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Frontiers in Neurology 2023
PubMed: 37609655
DOI: 10.3389/fneur.2023.1266540 -
International Journal of Molecular... Dec 2023The study of an organism's response to cerebral ischemia at different levels is essential to understanding the mechanism of the injury and protection. A great interest... (Review)
Review
The study of an organism's response to cerebral ischemia at different levels is essential to understanding the mechanism of the injury and protection. A great interest is devoted to finding the links between quantitative metabolic changes and post-ischemic damage. This work aims to summarize the outcomes of the most studied metabolites in brain tissue-lactate, glutamine, GABA (4-aminobutyric acid), glutamate, and NAA (N-acetyl aspartate)-regarding their biological function in physiological conditions and their role after cerebral ischemia/reperfusion. We focused on ischemic damage and post-ischemic recovery in both experimental-including our results-as well as clinical studies. We discuss the role of blood glucose in view of the diverse impact of hyperglycemia, whether experimentally induced, caused by insulin resistance, or developed as a stress response to the cerebral ischemic event. Additionally, based on our and other studies, we analyze and critically discuss post-ischemic alterations in energy metabolites and the elevation of blood ketone bodies observed in the studies on rodents. To complete the schema, we discuss alterations in blood plasma circulating amino acids after cerebral ischemia. So far, no fundamental brain or blood metabolite(s) has been recognized as a relevant biological marker with the feasibility to determine the post-ischemic outcome or extent of ischemic damage. However, studies from our group on rats subjected to protective ischemic preconditioning showed that these animals did not develop post-ischemic hyperglycemia and manifested a decreased metabolic infringement and faster metabolomic recovery. The metabolomic approach is an additional tool for understanding damaging and/or restorative processes within the affected brain region reflected in the blood to uncover the response of the whole organism via interorgan metabolic communications to the stressful cerebral ischemic challenge.
Topics: Rats; Animals; Brain Ischemia; Cerebral Infarction; Brain; Lactic Acid; gamma-Aminobutyric Acid; Hyperglycemia
PubMed: 38139131
DOI: 10.3390/ijms242417302 -
Journal of Cerebral Blood Flow and... Aug 2023The loss of cerebral autoregulation (CA) is a common and detrimental secondary injury mechanism following acute brain injury and has been associated with worse morbidity... (Review)
Review
The loss of cerebral autoregulation (CA) is a common and detrimental secondary injury mechanism following acute brain injury and has been associated with worse morbidity and mortality. However patient outcomes have not as yet been conclusively proven to have improved as a result of CA-directed therapy. While CA monitoring has been used to modify CPP targets, this approach cannot work if the impairment of CA is not simply related to CPP but involves other underlying mechanisms and triggers, which at present are largely unknown. Neuroinflammation, particularly inflammation affecting the cerebral vasculature, is an important cascade that occurs following acute injury. We hypothesise that disturbances to the cerebral vasculature can affect the regulation of CBF, and hence the vascular inflammatory pathways could be a putative mechanism that causes CA dysfunction. This review provides a brief overview of CA, and its impairment following brain injury. We discuss candidate vascular and endothelial markers and what is known about their link to disturbance of the CBF and autoregulation. We focus on human traumatic brain injury (TBI) and subarachnoid haemorrhage (SAH), with supporting evidence from animal work and applicability to wider neurologic diseases.
Topics: Animals; Humans; Neuroinflammatory Diseases; Brain Injuries; Brain Injuries, Traumatic; Subarachnoid Hemorrhage; Homeostasis; Cerebrovascular Circulation; Intracranial Pressure; Brain
PubMed: 37132274
DOI: 10.1177/0271678X231171991 -
International Journal of Molecular... Jun 2023Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in...
Tau protein aggregations are important contributors to the etiology of Alzheimer's disease (AD). Hydromethylthionine (HMT) is a potent inhibitor of tau aggregation in vitro and in vivo and is being developed as a possible anti-dementia medication. HMT was also shown to affect the cholinergic system and to interact with mitochondria. Here, we used tau-transgenic (L1 and L66) and wild-type NMRI mice that were treated with HMT, rivastigmine and memantine and with combinations thereof, for 2-4 weeks. We measured HMT concentrations in both brain homogenates and isolated mitochondria and concentrations of glucose, lactate and pyruvate in brain by microdialysis. In isolated brain mitochondria, we recorded oxygen consumption of mitochondrial complexes by respirometry. While rivastigmine and memantine lowered mitochondrial respiration, HMT did not affect respiration in wild-type animals and increased respiration in tau-transgenic L1 mice. Glucose and lactate levels were not affected by HMT administration. The presence of HMT in isolated mitochondria was established. In summary, traditional anti-dementia drugs impair mitochondrial function while HMT has no adverse effects on mitochondrial respiration in tau-transgenic mice. These results support the further development of HMT as an anti-dementia drug.
Topics: Mice; Animals; Rivastigmine; Memantine; tau Proteins; Mice, Transgenic; Cholinesterase Inhibitors; Alzheimer Disease; Mitochondria
PubMed: 37445987
DOI: 10.3390/ijms241310810 -
ACS Chemical Neuroscience Jul 2023Information about the rates of hydrolysis of neuropeptides by extracellular peptidases can lead to a quantitative understanding of how the steady-state and transient...
Information about the rates of hydrolysis of neuropeptides by extracellular peptidases can lead to a quantitative understanding of how the steady-state and transient concentrations of neuropeptides are controlled. We have created a small microfluidic device that electroosmotically infuses peptides into, through, and out of the tissue to a microdialysis probe outside the head. The device is created by two-photon polymerization (Nanoscribe). Inferring quantitative estimates of a rate process from the change in concentration of a substrate that has passed through tissue is challenging for two reasons. One is that diffusion is significant, so there is a distribution of peptide substrate residence times in the tissue. This affects the product yield. The other is that there are multiple paths taken by the substrate as it passes through tissue, so there is a distribution of residence times and thus reaction times. Simulation of the process is essential. The simulations presented here imply that a range of first order rate constants of more than 3 orders of magnitude is measurable and that 5-10 min is required to reach a steady state value of product concentration following initiation of substrate infusion. Experiments using a peptidase-resistant d-amino acid pentapeptide, yaGfl, agree with simulations.
Topics: Microdialysis; Peptides; Perfusion; Computer Simulation; Neuropeptides
PubMed: 37379416
DOI: 10.1021/acschemneuro.3c00057 -
Fluids and Barriers of the CNS Dec 2023Microdialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known...
BACKGROUND
Microdialysis is a technique that can be utilized to sample the interstitial fluid of the central nervous system (CNS), including in primary malignant brain tumors known as gliomas. Gliomas are mainly accessible at the time of surgery, but have rarely been analyzed via interstitial fluid collected via microdialysis. To that end, we obtained an investigational device exemption for high molecular weight catheters (HMW, 100 kDa) and a variable flow rate pump to perform microdialysis at flow rates amenable to an intra-operative setting. We herein report on the lessons and insights obtained during our intra-operative HMW microdialysis trial, both in regard to methodological and analytical considerations.
METHODS
Intra-operative HMW microdialysis was performed during 15 clinically indicated glioma resections in fourteen patients, across three radiographically diverse regions in each patient. Microdialysates were analyzed via targeted and untargeted metabolomics via ultra-performance liquid chromatography tandem mass spectrometry.
RESULTS
Use of albumin and lactate-containing perfusates impacted subsets of metabolites evaluated via global metabolomics. Additionally, focal delivery of lactate via a lactate-containing perfusate, induced local metabolic changes, suggesting the potential for intra-operative pharmacodynamic studies via reverse microdialysis of candidate drugs. Multiple peri-operatively administered drugs, including levetiracetam, cefazolin, caffeine, mannitol and acetaminophen, could be detected from one microdialysate aliquot representing 10 min worth of intra-operative sampling. Moreover, clinical, radiographic, and methodological considerations for performing intra-operative microdialysis are discussed.
CONCLUSIONS
Intra-operative HMW microdialysis can feasibly be utilized to sample the live human CNS microenvironment, including both metabolites and drugs, within one surgery. Certain variables, such as perfusate type, must be considered during and after analysis. Trial registration NCT04047264.
Topics: Humans; Microdialysis; Glioma; Extracellular Fluid; Lactic Acid; Catheters; Tumor Microenvironment
PubMed: 38115038
DOI: 10.1186/s12987-023-00497-2 -
Scientific Reports Oct 2023Hydrogen sulfide (HS) and polysulfides (HS, n ≥ 2) are signaling molecules produced by 3-mercaptopyruvate sulfurtransferase (3MST) that play various physiological...
Hydrogen sulfide (HS) and polysulfides (HS, n ≥ 2) are signaling molecules produced by 3-mercaptopyruvate sulfurtransferase (3MST) that play various physiological roles, including the induction of hippocampal long-term potentiation (LTP), a synaptic model of memory formation, by enhancing N-methyl-D-aspartate (NMDA) receptor activity. However, the presynaptic action of HS/HS on neurotransmitter release, regulation of LTP induction, and animal behavior are poorly understood. Here, we showed that HS/HS applied to the rat hippocampus by in vivo microdialysis induces the release of GABA, glutamate, and D-serine, a co-agonist of NMDA receptors. Animals with genetically knocked-out 3MST and the target of HS, transient receptor potential ankyrin 1 (TRPA1) channels, revealed that HS/HS, 3MST, and TRPA1 activation play a critical role in LTP induction, and the lack of 3MST causes behavioral hypersensitivity to NMDA receptor antagonism, as in schizophrenia. HS/HS, 3MST, and TRPA1 channels have therapeutic potential for psychiatric diseases and cognitive deficits.
Topics: Rats; Animals; Hydrogen Sulfide; Glutamic Acid; Long-Term Potentiation; Serine; Cytoskeletal Proteins; gamma-Aminobutyric Acid; Receptors, N-Methyl-D-Aspartate; Hippocampus
PubMed: 37907526
DOI: 10.1038/s41598-023-44877-y -
The Japanese Dental Science Review Dec 2023Approximately 10 % of the general population is affected by temporomandibular disorder (TMD) pain. Diagnosis of myogenous TMD pain (i.e., TM myalgia) may be challenging,... (Review)
Review
Approximately 10 % of the general population is affected by temporomandibular disorder (TMD) pain. Diagnosis of myogenous TMD pain (i.e., TM myalgia) may be challenging, while an adequate assessment of this pain is crucial to establish an adequate management strategy. We aim to analyze if there is a relation between inflammation and TM myalgia, and if we can identify and measure inflammatory markers in patients suffering from this condition. An electronic literature search was conducted from inception up to July 14 2022 through the databases PubMed, Cochrane Library, Web of Science, and Embase in collaboration with a medical information specialist. Studies on patients with masticatory muscle inflammation and/or pain were included. After a screening procedure, only nine full-text articles met the criteria for inclusion. In the included studies 9-131 patients showed TM myalgia, and presence of inflammation was reported with analysis of interleukines IL-1, IL-6, IL-10, tumor necrosis factor alpha, and prostaglandins from blood, saliva, and extracellular fluid of masseter muscle using microdialysis. Our results contributed to the identification of the relation between inflammation and TM myalgia and established that measurement of inflammatory cytokines may be a valid diagnostic tool, which is an essential step towards finding a better treatment.
PubMed: 37680612
DOI: 10.1016/j.jdsr.2023.08.006 -
European Surgical Research. Europaische... Dec 2023The perpetual organ shortage crisis worldwide has meant a paradigm shift in global thinking with subsequent expansion of the accepted criteria for an organ donor to meet... (Review)
Review
The perpetual organ shortage crisis worldwide has meant a paradigm shift in global thinking with subsequent expansion of the accepted criteria for an organ donor to meet the demand. Robust pre-transplant organ viability assessment is the next great challenge in the field of transplantation today. Organ preservation in the nature of static cold storage has reached its limits, and machine perfusion both cold and warm offers theoretically superior preservation and the potential to assess organs. Microdialysis is a novel technique with proven ability to allow remote assessment of tissue biochemistry and metabolism. It has been used in various pre-clinical and clinical models of abdominal organ preservation and transplantation. This review focuses on the use of microdialysis in the assessment of the kidney, liver, and pancreas, and where this novel technology is heading in the context of the assessing organ viability prior to and after transplantation.
PubMed: 38081157
DOI: 10.1159/000535744 -
The Journal of Clinical Endocrinology... Nov 2023Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the...
BACKGROUND
Patients with adrenal insufficiency (AI) require life-long glucocorticoid (GC) replacement therapy. Within tissues, cortisol (F) availability is under the control of the isozymes of 11β-hydroxysteroid dehydrogenase (11β-HSD). We hypothesize that corticosteroid metabolism is altered in patients with AI because of the nonphysiological pattern of current immediate release hydrocortisone (IR-HC) replacement therapy. The use of a once-daily dual-release hydrocortisone (DR-HC) preparation, (Plenadren®), offers a more physiological cortisol profile and may alter corticosteroid metabolism in vivo.
STUDY DESIGN AND METHODS
Prospective crossover study assessing the impact of 12 weeks of DR-HC on systemic GC metabolism (urinary steroid metabolome profiling), cortisol activation in the liver (cortisone acetate challenge test), and subcutaneous adipose tissue (microdialysis, biopsy for gene expression analysis) in 51 patients with AI (primary and secondary) in comparison to IR-HC treatment and age- and BMI-matched controls.
RESULTS
Patients with AI receiving IR-HC had a higher median 24-hour urinary excretion of cortisol compared with healthy controls (72.1 µg/24 hours [IQR 43.6-124.2] vs 51.9 µg/24 hours [35.5-72.3], P = .02), with lower global activity of 11β-HSD2 and higher 5-alpha reductase activity. Following the switch from IR-HC to DR-HC therapy, there was a significant reduction in urinary cortisol and total GC metabolite excretion, which was most significant in the evening. There was an increase in 11β-HSD2 activity. Hepatic 11β-HSD1 activity was not significantly altered after switching to DR-HC, but there was a significant reduction in the expression and activity of 11β-HSD1 in subcutaneous adipose tissue.
CONCLUSION
Using comprehensive in vivo techniques, we have demonstrated abnormalities in corticosteroid metabolism in patients with primary and secondary AI receiving IR-HC. This dysregulation of pre-receptor glucocorticoid metabolism results in enhanced glucocorticoid activation in adipose tissue, which was ameliorated by treatment with DR-HC.
Topics: Humans; Glucocorticoids; Hydrocortisone; Prospective Studies; 11-beta-Hydroxysteroid Dehydrogenase Type 1; 11-beta-Hydroxysteroid Dehydrogenase Type 2; Cross-Over Studies; Adrenal Cortex Hormones; Adrenal Insufficiency
PubMed: 37339332
DOI: 10.1210/clinem/dgad370