Trigeminovascular dysfunctions in the relationship between obesity and migraine: the role of meningeal chemosensitive nociceptors

Az elhízás növelheti a migrén kialakulásának kockázatát, valamint a fejfájásos rohamok gyakoriságát és súlyosságát. Munkánk során arra kerestük a választ, hogy az elhízás hatással lehet-e azokra a trigeminovaszkuláris rendszer aktivációjával összefüggő perifériás eseményekre, melyeknek szerepet tulajdonítanak a migrénes fejfájás patogenezisében. Vizsgálatainkat magas zsír és magas szacharóz tartalmú étrend következtében elhízott patkányokon végeztük. Igazoltuk elhízott állatokban a testsúly, a zsírszövet mennyiségének és a máj tömegének növekedése mellett a glükóz és inzulin homeosztázis károsodását, valamint a szisztémás gyulladásos állapot kialakulását. Eredményeink igazolták, hogy étrend-indukált elhízás hatására jelentősen fokozódik a kapszaicin és az akrolein által kiváltott szenzoros neurogén vazodilatáció mértéke, mely a meningeális kemoszenzitív afferensek tranziens receptor potenciál vanilloid 1 (TRPV1)- és tranziens receptor potenciál ankyrin 1 (TRPA1) receptorainak aktivációját követő nagyobb mértékű calcitonin gén-rokon peptid (CGRP) felszabadulásra vezethető vissza. Megállapítottuk továbbá, hogy az elhízás együtt jár a nyugalmi CGRP felszabadulás növekedésével és a magas extracelluláris kálium-klorid koncentráció által kiváltható CGRP felszabadulás csökkenésével. Eltekintve a CGRP-immunreaktivitás idegroston belüli megoszlásában megfigyelhető különbségtől, nem találtunk változást a dura mater TRPV1- és CGRP-immunreaktív idegrostjainak elhelyezkedésében és megoszlásában. A TRPA1 fehérje trigeminális ganglionban történő expressziója azonban enyhe, ugyanakkor szignifikáns csökkenést mutatott. A kapszaicin vazokonstriktor hatásának elhízott állatokban bekövetkező fokozódása felhívhatja a figyelmet az arteria meningea media érszűkítő folyamatainak elhízással összefüggő rendellenességeire. Eredményeink elhízott állatokban a CGRP tartalmú meningeális nociceptorok szenzitizációjára utalnak, a TRPV1- és a TRPA1-mediált trigeminovaszkuláris reakciók fokozódása ezen ioncsatornaként működő receptorok aktiválhatóságának megváltozásával állhat összefüggésben. Munkánk hozzájárulhat a fejfájásos fájdalom súlyosságának és a migrénes rohamokat provokáló tényezők iránti érzékenység elhízott egyénekben megfigyelhető növekedéséért felelős patofiziológiai folyamatok megértéséhez.Obesity may increase the risk for having migraine and appears to enhance the frequency and severity of headache attacks. Our study was aimed to investigate the effects of obesity on peripheral events related to the activation of trigeminovascular nociceptive system. Our experiments were performed in a rat model of high-fat and high-sucrose diet-induced obesity. Dietary treatment resulted in increased body weight, fat tissue and liver mass along with impaired glucose and insulin homeostasis in addition to exacerbated systemic proinflammatory milieu. The present study revealed that diet-induced obesity potentiates capsaicin- and acrolein-evoked neurogenic sensory vasodilatation in the meninges due to augmented release of calcitonin gene-related peptide (CGRP) from chemosensitive afferents upon the activation of transient receptor potential vanilloid 1 (TRPV1) and transient receptor potential ankyrin 1 (TRPA1) receptors. Obesity was also associated with an enhanced basal CGRP release and an attenuated response to potassium chloride in the dura mater. Except for minor morphological changes, the distribution of dural TRPV1- and CGRP-immunoreactive afferents was similar in control and obese animals. We measured a significant reduction in the expression of TRPA1 protein in the trigeminal ganglia of obese rats. The marked enhancement in capsaicin-induced vasoconstriction may suggest obesity-related changes in the vasoconstrictor properties of the middle meningeal artery. Our results indicate that diet-induced obesity leads to sensitization of CGRP-containing meningeal afferents. The potentiation in TRPV1- and TRPA1-mediated trigeminovascular responses are likely the result of altered gating properties of these ion channels. The present findings may provide insight into pathophysiological events responsible for migraine progression and the increased susceptibility to headache triggers in obese individuals

Diet-Induced Obesity Enhances TRPV1-Mediated Neurovascular Reactions in the Dura Mater

OBJECTIVE: Exploring the pathophysiological changes in transient receptor potential vanilloid 1 (TRPV1) receptor of the trigeminovascular system in high-fat, high-sucrose (HFHS) diet-induced obesity of experimental animals. BACKGROUND: Clinical and experimental observations suggest a link between obesity and migraine. Accumulating evidence indicates that metabolic and immunological alterations associated with obesity may potentially modulate trigeminovascular functions. A possible target for obesity-induced pathophysiological changes is the TRPV1/capsaicin receptor which is implicated in the pathomechanism of headaches in a complex way. METHODS: Male Sprague-Dawley rats were fed a regular (n = 25) or HFHS diet (n = 26) for 20 weeks. At the end of the dietary period, body weight of the animals was normally distributed in both groups and it was significantly higher in animals on HFHS diet. Therefore, experimental groups were regarded as control and HFHS diet-induced obese groups. Capsaicin-induced changes in meningeal blood flow and release of calcitonin gene-related peptide (CGRP) from dural trigeminal afferents were measured in control and obese rats. The distribution of TRPV1- and CGRP-immunoreactive meningeal sensory nerves was also compared in whole mount preparations of the dura mater. Metabolic parameters of the animals were assessed by examining glucose and insulin homeostasis as well as plasma cytokine concentrations. RESULTS: HFHS diet was accompanied by reduced food consumption and greater fluid and energy intakes in addition to increased body weight of the animals. HFHS diet increased fasting blood glucose and insulin concentrations as well as levels of circulating proinflammatory cytokines interleukin-1beta and interleukin-6. In obese animals, dural application of the archetypal TRPV1 agonist capsaicin resulted in significantly augmented vasodilatory and vasoconstrictor responses as compared to controls. Diet-induced obesity was also associated with enhanced basal and capsaicin-induced CGRP release from meningeal afferents ex vivo. Except for minor morphological changes, the distribution of dural TRPV1- and CGRP-immunoreactive afferents was similar in control and obese animals. CONCLUSIONS: Our results suggest that obesity induced by long-term HFHS diet results in sensitization of the trigeminovascular system. Changes in TRPV1-mediated vascular reactions and CGRP release are pathophysiological alterations that may be of relevance to the enhanced headache susceptibility of obese individuals

Insulin sensitivity is modified by a glycogen phosphorylase inhibitor: glucopyranosylidene-spiro-thiohydantoin in streptozotocin-induced diabetic rats

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Modelling intestinal glucose absorption in premature infants using continuous glucose monitoring data

Model-based glycaemic control protocols have shown promise in neonatal intensive care units (NICUs) for reducing both hyperglycaemia and insulin-therapy driven hypoglycaemia. However, current models for the appearance of glucose from enteral feeding are based on values from adult intensive care cohorts. This study aims to determine enteral glucose appearance model parameters more reflective of premature infant physiology.Peaks in CGM data associated with enteral milk feeds in preterm and term infants are used to fit a two compartment gut model. The first compartment describes glucose in the stomach, and the half life of gastric emptying is estimated as 20 min from literature. The second compartment describes glucose in the small intestine, and absorption of glucose into the blood is fit to CGM data. Two infant cohorts from two NICUs are used, and results are compared to appearances derived from data in highly controlled studies in literature.The average half life across all infants for glucose absorption from the gut to the blood was 50 min. This result was slightly slower than, but of similar magnitude to, results derived from literature. No trends were found with gestational or postnatal age. Breast milk fed infants were found to have a higher absorption constant than formula fed infants, a result which may reflect known differences in gastric emptying for different feed types.This paper presents a methodology for estimation of glucose appearance due to enteral feeding, and model parameters suitable for a NICU model-based glycaemic control context