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EJNMMI Research Jul 2024N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising...
BACKGROUND
N-(3-fluoropropyl)-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane (FP-CIT), the representative cocaine derivative used in dopamine transporter imaging, is a promising biomarker, as it reflects the severity of Parkinson's disease (PD). I- and F-labeled FP-CIT has been used for PD diagnosis. However, preclinical studies evaluating [F]FP-CIT as a potential diagnostic biomarker are scarce. Among translational research advancements from bench to bedside, translating preclinical findings into clinical practice is one-directional. The aim of this study is to employ a circular approach, beginning back from the preclinical stage, progressing to the supplementation of [F]FP-CIT, and subsequently returning to clinical application. We investigated the pharmacokinetic properties of [F]FP-CIT and its efficacy for PD diagnosis using murine models.
RESULTS
Biodistribution, metabolite and excretion analyses were performed in mice and PD models were induced in rats using 6-hydroxydopamine (6-OHDA). The targeting efficiency of [F]FP-CIT for the dopamine receptor was assessed through animal PET/CT imaging. Subsequently, correlation analysis was conducted between animal PET/CT imaging results and immunohistochemistry (IHC) targeting tyrosine hydroxylase. Rapid circulation was confirmed after [F]FP-CIT injection. [F]FP-CIT reached the highest uptake of 23.50 ± 12.46%ID/g in the striatum 1 min after injection, and it was rapidly excreted within 60 min. The major metabolic organs of [F]FP-CIT were confirmed to be the intestines, liver, and kidneys. Its uptake in the intestine was approximately 5% ID/g. The uptake in the liver gradually increased, with excretion beginning after reaching a maximum after 60 min. The kidneys exhibited rapid elimination after 10 min. In the excretion study, rapid elimination was verified, with 21.46 ± 9.53% of the compound excreted within a 6 h period. Additionally, the efficacy of [F]FP-CIT PET was demonstrated in the PD model, with a high correlation with IHC for both the absolute value (R = 0.803, p = 0.0017) and the ratio value (R = 0.973, p = 0.0011).
CONCLUSIONS
This study fills the gap regarding insufficient preclinical studies on [F]FP-CIT, including its ADME, metabolites, and efficiency. The pharmacological results, including accurate diagnosis, rapid circulation, and [F]FP-CIT excretion, provide complementary evidence that [F]FP-CIT can be used safely and efficiently to diagnose PD in clinics, although it is already used in clinics.
PubMed: 38958796
DOI: 10.1186/s13550-024-01121-6 -
Chemical Research in Toxicology Jul 2024Parkinson's disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in... (Review)
Review
Parkinson's disease (PD) affects more people worldwide than just aging alone can explain. This is likely due to environmental influences, genetic makeup, and changes in daily habits. The disease develops in a complex way, with movement problems caused by Lewy bodies and the loss of dopamine-producing neurons. Some research suggests Lewy bodies might start in the gut, hinting at a connection between these structures and gut health in PD patients. These patients often have different gut bacteria and metabolites. Pesticides are known to increase the risk of PD, with evidence showing they harm more than just dopamine neurons. Long-term exposure to pesticides in food might affect the gut barrier, gut bacteria, and the blood-brain barrier, but the exact link is still unknown. This review looks at how pesticides and gut bacteria separately influence PD development and progression, highlighting the harmful effects of pesticides and changes in gut bacteria. We have examined the interaction between pesticides and gut bacteria in PD patients, summarizing how pesticides cause imbalances in gut bacteria, the resulting changes, and their overall effects on the PD prognosis.
PubMed: 38958636
DOI: 10.1021/acs.chemrestox.4c00057 -
Journal of Neurophysiology Jul 2024Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion...
Neuromodulation in the retina is crucial for effective processing of retinal signal at different levels of illuminance. Intrinsically photosensitive retinal ganglion cells (ipRGCs), the neurons that drive non-image forming visual functions, express a variety of neuromodulatory receptors that tune intrinsic excitability as well as synaptic inputs. Past research has examined actions of neuromodulators on light responsiveness of ipRGCs, but less is known about how neuromodulation affects synaptic currents in ipRGCs. To better understand how neuromodulators affect synaptic processing in ipRGC, we examine actions of opioid and dopamine agonists have on inhibitory synaptic currents in ipRGCs. Although µ-opioid receptor (MOR) activation had no effect on γ-aminobutyric acid (GABA) currents, dopamine (via the D1R) amplified GABAergic currents in a subset of ipRGCs. Furthermore, this D1R-mediated facilitation of the GABA conductance in ipRGCs was mediated by a cAMP/PKA-dependent mechanism. Taken together, these findings reinforce the idea that dopamine's modulatory role in retinal adaptation affects both non-image forming as well as image forming visual functions.
PubMed: 38958282
DOI: 10.1152/jn.00457.2023 -
ACS Chemical Neuroscience Jul 2024Electrical brain stimulation has been used and to investigate neural circuitry. Historically, stimulation parameters such as amplitude, frequency, and pulse width were...
Dopamine Release Dynamics in the Nucleus Accumbens Are Modulated by the Timing of Electrical Stimulation Pulses When Applied to the Medial Forebrain Bundle and Medial Prefrontal Cortex.
Electrical brain stimulation has been used and to investigate neural circuitry. Historically, stimulation parameters such as amplitude, frequency, and pulse width were varied to investigate their effects on neurotransmitter release and behavior. These experiments have traditionally employed fixed-frequency stimulation patterns, but it has previously been found that neurons are more precisely tuned to variable input. Introducing variability into the interpulse interval of stimulation pulses will inform on how dopaminergic release can be modulated by variability in pulse timing. Here, dopaminergic release in rats is monitored in the nucleus accumbens (NAc), a key dopaminergic center which plays a role in learning and motivation, by fast-scan cyclic voltammetry. Dopaminergic release in the NAc could also be modulated by stimulation region due to differences in connectivity. We targeted two regions for stimulation─the medial forebrain bundle (MFB) and the medial prefrontal cortex (mPFC)─due to their involvement in reward processing and projections to the NAc. Our goal is to investigate how variable interpulse interval stimulation patterns delivered to these regions affect the time course of dopamine release in the NAc. We found that stimulating the MFB with these variable stimulation patterns saw a highly responsive, frequency-driven dopaminergic response. In contrast, variable stimulation patterns applied to the mPFC were not as sensitive to the variable frequency changes. This work will help inform on how stimulation patterns can be tuned specifically to the stimulation region to improve the efficiency of electrical stimulation and control dopamine release.
PubMed: 38958080
DOI: 10.1021/acschemneuro.4c00115 -
Journal of Materials Chemistry. B Jul 2024Surgical site infection (SSI) caused by pathogenic bacteria leads to delayed wound healing and extended hospitalization. Inappropriate uses of antibiotics have caused a...
Surgical site infection (SSI) caused by pathogenic bacteria leads to delayed wound healing and extended hospitalization. Inappropriate uses of antibiotics have caused a surge in SSI and common antibiotics are proving to be ineffective against SSI. Antimicrobial peptides (AMPs) can be a potential solution to prevent SSI because of their broad spectrum of antimicrobial activities. In this study, naturally sourced AMPs were studied along with microfibers, fabricated by a novel wet-spinning method using sodium alginate and polycaprolactone. Afterward, fibers were functionalized by the catechol groups of dopamine immobilizing nucleophilic AMPs on the surface. Conjugation between PCL and alginate resulted in fibers with smooth surfaces improving their mechanical strength hydrogen bonds. Having an average diameter of 220 μm, the mechanical properties of the fiber complied with USP standards for suture size 3-0. Engineered microfibers were able to hinder the growth of spp., a pathogenic bacterium for at least 60 hours whereas antibiotic ceftazidime failed. When subjected to a linear incisional wound model study, accelerated healing was observed when the wound was closed using the engineered fiber compared to Vicryl. The microfibers promoted faster re-epithelialization compared to Vicryl proving their higher wound healing capacity.
PubMed: 38958038
DOI: 10.1039/d4tb00889h -
Addiction Neuroscience Jun 2024A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual...
A preclinical model of cue exposure therapy, cue extinction, reduces cue-induced cocaine seeking that is goal-directed but not habit-like. Goal-directed and habitual behaviors differentially rely on the dorsomedial striatum (DMS) and dorsolateral striatum (DLS), but the effects of cue extinction on dorsal striatal responses to cue-induced drug seeking are unknown. We used fiber photometry in rats trained to self-administer cocaine paired with an audiovisual cue to examine how dorsal striatal intracellular calcium and extracellular dopamine activity differs between goal-directed and habit-like cue-induced cocaine seeking and how it is impacted by cue extinction. After minimal fixed-ratio training, rats showed enhanced DMS and DLS calcium responses to cue-reinforced compared to unreinforced lever presses. After rats were trained on goal-promoting fixed ratio schedules or habit-promoting second-order schedules of reinforcement, different patterns of dorsal striatal calcium and dopamine responses to cue-reinforced lever presses emerged. Rats trained on habit-promoting second-order schedules showed reduced DMS calcium responses and enhanced DLS dopamine responses to cue-reinforced lever presses. Cue extinction reduced calcium responses during subsequent drug seeking in the DMS, but not in the DLS. Therefore, cue extinction may reduce goal-directed behavior through its effects on the DMS, whereas habit-like behavior and the DLS are unaffected.
PubMed: 38957402
DOI: 10.1016/j.addicn.2024.100149 -
Frontiers in Pharmacology 2024Severe neonatal hyponatremia represents a critical electrolyte imbalance with potentially severe neurological outcomes, a condition rarely documented in...
Severe neonatal hyponatremia represents a critical electrolyte imbalance with potentially severe neurological outcomes, a condition rarely documented in community-acquired, full-term newborns. This report underscores a unique case of a 23-day-old, previously healthy, full-term male neonate experiencing severe hyponatremia that precipitated seizures, underscoring the urgency of prompt recognition and intervention. The neonate presented with symptoms including vomiting, groaning, chills, fixed staring, and limb tremors. Critical findings upon admission encompassed hypothermia, hypotension, tachycardia, and tachypnea accompanied by significant weight loss. The clinical presentation was marked by dehydration, lethargy, weak crying, a fixed gaze, irregular breathing, and coarse lung sounds, yet a distended abdomen, hypertonic limb movements, and recurrent seizures were observed. Immediate interventions included establishing IV access, rewarming, mechanical ventilation, seizure management, volume expansion, dopamine for circulatory support, and initiation of empirical antibiotics. Diagnostic evaluations revealed a sodium ion concentration of 105.9 mmol/L, while amplitude-integrated electroencephalography (aEEG) detected pronounced seizure activity characterized by a lack of sleep-wake rhythmicity, noticeable elevation in both the lower and upper amplitude margins, and a sustained decrease in the lower margin voltage dropping below 5 μV, presenting as sharp or serrated waveforms. The management strategy entailed rapid electrolyte normalization using hypertonic saline and sodium bicarbonate, anticonvulsant therapy, and comprehensive supportive care, with continuous aEEG monitoring until the cessation of seizures. Remarkably, by the third day, the neonate's condition had stabilized, allowing for discharge in good health 10 days post-admission. At a 16-month follow-up, the child exhibited no adverse neurological outcomes and demonstrated favorable growth and development. Our extensive review on the etiology, clinical manifestations, aEEG monitoring, characteristics of seizures induced by severe neonatal hyponatremia, treatment approaches, and the prognosis for seizures triggered by severe hyponatremia aims to deepen the understanding and enhance clinical management of this complex condition. It stresses the importance of early detection, accurate diagnosis, and customized treatment protocols to improve outcomes for affected neonates. Additionally, this review accentuates the indispensable role of aEEG monitoring in managing neonates at elevated risk for seizures. Yet, the safety and efficacy of swiftly administering hypertonic saline for correcting severe hyponatremia-induced seizures necessitate further investigation through medical research.
PubMed: 38957388
DOI: 10.3389/fphar.2024.1391024 -
Brain and Behavior Jul 2024High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor...
The protective effects of repetitive transcranial magnetic stimulation with different high frequencies on motor functions in MPTP/probenecid induced Parkinsonism mouse models.
BACKGROUND
High-frequency repeated transcranial magnetic stimulation (rTMS) stimulating the primary motor cortex (M1) is an alternative, adjunctive therapy for improving the motor symptoms of Parkinson's disease (PD). However, whether the high frequency of rTMS positively correlates to the improvement of motor symptoms of PD is still undecided. By controlling for other parameters, a disease animal model may be useful to compare the neuroprotective effects of different high frequencies of rTMS.
OBJECTIVE
The current exploratory study was designed to compare the protective effects of four common high frequencies of rTMS (5, 10, 15, and 20 Hz) and iTBS (a special form of high-frequency rTMS) and explore the optimal high-frequency rTMS on an animal PD model.
METHODS
Following high frequencies of rTMS application (twice a week for 5 weeks) in a MPTP/probenecid-induced chronic PD model, the effects of the five protocols on motor behavior as well as dopaminergic neuron degeneration levels were identified. The underlying molecular mechanisms were further explored.
RESULTS
We found that all the high frequencies of rTMS had protective effects on the motor functions of PD models to varying degrees. Among them, the 10, 15, and 20 Hz rTMS interventions induced comparable preservation of motor function through the protection of nigrostriatal dopamine neurons. The enhancement of brain-derived neurotrophic factor (BDNF), dopamine transporter (DAT), and vesicular monoamine transporter 2 (VMAT-2) and the suppression of TNF-α and IL-1β in the nigrostriatum were involved in the process. The efficacy of iTBS was inferior to that of the above three protocols. The effect of 5 Hz rTMS protocol was weakest.
CONCLUSIONS
Combined with the results of the present study and the possible side effects induced by rTMS, we concluded that 10 Hz might be the optimal stimulation frequency for preserving the motor functions of PD models using rTMS treatment.
Topics: Animals; Transcranial Magnetic Stimulation; Mice; Male; Disease Models, Animal; Probenecid; Parkinsonian Disorders; Mice, Inbred C57BL; Brain-Derived Neurotrophic Factor; Motor Cortex; Dopaminergic Neurons; Dopamine Plasma Membrane Transport Proteins; Interleukin-1beta; Substantia Nigra; Corpus Striatum; Vesicular Monoamine Transport Proteins; MPTP Poisoning; Motor Activity; 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine
PubMed: 38956819
DOI: 10.1002/brb3.3605 -
BMC Urology Jul 2024Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to...
Prostate cancer (PCa) is a complex and biologically diverse disease with no curative treatment options at present. This study aims to utilize computational methods to explore potential anti-PCa compounds based on differentially expressed genes (DEGs), with the goal of identifying novel therapeutic indications or repurposing existing drugs. The methods employed in this study include DEGs-to-drug prediction, pharmacokinetics prediction, target prediction, network analysis, and molecular docking. The findings revealed a total of 79 upregulated DEGs and 110 downregulated DEGs in PCa, which were used to identify drug compounds capable of reversing the dysregulated conditions (dexverapamil, emetine, parthenolide, dobutamine, terfenadine, pimozide, mefloquine, ellipticine, and trifluoperazine) at a threshold probability of 20% on several molecular targets, such as serotonin receptors 2a/2b/2c, HERG protein, adrenergic receptors alpha-1a/2a, dopamine D3 receptor, inducible nitric oxide synthase (iNOS), epidermal growth factor receptor erbB1 (EGFR), tyrosine-protein kinases, and C-C chemokine receptor type 5 (CCR5). Molecular docking analysis revealed that terfenadine binding to inducible nitric oxide synthase (-7.833 kcal.mol) and pimozide binding to HERG (-7.636 kcal.mol). Overall, binding energy ΔG (Total) at 0 ns was lower than that of 100 ns for both the Terfenadine-iNOS complex (-101.707 to -103.302 kcal.mol) and Ellipticine-TOPIIα complex (-42.229 to -58.780 kcal.mol). In conclusion, this study provides insight on molecular targets that could possibly contribute to the molecular mechanisms underlying PCa. Further preclinical and clinical studies are required to validate the therapeutic effectiveness of these identified drugs in PCa disease.
Topics: Prostatic Neoplasms; Humans; Male; Molecular Docking Simulation; Computer Simulation; Antineoplastic Agents; Gene Expression Regulation, Neoplastic; Gene Expression Profiling
PubMed: 38956591
DOI: 10.1186/s12894-024-01521-9 -
Nature Communications Jul 2024Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially...
Genetically-encoded dopamine (DA) sensors enable high-resolution imaging of DA release, but their ability to detect a wide range of extracellular DA levels, especially tonic versus phasic DA release, is limited by their intrinsic affinity. Here we show that a human-selective dopamine receptor positive allosteric modulator (PAM) can be used to boost sensor affinity on-demand. The PAM enhances DA detection sensitivity across experimental preparations (in vitro, ex vivo and in vivo) via one-photon or two-photon imaging. In vivo photometry-based detection of optogenetically-evoked DA release revealed that DETQ administration produces a stable 31 minutes window of potentiation without effects on animal behavior. The use of the PAM revealed region-specific and metabolic state-dependent differences in tonic DA levels and enhanced single-trial detection of behavior-evoked phasic DA release in cortex and striatum. Our chemogenetic strategy can potently and flexibly tune DA imaging sensitivity and reveal multi-modal (tonic/phasic) DA signaling across preparations and imaging approaches.
Topics: Dopamine; Animals; Humans; Optogenetics; Mice; Male; Corpus Striatum; Receptors, Dopamine; Mice, Inbred C57BL; Allosteric Regulation; Photometry; HEK293 Cells
PubMed: 38956067
DOI: 10.1038/s41467-024-49442-3