Search Results (170)

Introduction: Two-stage revision with an antibiotic-loaded, temporary static cement spacer is a common treatment for periprosthetic joint infection (PJI) of the knee. However, limited data exists on in vivo antibiotic elution kinetics after spacer implantation. This pilot study uses the technique of microdialysis (MD) to collect intra-articular knee samples. The aim was to evaluate MD as an intra-articular sampling method to detect spacer-eluted antibiotics within 72 h after surgery and to determine whether they show specific elution kinetics. Methods: Ten patients (six male, four female; age median 71.5 years) undergoing two-stage revision for knee PJI were included. A MD catheter was inserted into the joint during explantation of the infected inlying implant and implantation of a custom-made static spacer coated with COPAL cement (0.5 g gentamicin (G) and 2 g vancomycin (V)). Over 72 h postoperatively, samples were collected and analyzed for spacer-eluted antibiotics, intravenously administered antibiotics (e.g., cefazolin and cefuroxime), metabolic markers (glucose and lactate), and Interleukin-6 (IL-6). Local and systemic levels were compared. Results: All catheters were positioned successfully and well tolerated for 72 h. Antibiotic concentrations in MD samples peaked within the first 24 h (G: median 9.55 µg/mL [95% CI: 0.4–17.36]; V: 37.57 µg/mL [95% CI: 3.26–81.6]) and decreased significantly over 72 h (for both p < 0.05, G: 4.27 µg/mL [95% CI: 2.26–7.2]; V: 9.69 µg/mL [95% CI: 3.86–24]). MD concentrations consistently exceeded blood levels (p < 0.05), while intravenously administered antibiotics showed higher blood concentrations. Glucose in MD samples decreased from 17.71 mg/dL to 0.89 mg/dL (p < 0.05). IL-6 and lactate concentrations showed no difference between MD and blood samples. Conclusions: Monitoring antibiotics eluted by a static spacer with intra-articular MD for 72 h is feasible. Gentamicin and vancomycin levels remained above the minimal inhibitory concentration. Differentiating infection from surgical response using metabolic and immunological markers remains challenging. Prolonged in vivo studies with MD are required to evaluate extended antibiotic release in two-stage exchanges. Full article

The enzymatic formation of kynurenic acid (KYNA), a neuromodulator metabolite of the kynurenine pathway (KP) of tryptophan metabolism, in the mammalian brain is widely attributed to kynurenine aminotransferase II (KATII). However, an alternative biosynthetic route, involving the conversion of D-kynurenine (D-KYN) to KYNA by D-amino acid oxidase (D-AAO), may play a role as well. In the present study, we first confirmed that purified D-AAO efficiently converted D-KYN—but not L-KYN—to KYNA. We then examined KYNA formation from D-KYN (100 µM) in vitro, using tissue homogenates from several human brain regions. KYNA was generated in all areas, with D-AAO-specific production being most effective by far in the cerebellum. Next tested in homogenates from rat cerebellum, KYNA neosynthesis was significantly reduced by D-AAO inhibition, whereas KATII inhibition had no effect. Finally, KYNA production was assessed by in vivo microdialysis in rat cerebellum. Local D-KYN perfusion, alone and in combination with inhibitors of D-AAO (kojic acid) or aminotransferases (AOAA), caused a substantive increase in extracellular KYNA levels. This effect was attenuated dose-dependently by micromolar concentrations of kojic acid, whereas co-perfusion of AOAA (1 mM) was ineffective. Together, our findings indicate that D-AAO should be considered a major contributor to KYNA production in the cerebellum, highlighting region-specific qualitative differences in cerebral KYNA metabolism. Full article

Neurotransmitters such as serotonin regulate key physiological and cognitive functions, yet real-time detection remains challenging due to the limitations of conventional techniques like amperometry and microdialysis. Fluorescent molecularly imprinted polymer nanoparticles (fMIP-NPs) offer a promising alternative and are typically synthesized via solid-phase synthesis, in which template molecules are covalently immobilized on a solid support to enable site-specific imprinting. However, strong template–template interactions during this process can compromise selectivity. To overcome this, we incorporated a poly(methacrolein-co-methacrylamide)-based template anchoring strategy to minimize undesired template interactions and enhance imprinting efficiency. We optimized the synthesis of poly(methacrolein-co-methacrylamide) under three different conditions by varying the monomer compositions and reaction parameters. The poly(methacrolein-co-methacrylamide) synthesized under Condition 3 (5:1 methacrolein-to-methacrylamide molar ratio, 1:150 initiator-to-total monomer ratio, and 4.59 M total monomer concentration) yielded the most selective fMIP-NPs, whose fluorescence intensity increased with an increase in serotonin concentration, rising by up to 37% upon serotonin binding. This improvement is attributed to higher aldehyde functionality in the poly(methacrolein-co-methacrylamide) which enhances template immobilization and generates a rigid imprinted cavity to interact with serotonin. These findings suggest that the developed fMIP-NPs hold significant potential as imaging probes for neurotransmitter detection, contributing to advanced studies in neural network analysis. Full article

A part of autosomal dominant sleep-related hypermotor epilepsy (ADSHE) is caused by mutant CHRNA4. The pathomechanisms underlying motor seizures followingly brief/sudden awakening (paroxysmal arousal) in ADSHE seizures remain to be clarified. This study determined extracellular levels of ACh and L-glutamate in the pedunculopontine nucleus (PPN) and its projection regions, including the thalamus and basal ganglia, during wakefulness, slow-wave sleep (SWS) and paroxysmal arousal of transgenic rats bearing rat S286L-mutant Chrna4 (S286L-TG), corresponding to human S284L-mutant CHRNA4, using microdialysis. The expression of connexin43 and pannexin1 in the plasma membrane of the PPN was determined using capillary immunoblotting. The expressions of connexin43 and pannexin1 in the PPN plasma membrane of S286L-TG were larger than the wild type. The extracellular L-glutamate levels in the PPN and projection regions of S286L-TG consistently increased during both wakefulness and SWS compared to the wild type. The extracellular levels of ACh and L-glutamate in the PPN and projection regions decreased accompaning SWS in the wild type. In S286L-TG, this decreasing extracellular ACh level was observed, whereas decreasing L-glutamate level was impaired. Both extracellular levels of ACh and L-glutamate in the PPN and projection regions drastically increased during paroxysmal arousal. Hemichannel inhibitors suppressed the increasing releases of ACh and L-glutamate induced by paroxysmal arousal but decreased and did not affect extracellular levels of L-glutamate and ACh during wakefulness and SWS, respectively. In particular, under hemichannels inhibition, decreasing L-glutamate release accompanying SWS was observed in S286L-TG. This study elucidated that enhanced hemichannels are predominantly involved in the dysfunction of glutamatergic transmission compared to AChergic transmission during the interictal stage in S286L-TG, whereas the hyperactivation of hemichannels contributes to the generation of paroxysmal arousal. Therefore, the hyperactivated excitatory tripartite synaptic transmission associated with hemichannels in the PPN and projection regions plays important roles in epileptogenesis/ictogenesis in S286L-TG. Full article

Ischemic stroke leads to cerebral ionic imbalance, increases acidosis, oxidative stress and release of glutamate and inflammatory mediators. Removing solute or stimulants from the ischemic core may block cell-damaging events and confer neuroprotection. In this study, we developed a minimally invasive therapeutic microdialysis (tMD) method, choosing to include serum albumin in the buffer because it is a multifunctional protein with osmotic properties. Aiming at the ischemic core, continuous perfusion of buffer supplemented with osmotic agents removes mediators of inflammation/cell damage/death from the lesion. This tMD treatment significantly removed the glutamate and zinc ions from the core, thereby reducing infarct volumes and affording high-grade neurobehavioral protection against ischemic stroke. The tMD treatment effectively protected neurons and reduced microglial activation. Furthermore, this tMD approach extended the therapeutic window to protect beyond 6 h after stroke onset. These findings support the potential clinical feasibility of applying tMD to patients with ischemic stroke, potentially without adverse effects. Full article

25I-NBOMe (4-Iodo-2,5-dimethoxy-N-(2-methoxybenzyl) phenethylamine) is a synthetic psychedelic compound abused for its ambiguous legal state as a counterfeit lysergic acid diethylamide (LSD). 25I-NBOMe acts as a selective agonist of 5HT_2A receptors leading to hallucinations, intoxications, and fatalities. Here, we assessed the rewarding properties of 25I-NBOMe and its behavioral and neurotoxic acute effects on the central nervous system of C57BL/6J mice. We evaluated the dopamine (DA) levels using in vivo microdialysis in the nucleus accumbens (NAc) shell after 25I-NBOMe (0.1–1 mg/kg i.p.) injection. We also investigated the effects of 25I-NBOMe (0.1–1 mg/kg i.p.) on locomotor activity, reaction time, and prepulse inhibition. Moreover, we assessed the acute 25I-NBOMe (1 µM) effects on synaptic transmission and plasticity in the medial prefrontal cortex (mPFC) by using ex vivo electrophysiology. Our findings suggest that 25I-NBOMe affects the DA transmission in NAc shell at the highest dose tested, increases the reaction time within 30 min after the administration, and disrupts the PPI. In slices, it prevents long-term synaptic potentiation (LTP) in the mPFC, an effect that could not be reverted by the co-administration of the selective 5HT_2A antagonist (MDL100907). Overall, these findings provide valuable new insights into the effects of 25I-NBOMe and the associated risks of its use. Full article

Brain function declines because of aging and several metabolites change their concentration. However, this decrease may be a consequence or a driver of aging. It has been described that taurine levels decrease with age and that taurine supplementation increases health span in mice and monkeys, finding taurine as a driver of aging. The frontal cortex is one of the most key areas studied to know the normal processes of cerebral aging, due to its relevant role in cognitive processes, emotion, and motivation. In the present work, we analyzed by intracerebral microdialysis in vivo in the prefrontal cortex of young (3 months) and old (24 months) awake rats, the basal- and K⁺-evoked release of taurine, and its precursors methionine and serine. The taurine/serine/methionine (TSM) ratio was also calculated as an index of transmethylation reactions. No changes were found in the basal levels of taurine, serine, or methionine between young and aged animals. On the contrary, a significant decrease in the K⁺-evoked release of serine and taurine appeared in aged rats when compared with young animals. No changes were seen in methionine. TSM ratio also decreased with age in both basal- and K⁺-stimulated conditions. Therefore, taurine and its related precursor serine decrease with age in the frontal cortex of aged animals under K⁺-stimulated but not basal conditions, which supports the importance of the decline of evoked taurine in its functions at the brain level, also supporting the idea proposed by other authors of a pharmacological and/or nutritional intervention to its restoration. A deficit of precursors for transmethylation reactions in the brain with age is also considered. Full article

Since its first introduction, levodopa has remained the cornerstone treatment for Parkinson’s disease. However, as the disease advances, the therapeutic window for levodopa narrows, leading to motor complications like fluctuations and dyskinesias. Clinicians face challenges in optimizing daily therapeutic regimens, particularly in advanced stages, due to the lack of quantitative biomarkers for continuous motor monitoring. Biochemical sensing of levodopa offers a promising approach for real-time therapeutic feedback, potentially sustaining an optimal motor state throughout the day. These sensors vary in invasiveness, encompassing techniques like microdialysis, electrochemical non-enzymatic sensing, and enzymatic approaches. Electrochemical sensing, including wearable solutions that utilize reverse iontophoresis and microneedles, is notable for its potential in non-invasive or minimally invasive monitoring. Point-of-care devices and standard electrochemical cells demonstrate superior performance compared to wearable solutions; however, this comes at the cost of wearability. As a result, they are better suited for clinical use. The integration of nanomaterials such as carbon nanotubes, metal–organic frameworks, and graphene has significantly enhanced sensor sensitivity, selectivity, and detection performance. This framework paves the way for accurate, continuous monitoring of levodopa and its metabolites in biofluids such as sweat and interstitial fluid, aiding real-time motor performance assessment in Parkinson’s disease. This review highlights recent advancements in biochemical sensing for levodopa and catecholamine monitoring, exploring emerging technologies and their potential role in developing closed-loop therapy for Parkinson’s disease. Full article

Elevated risk for schizophrenia is associated with a variation in the DTNBP1 gene encoding dysbindin-1, which may underpin cognitive impairments in this prevalent neuropsychiatric disorder. The cognitive symptoms of schizophrenia involve anomalies in glutamate and dopamine signaling, particularly within the prefrontal cortex (PFC). Indeed, mice with Dtnbp1 mutations exhibit spatial and working memory deficits that are associated with deficits in glutamate release and NMDA receptor function as determined by slice electrophysiology. The present study extended the results from ex vivo approaches by examining how the Dtnbp1 mutation impacts high K+- and NMDA receptor-evoked glutamate release within the PFC using in vivo microdialysis procedures. Dntbp1 mutant mice are also reported to exhibit blunted K+-evoked dopamine release within the PFC. Thus, we examined also K+- and NMDA-evoked dopamine release within this region. Perfusion of high-concentration K+ or NMDA solutions increased the PFC levels of both dopamine and glutamate in wild-type (WT) but not in Dtnbp1 mutants (MUT), whereas mice heterozygous for the Dtnbp1 mutation (HET) exhibited blunted K+-evoked dopamine release. No net-flux microdialysis procedures confirmed elevated basal extracellular content of both glutamate and dopamine within the PFC of HET and MUT mice. These in vivo microdialysis results corroborate prior indications that Dtnbp1 mutations perturb evoked dopamine and glutamate release within the PFC, provide in vivo evidence for impaired NMDA receptor function within the PFC, and suggest that these neurochemical anomalies may be related to abnormally elevated basal neurotransmitter content. Full article

Abstract: The introduction of biological therapies has revolutionized inflammatory bowel disease (IBD) management. A critical consideration in developing these therapies is ensuring adequate drug concentrations at the site of action. While blood-based biomarkers have shown limited utility in optimizing treatment (except for TNF-alpha inhibitors and thiopurines), tissue drug concentrations may offer valuable insights. In antimicrobial therapies, tissue concentration monitoring is standard practice and could provide a new avenue for understanding the pharmacokinetics of biological and small-molecule therapies in IBD. Various methods exist for measuring tissue concentrations, including whole tissue sampling, MALDI-MSI, microdialysis, and fluorescent labeling. These techniques offer unique advantages, such as spatial drug-distribution mapping, continuous sampling, or cellular-level analysis. However, challenges remain, including sampling invasiveness, heterogeneity in tissue compartments, and a lack of standardized bioanalytical guidelines. Drug pharmacokinetics are influenced by multiple factors, including molecular properties, disease-induced changes in the gastrointestinal tract, and the timing of sample collection. For example, drug permeability, solubility, and interaction with transporters may vary between Crohn’s disease and ulcerative colitis. Research into the tissue concentrations of drugs like anti-TNF agents, ustekinumab, vedolizumab, and tofacitinib has shown variable correlations with clinical outcomes, suggesting potential roles for tissue concentration monitoring in therapeutic drug management. Although routine clinical application is not yet established, exploring tissue drug concentrations may enhance understanding of IBD pharmacotherapy. Full article

Background/Objectives: Tinnitus is a debilitating auditory disorder commonly described as a ringing in the ears in the absence of an external sound source. Sound trauma is considered a primary cause. Neuronal hyperactivity is one potential mechanism for the genesis of tinnitus and has been identified in the cochlear nucleus (CN) and the auditory cortex (AC), where there may be an imbalance of excitatory and inhibitory neurotransmissions. However, no study has directly correlated tinnitus with the extracellular levels of amino acids in the CN and the AC using microdialysis, which reflects the functions of these neurochemicals. In the present study, rats were exposed to acoustic trauma and then subjected to behavioural confirmation of tinnitus after one month, followed by microdialysis. Methods: Rats were divided into sham (aged, n = 6; young, n = 6); tinnitus-positive (aged, n = 7; young, n = 7); and tinnitus-negative (aged, n = 3; young, n = 3) groups. In vivo microdialysis was utilized to collect samples from the CN and the AC, simultaneously, in the same rat. Extracellular levels of amino acids were quantified using high-performance liquid chromatography (HPLC) coupled with an electrochemical detector (ECD). The effects of sound stimulation and age on neurochemical changes associated with tinnitus were also examined. Results: There were no significant differences in either the basal levels or the sound stimulation-evoked changes of any of the amino acids examined in the CN and the AC between the sham and tinnitus animals. However, the basal levels of serine and threonine exhibited age-related alterations in the AC, and significant differences in threonine and glycine levels were observed in the responses to 4 kHz and 16 kHz stimuli in the CN. Conclusions: These results demonstrate the lack of a direct link between extracellular levels of amino acids in the CN and the AC and tinnitus perception in a rat model of tinnitus. Full article

Background: Studies that assess the effects of the interaction of psychoactive substances on dopamine release, the key neurotransmitter in the neurochemical and behavioral effects related to drug consumption, are crucial to understand both their roles and the dysfunctions they produce in the central nervous system. Objective: We evaluated the effects of individual and combined administration of the three most widely consumed psychoactive substances in the world, ethanol, caffeine, and nicotine, on dopaminergic neurotransmission in three brain regions of rats related to addiction: the prefrontal cortex (PFC), the nucleus accumbens (NAcc), and the dorsal striatum. Methods: The dopamine levels were measured in vivo by cerebral microdialysis associated with HPLC-ED. Results: We observed that local administration of a single concentration of caffeine (5 mM) or nicotine (5 mM) significantly increased the dopamine levels in all three areas studied, while ethanol (300 mM) increased them in the NAcc and striatum. Perfusion of nicotine + caffeine produced a synergistic effect in both the NAcc and striatum, with increases in the in vivo dopamine release greater than the sum of the effects of both substances. When administering the combination of nicotine + caffeine + ethanol, we observed an additive effect in the NAcc, while in the PFC we observed a synergistic effect. Conclusions: Our results support the stimulating effects of caffeine, nicotine, and ethanol on the brain reward system. In addition, we also observed that the administration of different mixtures of these substances produces synergistic and additive effects on the release of dopamine in the mesocortical and nigrostriatal systems. Full article

(1) Background: The purpose of this systematic review is to investigate the prevalent use of non-steroidal anti-inflammatory drugs (NSAIDs) in athletes and to comprehensively review the effectiveness and the results of these medications as it relates to injury management, training response, and overall sport performance. (2) Methods: An electronic literature search was performed in accordance with the recommendations and guidelines of the Preferred Reporting Items for Systematic reviews and Meta-Analysis (PRISMA) protocol. A total of 7 randomized controlled studies met the review’s specific inclusion criteria from the 2250 studies initially identified within the PubMed database. (3) Results: In total, 346 adult female and male athletes from a variety of sporting activities and fitness levels were observed, of which 175 athletes were treated with either oral, topical, or local muscular infusion of an NSAID. Depending on study design, the outcomes focused on results obtained through physical exam findings, questionnaires, various performance metrics, and direct tissue sampling from microdialysis or biopsies. Across the 7 total studies, 2 articles focused on injured athletes and their varying pain responses with NSAIDs; 2 studies assessed the limited impact of NSAIDs on performance; and 3 articles revealed the use of NSAIDs correlating to no increases in either collagen synthesis or satellite cell activity after exercise. (4) Conclusions: The systematic review affirmed that NSAIDs can be effective for managing acute pain. However, their value appears to diminish when treating chronic injuries or if NSAIDs are expected to improve performance or have other ergogenic effects in athletes, as the aggregate data did not support such benefits. (5) Practical applications: NSAIDs can be beneficial for athletes in the right situation, but the fact that there are risks and possible disadvantageous results with their use highlights the importance of promoting appropriate expectations and the judicious use of these medications with the athletic community. Full article

Xerostomia induced by antidepressants such as imipramine has long been thought to be due to their anticholinergic effects. However, even antidepressants with low anticholinergic effects may have a high incidence of xerostomia. In salivary glands, norepinephrine activates alpha-adrenergic receptors in blood vessels and beta-adrenergic receptors in acinar cells, respectively, causing a decrease in the blood flow and an increase in the protein secretion, resulting in the secretion of viscous saliva with low water content and high protein content. A previous study demonstrated that perfusion of the submandibular glands of rats with serotonin significantly decreased saliva secretion. The results of the present study revealed the following: (1) that norepinephrine and serotonin, but not epinephrine nor dopamine, were detected in the interstitial fluids in rat submandibular glands; (2) that norepinephrine and serotonin concentrations in the dialysate was 4.3 ± 2.8 nM and 32.3 ± 19.6 nM at stable level, respectively; (3) that infusion with imipramine, a reuptake inhibitor of norepinephrine and serotonin, significantly and dose-dependently increased both norepinephrine and serotonin concentrations in the dialysate; and (4) that intraperitoneal administration of imipramine significantly increased both norepinephrine and serotonin concentrations in the dialysate. These results suggested that one of the mechanisms of xerostomia induced by reuptake inhibitors of norepinephrine and serotonin involves the activation of adrenergic and serotonin receptors in the salivary glands, respectively. Full article

Aberrant metabolism is a hallmark of malignancies including gliomas. Intracranial microdialysis enables the longitudinal collection of extracellular metabolites within CNS tissues including gliomas and can be leveraged to evaluate changes in the CNS microenvironment over a period of days. However, delayed metabolic impacts of CNS injury from catheter placement could represent an important covariate for interpreting the pharmacodynamic impacts of candidate therapies. Intracranial microdialysis was performed in patient-derived glioma xenografts of glioma before and 72 h after systemic treatment with either temozolomide (TMZ) or a vehicle. Microdialysate from GBM164, an IDH-mutant glioma patient-derived xenograft, revealed a distinct metabolic signature relative to the brain that recapitulated the metabolic features observed in human glioma microdialysate. Unexpectedly, catheter insertion into the brains of non-tumor-bearing animals triggered metabolic changes that were significantly enriched for the extracellular metabolome of glioma itself. TMZ administration attenuated this resemblance. The human glioma microdialysate was significantly enriched for both the PDX versus brain signature in mice and the induced metabolome of catheter placement within the murine control brain. These data illustrate the feasibility of microdialysis to identify and monitor the extracellular metabolome of diseased versus relatively normal brains while highlighting the similarity between the extracellular metabolome of human gliomas and that of CNS injury. Full article