release in the dorsal striatum is positively correlated with withdrawal aversion. Here, we examined regional differences in striatal DA function associated with opioid withdrawal in rats exposed to intermittent morphine injections for 31 days. Basal concentrations of DA were reduced (i.e., indicating a hypodopaminergic state) in the ventral striatum on Day 10 of morphine exposure, whereas a more prolonged period of morphine treatment was required to reveal hypodopaminergia in the dorsal striatum on Day 31. The ventral striatum consistently exhibited naloxone-induced transient reductions in DA below the hypodopaminergic basal levels, whereas morphine enhanced DA efflux. In the dorsal striatum, DA responsivity to naloxone shifted from a significant decrease on Day 10 to a notable increase above hypodopaminergic basal levels on Day 31, corroborating the findings in the human dorsal striatum. Unexpectedly, the magnitude of morphine-evoked increases in DA efflux on Day 31 was significantly blunted relative to values on Day 10. These findings indicate that prolonged-intermittent access to morphine results in a sustained hypodopaminergic state as reflected in basal levels in the striatum, which is accompanied by regional differences in DA responsivity to naloxone and morphine. Overall, our findings suggest that prolonging the duration of morphine exposure to 31 days is sufficient to reveal neuroadaptations that may underlie the transition from initial drug exposure to opioid dependence.

Dopaminergic denervation and associated MRI microstructural changes in the nigrostriatal projection in early Parkinson’s disease patients

Loss of dopaminergic neurons in the substantia nigra pars compacta (SNc) and a profound reduction of striatal dopamine are two hallmarks of Parkinson’s disease (PD). However, it’s unclear whether degeneration starts at the neuronal soma or the striatal presynaptic terminals, and how microstructural degeneration is linked to dopaminergic loss is also uncertain. In this study, thirty de novo PD patients and twenty healthy subjects (HS) underwent 6-[18F]-fluoro-L-dopa (FDOPA) PET and MRI studies no later than 12 months from clinical diagnosis. FDOPA uptake rate (Ki), fractional volume of free-water (FW), and iron-sensitive R2* relaxometry were quantified within nigrostriatal regions. Inter-group differences (PD vs HS) were studied using non-parametric statistics and complemented with Cohen’s d effect sizes and Bayesian statistics. Correlation analyses were performed exploring biomarker dependencies and their association with bradykinesia scores. PD patients exhibited a significant decline in nigrostriatal dopaminergic activity, being post-commissural putamen (−67%) and posterolateral SNc (−11.7%) the most affected subregions within striatum and SNc respectively. Microstructural alterations (FW) were restricted to the hemisphere corresponding to the most affected side and followed similar spatial gradients as FDOPA Ki (+20% in posterior putamen and +11% in posterolateral SNc). R2* revealed no relevant significant changes. FDOPA and FW were correlated within the posterolateral SNc, and clinical severity was associated with FDOPA Ki loss. The asymmetry between striatal and SNc changes for both dopaminergic depletion and microstructural degeneration biomarkers is consistent with a neurodegenerative process that begins in the striatal terminals before progressing toward the cell bodies in the SNc.

Locomotor Behavior and Memory Dysfunction Induced by 3-Nitropropionic Acid in Adult Zebrafish: Modulation of Dopaminergic Signaling.

Huntington's disease (HD) is a progressive neurodegenerative disease characterized by neuropsychiatric disturbance, cognitive impairment, and locomotor dysfunction. In the early stage (chorea) of HD, expression of dopamine D2 receptors (D2R) is reduced, whereas dopamine (DA) levels are increased. Contrary, in the late stage (bradykinesia), DA levels and the expression of D2R and dopamine D1 receptors (D1R) are reduced. 3-Nitropropionic acid (3-NPA) is a toxin that may replicate HD behavioral phenotypes and biochemical aspects. This study assessed the neurotransmitter levels, dopamine receptor gene expression, and the effect of acute exposure to quinpirole (D2R agonist) and eticlopride (D2R antagonist) in an HD model induced by 3-NPA in adult zebrafish. Quinpirole and eticlopride were acutely applied by i.p. injection in adult zebrafish after chronic treatment of 3-NPA (60mg/kg). 3-NPA treatment caused a reduction in DA, glutamate, and serotonin levels. Quinpirole reversed the bradykinesia and memory loss induced by 3-NPA. Together, these data showed that 3-NPA acts on the dopaminergic system and causes biochemical alterations similar to late-stage HD. These data reinforce the hypothesis that DA levels are linked with locomotor and memory deficits. Thus, these findings may suggest that the use of DA agonists could be a pharmacological strategy to improve the bradykinesia and memory deficits in the late-stage HD.

Fecal Microbiota Transplantation from Aged Mice Render Recipient Mice Resistant to MPTP-Induced Nigrostriatal Degeneration Via a Neurogenesis-Dependent but Inflammation-Independent Manner.

Accumulating data support a crucial role of gut microbiota in Parkinson's disease (PD). However, gut microbiota vary with age and, thus, will affect PD in an age-dependent, but unknown manner. We examined the effects of fecal microbiota transplantation (FMT) pretreatment, using fecal microbiota from young (7weeks) or aged mice (23months), on MPTP-induced PD model. Motor function, pathological changes, striatal neurotransmitters, neuroinflammation, gut inflammation and gut permeability were examined. Gut microbiota composition and metabolites, namely short-chain fatty acids (SCFAs), were analyzed. Neurogenesis was also evaluated by measuring the number of doublecortin-positive (DCX+) neurons and Ki67-positive (Ki67+) cells in the hippocampus. Expression of Cd133 mRNA, a cellular stemness marker, in the hippocampus was also examined. Mice who received FMT from young mice showed MPTP-induced motor dysfunction, and reduction of striatal dopamine (DA), dopaminergic neurons and striatal tyrosine hydroxylase (TH) levels. Interestingly and unexpectedly, mice that received FMT from aged mice showed recovery of motor function and rescue of dopaminergic neurons and striatal 5-hydroxytryptamine (5-HT), as well as decreased DA metabolism after MPTP challenge. Further, they showed improved metabolic profiling and a decreased amount of fecal SCFAs. High-throughput sequencing revealed that FMT remarkably reshaped the gut microbiota of recipient mice. For instance, levels of genus Akkermansia and Candidatus Saccharimonas were elevated in fecal samples of recipient mice receiving aged microbiota (AM + MPTP mice) than YM + MPTP mice. Intriguingly, both young microbiota and aged microbiota had no effect on neuroinflammation, gut inflammation or gut permeability. Notably, AM + MPTP mice showed a marked increase in DCX+ neurons, as well as Ki67+ cells and Cd133 expression in the hippocampal dentate gyrus (DG) compared to YM + MPTP mice. These results suggest that FMT from aged mice augments neurogenesis, improves motor function and restores dopaminergic neurons and neurotransmitters in PD model mice, possibly through increasing neurogenesis.

A review of frequently used Kampo prescriptions: Part 2—Hangekobokuto

AbstractBackgroundThe origin of hangekobokuto (HKT) is from Jin Gui Yao Lue (Kinkiyōryaku in Japanese), and it has been indicated for treating throat discomfort in women.Key FindingsHKT consists of five crude drugs. Clinical studies have shown that HKT can improve the swallowing reflex by increasing the substance P level in saliva; improve the cough reflex; reduce pneumonia in patients with dementia, cerebrovascular disease, Alzheimer's disease, or Parkinson's disease; reduce postoperative aspiration pneumonia in patients who undergo cardiovascular surgery; and improve depression and anxiety scores in patients with globus hystericus. Furthermore, HKT has been reported to increase serotonin (5‐HT) and noradrenaline levels in the hypothalamus, and dopamine (DA) levels in the striatum in a healthy rodent model; improve 5‐HT levels in the striatum and hippocampus, and ameliorate 5‐HT and DA reductions in the whole brain in an acute stress model; improve 5‐HT levels in the striatum, and ameliorate 5‐HT and DA reductions in the prefrontal cortex in a chronic stress model; and decrease corticosterone and corticotropin‐releasing factor levels in a chronic stress model. Reported adverse events of HKT include interstitial pneumonia (0.38 per 100 000 cases) and liver damage (0.89 per 100 000 cases), which are rare.ConclusionHKT is widely used and shows a low rate of adverse events. Several clinical studies have reported its effects in reducing aspiration pneumonia and improving depression and anxiety, some of which may be explained by the regulation of monoamines and stress hormones in the brain and substance P levels in the oral cavity.

Potential Mechanisms of Imidacloprid-Induced Neurotoxicity in Adult Rats with Attempts on Protection Using Origanum majorana L. Oil/Extract: In Vivo and In Silico Studies.

Imidacloprid (IMI) insecticide is rapidly metabolized in mammals and contributes to neurotoxicity via the blocking of nicotinic acetylcholine receptors, as in insects. Origanum majorana retains its great antioxidant potential in both fresh and dry forms. No data is available on the neuroprotective effect of this plant in laboratory animals. In this context, aerial parts of O. majorana were used to prepare the essential oil (OMO) and methanol extract (OME). The potential neuroprotective impact of both OMO and OME against IMI-induced neurotoxicity in rats was explored. Forty-two rats were divided into 6 groups, with 7 rats in each one. Rats were daily administered the oral treatments: normal saline, OMO, OME, IMI, IMI + OMO, and IMI + OME. Our results revealed the identification of 55 components in O. majorana essential oil, most belonging to the oxygenated and hydrocarbon monoterpenoid group. Moreover, 37 constituents were identified in the methanol extract, mostly phenolics. The potent neurotoxic effect of IMI on rats was confirmed by neurobehavioral and neuropathological alterations and a reduction of both acetylcholine esterase (AchE) activity and dopamine (DA), serotonin (5HT), and γ-aminobutyric acid (GABA) levels in the brain. Exposure of rats to IMI elevates the malondialdehyde (MDA) levels and reduces the antioxidant capacity. IMI could upregulate the transcription levels of nuclear factor-κB (NF-κB), interleukin-1 β (IL-1β), and tumor necrosis factor (TNF-α) genes and express strong caspase-3 and inducible nitric oxide synthase (iNOS) immunostaining in most examined brain areas. On the other hand, rats coadministered OMO or OME with IMI showed a marked improvement in all of the studied toxicological parameters. In conclusion, cotreatment of O. majorana extracts with IMI can protect against IMI neurotoxicity via their potent antioxidant, anti-inflammatory, and anti-apoptotic effects. Thus, we recommend a daily intake of O. majorana to protect against insecticide's oxidative stress-mediated neuroinflammatory stress and apoptosis. The molecular docking study of linalool, rosmarinic acid, γ-terpene, and terpene-4-ol justify the observed normalization of the elevated iNOS and TNF-α levels induced after exposure to IMI.