PROPOFOL DECREASES ^(125)I-β-CIT BINDING TO THE DOPAMINE TRANSPORTER

Objective To determine the changes of brain dopamine transporter in mice receiving propofol anesthesia, 125I-β-CIT binding sites were observed at different time course. Methods 1. Twenty-seven normal Kunming mice were randomizedly divided into 3 groups (n = 9 ) and received intraperitoneal injection of propofol 100, 200 mg/kg and 10% intralipid (as control ) respetively. The time of losing righting reflex and displaying excitatory symptoms were recorded within 10min after administration. 2. Sixty Kunming mice were randomizedly assigned into 2 groups (n = 30 ). The mice were given 125I-β-CIT intravenously and propofol 200mg/kg or 10% intralipid (as control ) intraperitoneally. Five mice in every group were killed at different time course and their brain removed to isolate cerebellar, hypothalamus, striatum and cerebral cones. After weighting brain tissues, the radioactivity of 125I-β-CIT in different brain tissue was measured. Results 1. The time of losing righting reflex wes reduced from 319. 167 ± 88. 228s in proud 100mg/kg group to 231. 667 ± 46. 233s in propofol 200mg/kg group, and it fell from 193. 75 ± 27. 233s to 145. 556 ± 27. 437s for presenting excitatory activity. 2. Propofol intraperitoneal groups significantly decreed the combination of 125I-β-CIT and dopamine transporter in the striatum (P< 0. 01 ) and cerebral cortex (P < 0. 05) 120min after injection of propofol compared with the control group. But propofol increased the binding (P< 0. 05 ) in the striatum 30min after injection. theclusion The inhibitive effect of propofol on dopamine transporter to uptake dopamine in mice brain may contribute to some anesthetic mechanisms.

Dopamine in the prefrontal cortex plays multiple roles in the executive function of patients with Parkinson's disease

Parkinson’s disease can affect not only motor functions but also cognitive abilities,leading to cognitive impairment.One common issue in Parkinson’s disease with cognitive dysfunction is the difficulty in executive functioning.Executive functions help us plan,organize,and control our actions based on our goals.The brain area responsible for executive functions is called the prefrontal co rtex.It acts as the command center for the brain,especially when it comes to regulating executive functions.The role of the prefrontal cortex in cognitive processes is influenced by a chemical messenger called dopamine.However,little is known about how dopamine affects the cognitive functions of patients with Parkinson’s disease.In this article,the authors review the latest research on this topic.They start by looking at how the dopaminergic syste m,is alte red in Parkinson’s disease with executive dysfunction.Then,they explore how these changes in dopamine impact the synaptic structure,electrical activity,and connection components of the prefrontal cortex.The authors also summarize the relationship between Parkinson’s disease and dopamine-related cognitive issues.This information may offer valuable insights and directions for further research and improvement in the clinical treatment of cognitive impairment in Parkinson’s disease.

Blunt dopamine transmission due to decreased GDNF in the PFC evokes cognitive impairment in Parkinson’s disease

Studies have found that the absence of glial cell line-derived neurotrophic factor may be the primary risk factor for Parkinson’s disease. However, there have not been any studies conducted on the potential relationship between glial cell line-derived neurotrophic factor and cognitive performance in Parkinson’s disease. We first performed a retrospective case-control study at the Affiliated Hospital of Xuzhou Medical University between September 2018 and January 2020 and found that a decreased serum level of glial cell line-derived neurotrophic factor was a risk factor for cognitive disorders in patients with Parkinson’s disease. We then established a mouse model of Parkinson’s disease induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine and analyzed the potential relationships among glial cell line-derived neurotrophic factor in the prefrontal cortex, dopamine transmission, and cognitive function. Our results showed that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex weakened dopamine release and transmission by upregulating the presynaptic membrane expression of the dopamine transporter, which led to the loss and primitivization of dendritic spines of pyramidal neurons and cognitive impairment. In addition, magnetic resonance imaging data showed that the long-term lack of glial cell line-derived neurotrophic factor reduced the connectivity between the prefrontal cortex and other brain regions, and exogenous glial cell line-derived neurotrophic factor significantly improved this connectivity. These findings suggested that decreased glial cell line-derived neurotrophic factor in the prefrontal cortex leads to neuroplastic degeneration at the level of synaptic connections and circuits, which results in cognitive impairment in patients with Parkinson’s disease.

Effects of levodopa on dopaminergic neurons and induced dyskinesia A radio-imaging study

BACKGROUND: Radio-imaging has been used in neurological diagnosis,in particular for extrapyramidal disease.Moreover,it has been extensively utilized for early diagnosis of Parkinson’s disease (PD) patients and in animal studies.However,it has rarely been utilized to assess drug-induced side effects in PD.OBJECTIVE: To investigate changes in dopamine transporter expression in a rat model of PD through the use of radio-imaging taking 99mTc-TRODAT-1 as an imaging agent,and to explore the effect of levodopa (L-dopa) on dopaminergic neurons and the possible mechanisms of dyskinesia induction.DESIGN,TIME AND SETTING: A randomized,controlled,animal study was performed at the Laboratory of Department of Nuclear Medicine,Soochow University from April 2006 to June 2007.MATERIALS: 6-hydroxydopamine was purchased from Sigma,USA and L-dopa was purchased from Shanghai Fuda Pharmaceutical,China.99mTcO4-fresh elutriant was provided by the Department of Nuclear Medicine,First Hospital Affiliated to Soochow University.TRODAT-1 image kit was provided by Jiangsu Atomic Energy Research Establishment,China.The SN-695B radioimmunoassay gamma counter was purchased from Shanghai Hesuo Rihuan Photoelectric Instrument,China.The AZ-CA256eZ-Scope portable γ camera was purchased from Anzai Medical,Japan.METHODS: A total of 34 healthy,male,Sprague Dawley rats were selected.Thirty were used to establish a PD model by injecting 6-hydroxydopamine into the right medial forebrain bundle,and four were injected with normal saline and served as the sham-surgery group.At the end of 4 weeks,21 successful PD models were selected and randomly assigned to the L-dopa (n = 15,20 mg/kg per day),model (n = 6,normal saline),and sham-surgery (n = 4,no treatment) groups.After 1 month of treatment,involuntary movement was evaluated twice weekly in each rat.A total of 0.2 mL 99mTc-TRODAT-1 was injected into the tail vein 2 days following drug termination,and images of dopamine transporters were acquired 2 hours later.The rats were sacrificed and the ratios of specific radioactivity uptake were calculated.MAIN OUTCOME MEASURES: Manifestations of abnormal involuntary movement (AIM) were observed and total AIM scores were calculated.Images of dopamine transporters were acquired using an eZ-Scope portable γ camera,and radioactive γ quantification of 99mTc-TRODAT-1 in the rat brains was assayed.The ratios of the left and right corpora striata were determined.The number and function of dopamine transporters was evaluated according to specific radioactivity uptake ratio (R) from the left and right corpora striata.RESULTS: Of 15 PD rats,nine exhibited AIM following L-dopa treatment: five scored > 20,i.e.,severe grade,four scored 8–16,mild grade,and the remaining exhibited normal behavior.There were no differences in specific radioactivity uptake of dopamine transporter between the left and right corpora striata in the sham-surgery rats,and the images were clear and symmetrically distributed.Specific radioactivity uptake of the normal side (left) was significantly greater than the lesioned side (right) in the model group rats (P < 0.01),and the R value was significantly increased compared with the sham-surgery group (P < 0.01).The radio-ligand accumulation in the right corpus striatum was sparse.In the L-dopa group,specific radioactivity uptake was significantly decreased in the lesioned (right) side of the AIM rats,and the R value was increased compared with the model group (P < 0.05).The amount of radio-ligand in the right corpus striatum was diminished.The R value was significantly reduced in the non-AIM rats compared with the AIM rats (P < 0.05),and specific radioactivity uptake was significantly increased in the lesioned (right) side compared with the normal side (P < 0.05).Moreover,radio-ligand accumulation was observed in the right corpus striatum,and differences in radio-ligand accumulation between the two sides were reduced.CONCLUSION: Following L-dopa treatment,the number and function of dopamine transporter in some PD rats were reduced.L-dopa was shown to be toxic to dopaminergic neurons and induced dyskinesia.

Single-nuclei RNA sequencing uncovers heterogenous transcriptional signatures in Parkinson's disease associated with nuclear receptor-related factor 1 defect

Previous studies have found that deficiency in nuclear receptor-related factor 1(Nurr1),which participates in the development,differentiation,survival,and degeneration of dopaminergic neurons,is associated with Parkinson s disease,but the mechanism of action is perplexing.Here,we first asce rtained the repercussion of knocking down Nurr1 by pe rforming liquid chromatography coupled with tandem mass spectrometry.We found that 231 genes were highly expressed in dopaminergic neurons with Nurr1 deficiency,14 of which were linked to the Parkinson’s disease pathway based on Kyoto Encyclopedia of Genes and Genomes analysis.To better understand how Nurr1 deficiency autonomously invokes the decline of dopaminergic neurons and elicits Parkinson’s disease symptoms,we performed single-nuclei RNA sequencing in a Nurr1 LV-shRNA mouse model.The results revealed cellular heterogeneity in the substantia nigra and a number of activated genes,the preponderance of which encode components of the major histocompatibility Ⅱ complex.Cd74,H2-Ab1,H2-Aα,H2-Eb1,Lyz2,Mrc1,Slc6α3,Slc47α1,Ms4α4b,and Ptprc2 were the top 10 diffe rentially expressed genes.Immunofluorescence staining showed that,after Nurr1knockdown,the number of CD74-immunoreactive cells in mouse brain tissue was markedly increased.In addition,Cd74 expression was increased in a mouse model of Parkinson’s disease induced by treatment with 6-hydroxydopamine.Ta ken togethe r,our res ults suggest that Nurr1 deficiency results in an increase in Cd74 expression,thereby leading to the destruction of dopaminergic neuro ns.These findings provide a potential therapeutic target for the treatment of Parkinson’s disease.

Recent progress in the applications of presynaptic dopaminergic positron emission tomography imaging in parkinsonism

Nowadays,presynaptic dopaminergic positron emission tomography,which assesses deficiencies in dopamine synthesis,storage,and transport,is widely utilized for early diagnosis and differential diagnosis of parkinsonism.This review provides a comprehensive summary of the latest developments in the application of presynaptic dopaminergic positron emission tomography imaging in disorders that manifest parkinsonism.We conducted a thorough literature search using reputable databases such as PubMed and Web of Science.Selection criteria involved identifying peer-reviewed articles published within the last 5 years,with emphasis on their relevance to clinical applications.The findings from these studies highlight that presynaptic dopaminergic positron emission tomography has demonstrated potential not only in diagnosing and differentiating various Parkinsonian conditions but also in assessing disease severity and predicting prognosis.Moreover,when employed in conjunction with other imaging modalities and advanced analytical methods,presynaptic dopaminergic positron emission tomography has been validated as a reliable in vivo biomarker.This validation extends to screening and exploring potential neuropathological mechanisms associated with dopaminergic depletion.In summary,the insights gained from interpreting these studies are crucial for enhancing the effectiveness of preclinical investigations and clinical trials,ultimately advancing toward the goals of neuroregeneration in parkinsonian disorders.

Abuse-related effects of synthetic cathinones：importance of DAT/SERT relationships

OBJECTIVE Wide spread abuse of synthetic cathinones found in bath salts preparations has resulted in regulation of some cathinones internationally.Chemists skirt these laws by altering the chemical structures of first-generation cathinones(ie,MDPV,methylone,and mephedrone),resulting in second-generation cathinones(eg,α-PVP,α-PPP,MDPPP,and MDPBP).Although MDPV is a more effective reinforcer than cocaine,little is known about the reinforcing effectiveness of secondgeneration cathinones.To test the hypothesis that synthetic cathinones with higher selectivity for DAT relative to SERT are more effective reinforcers.METHODS Monoamine transporter inhibition was determined using synaptosomes prepared from rat brains.The relative reinforcing effectiveness of intravenously self-administered MDPV,MDPBP,MDPPP,α-PVP,α-PPP,and cocaine were directly compared through evaluations of (1)dose-response curves under a progressive ratio(PR)schedule of reinforcement and (2)demand curves obtained for each drug in male Sprague-Dawley rats.RESULTS Rank order selectivity for DAT/SERT wasα-PVP>MDPV>α-PPP≈MDPBP>MDPPP>cocaine.Comparisons of the maximum number of infusions obtained under a PR schedule of reinforcement(α-PVP>MDPV>α-PPP>MDPBP≈MDPPP>cocaine)and the essential value obtained for each drug in demand analyses(α-PVP>MDPV>α-PPP≈MDPBP≈MDPPP>cocaine)suggest relative reinforcing effectiveness is related to DAT/SERT selectivity.CONCLUSION These data provide evidence that DAT/SERT selectivity accounts for select synthetic cathinones functioning as more effective reinforcers than cocaine and may predict the abuse-related effects of novel synthetic cathinones in humans.

Dopaminergic Dysfunction and Glucose Metabolism Characteristics in Parkin-Induced Early-Onset Parkinson’s Disease Compared to Genetically Undetermined Early-Onset Parkinson’s Disease

While early-onset Parkinson’s disease(EOPD)caused by mutations in the parkin gene(PRKN)tends to have a relatively benign course compared to genetically undetermined(GU)-EOPD,the exact underlying mechanisms remain elusive.We aimed to search for the differences between PRKN-EOPD and GU-EOPD by dopamine transporter(DAT)and glucose metabolism positron-emission-tomography(PET)imaging.Twelve patients with PRKN-EOPD and 16 with GU-EOPD who accepted both ^(11)C-2b-carbomethoxy-3b-(4-trimethylstannylphenyl)tropane(^(11)C-CFT)and ^(18)F-fluorodeoxyglucose PET were enrolled.The ^(11)C-CFT uptake was analyzed on both regional and voxel levels,whereas glucose metabolism was assessed in a voxel-wise fashion.Correlations between DAT and glucose metabolism imaging,DAT imaging and clinical severity,as well as glucose metabolism imaging and clinical severity were explored.Both clinical symptoms and DAT-binding pat-terns in the posterior putamen were highly symmetrical in patients with PRKN-EOPD,and dopaminergic dysfunction in the ipsilateral putamen was severer in patients with PRKN-EOPD than GU-EOPD.Meanwhile,the DAT binding was associ-ated with the severity of motor dysfunction in patients with GU-EOPD only.Patients with PRKN-EOPD showed increased glucose metabolism in the contralateral medial frontal gyrus(supplementary motor area(SMA)),contralateral substantia nigra,contralateral thalamus,and contralateral cerebellum.Notably,glucose metabolic activity in the contralateral medial frontal gyrus was inversely associated with regional DAT binding in the bilateral putamen.Patients with PRKN-EOPD showed enhanced metabolic connectivity within the bilateral putamen,ipsilateral paracentral and precentral lobules,and the ipsilateral SMA.Collectively,compared to GU-EOPD,PRKN-EOPD is characterized by symmetrical,more severe dopaminergic dysfunction and relative increased glucose metabolism.Meanwhile,SMA with elevated glucose metabolism and enhanced connectivity may act as compensatory mechanisms in PRKN-EOPD.

Additive neurorestorative effects of exercise and docosahexaenoic acid intake in a mouse model of Parkinson’s disease

There is a need to develop interventions to slow or reverse the degeneration of dopamine neurons in Parkinson’s disease after diagnosis.Given that preclinical and clinical studies suggest benefits of dietary n-3 polyunsaturated fatty acids,such as docosahexaenoic acid,and exercise in Parkinson’s disease,we investigated whether both could synergistically interact to induce recovery of the dopaminergic pathway.First,mice received a unilateral stereotactic injection of 6-hydroxydopamine into the striatum to establish an animal model of nigrostriatal denervation.Four weeks after lesion,animals were fed a docosahexaenoic acid-enriched or a control diet for the next 8 weeks.During this period,the animals had access to a running wheel,which they could use or not.Docosahexaenoic acid treatment,voluntary exercise,or the combination of both had no effect on(i)distance traveled in the open field test,(ii)the percentage of contraversive rotations in the apomorphine-induction test or(iii)the number of tyrosine-hydroxylase-positive cells in the substantia nigra pars compacta.However,the docosahexaenoic acid diet increased the number of tyrosine-hydroxylase-positive terminals and induced a rise in dopamine concentrations in the lesioned striatum.Compared to docosahexaenoic acid treatment or exercise alone,the combination of docosahexaenoic acid and exercise(i)improved forelimb balance in the stepping test,(ii)decreased the striatal DOPAC/dopamine ratio and(iii)led to increased dopamine transporter levels in the lesioned striatum.The present results suggest that the combination of exercise and docosahexaenoic acid may act synergistically in the striatum of mice with a unilateral lesion of the dopaminergic system and provide support for clinical trials combining nutrition and physical exercise in the treatment of Parkinson’s disease.

Positron emission computed tomography/single photon emission computed tomography in Parkinson disease

Parkinson disease(PD)is the second-most common neurodegenerative disorder.Its main pathological mechanism is the selective degeneration and deletion of dopaminergic neurons in the dense part of the substantia nigra and the damage of dopaminergic neurons caused by the abnormal deposition of a Lewy body,leading to a decreased dopamine level.Positron emission computed tomography(PET)/single photon emission computed tomography(SPECT)is a molecular imaging technology that can directly or indirectly reflect changes in molecular levels by using a specific tracer.With the research and development on the tracers of related enzymes for labeling dopamine transporter and dopamine receptor and for being involved in dopamine formation,this imaging technology has been applied to all aspects of PD research.It not only contributes to clinical work but also provides an important theoretical basis for exploring the pathological mechanism of PD at a molecular level.Therefore,this review discusses the application value of PET/SPECT in PD in terms of early diagnosis,disease severity evaluation,clinical manifestations,differential diagnosis,and pathological mechanism.

The role of nitric oxide and neuronal nitric oxide synthase in zebrafish(Danio rerio)shoaling

Nitric oxide(NO)-the product of arginine metabolism catalyzed by nitric oxide synthases(NOS)-is a well-known neurotransmitter which plays an important role in metabolism and amino acid transportation in the nervous system.In particular,it can inhibit monoamine neurotransmitter transportation which affects animal behavior,especially social behavior.Shoaling-is a one kind of social behavior.It is a behavior that individual fish choose to join with their group within two factors;food and predation risk.Shoaling fish has quickly responded to predator and increased the change in feeding competition.In addition,shoaling also effect to stress response on stock density of aquaculture system.The effect of NO molecular signaling on the dopamine pathway was investigated using zebrafish(Danio rerio)as a model organism.Our aim was to understand the role of NOS and NO in shoaling behavior,which is typical of zebrafish.The concentration of NO in the zebrafish brain was modulated using a knockout for the neuronal NOS gene,and NO production was induced through treatment with L-arginine.The existence of NO in the zebrafish brain was confirmed by using a fluorescent probe.Dopamine concentration in the brain was measured by UPLC tandem mass spectrometer.We measured shoaling cohesion of all individual fish of D.rerio,using average distance between all pairs of fish(nearest neighbor distance)and analyzed tracking by Zebralab ViewPoint software.Collectively,our results suggest that a lower level of NO was associated with a higher level of dopamine,which in turn leads to the shoaling behavior.