The Journal of physiology
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The Journal of physiology · Jun 2016
Increasing taurine intake and taurine synthesis improves skeletal muscle function in the mdx mouse model for Duchenne muscular dystrophy.
Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease associated with increased inflammation, oxidative stress and myofibre necrosis. Cysteine precursor antioxidants such as N-acetyl cysteine (NAC) and l-2-oxothiazolidine-4-carboxylate (OTC) reduce dystropathology in the mdx mouse model for DMD, and we propose this is via increased synthesis of the amino acid taurine. We compared the capacity of OTC and taurine treatment to increase taurine content of mdx muscle, as well as effects on in vivo and ex vivo muscle function, inflammation and oxidative stress. Both treatments increased taurine in muscles, and improved many aspects of muscle function and reduced inflammation. Taurine treatment also reduced protein thiol oxidation and was overall more effective, as OTC treatment reduced body and muscle weight, suggesting some adverse effects of this drug. These data suggest that increasing dietary taurine is a better candidate for a therapeutic intervention for DMD. ⋯ Duchenne muscular dystrophy (DMD) is a fatal muscle wasting disease for which there is no widely available cure. Whilst the mechanism of loss of muscle function in DMD and the mdx mouse model are not fully understood, disruptions in intracellular calcium homeostasis, inflammation and oxidative stress are implicated. We have shown that protein thiol oxidation is increased in mdx muscle, and that the indirect thiol antioxidant l-2-oxothiazolidine-4-carboxylate (OTC), which increases cysteine availability, decreases pathology and increases in vivo strength. We propose that the protective effects of OTC are a consequence of conversion of cysteine to taurine, which has itself been shown to be beneficial to mdx pathology. This study compares the efficacy of taurine with OTC in decreasing dystropathology in mdx mice by measuring in vivo and ex vivo contractile function and measurements of inflammation and protein thiol oxidation. Increasing the taurine content of mdx muscle improved both in vivo and ex vivo muscle strength and function, potentially via anti-inflammatory and antioxidant effects of taurine. OTC treatment increased taurine synthesis in the liver and taurine content of mdx muscle, improved muscle function and decreased inflammation. However, OTC was less effective than taurine treatment, with OTC also decreasing body and EDL muscle weights, suggesting that OTC had some detrimental effects. These data support continued research into the use of taurine as a therapeutic intervention for DMD, and suggest that increasing dietary taurine is the better strategy for increasing taurine content and decreasing severity of dystropathology.
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The Journal of physiology · May 2016
Developmental trajectories of cerebrovascular reactivity in healthy children and young adults assessed with magnetic resonance imaging.
Cerebrovascular reactivity (CVR) reflects the vasodilatory reserve of cerebral resistance vessels. Normal development in children is associated with significant changes in blood pressure, cerebral blood flow (CBF) and cerebral oxygen metabolism. Therefore, it stands to reason that CVR will also undergo changes during this period. The study acquired magnetic resonance imaging measures of CVR and CBF in healthy children and young adults to trace their changes with age. We found that CVR changes in two phases, increasing with age until the mid-teens, followed by a decrease. Baseline CBF declined steadily with age. We conclude that CVR varies with age during childhood, which prompts future CVR studies involving children to take into account the effect of development. ⋯ Cerebrovascular reactivity (CVR) reflects the vasculature's ability to accommodate changes in blood flow demand thereby serving as a critical imaging tool for mapping vascular reserve. Normal development is associated with extensive physiological changes in blood pressure, cerebral blood flow and cerebral metabolic rate of oxygen, all of which can affect CVR. Moreover, the evolution of these physiological parameters is most prominent during childhood. Therefore, the aim of this study was to use non-invasive magnetic resonance imaging (MRI) to characterize the developmental trajectories of CVR in healthy children and young adults, and relate them to changes in cerebral blood flow (CBF). Thirty-four healthy subjects (17 males, 17 females; age 9-30 years) underwent CVR assessment using blood oxygen level-dependent MRI in combination with a computer controlled CO2 stimulus. In addition, baseline CBF was measured with a pulsed arterial spin labelling sequence. CVR exhibited a gradual increase with age in both grey and white matter up to 14.7 years. After this break point, a negative correlation with age was detected. Baseline CBF maintained a consistent negative linear correlation across the entire age range. The significant age-dependent changes in CVR and CBF demonstrate the evolution of cerebral haemodynamics in children and should be taken into consideration. The shift in developmental trajectory of CVR from increasing to decreasing suggests that physiological factors beyond baseline CBF also influence CVR.
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The Journal of physiology · Apr 2016
Pre-emptive analgesia and its supraspinal mechanisms: enhanced descending inhibition and decreased descending facilitation by dexmedetomidine.
Despite the clinical importance of pre-emptive analgesia, the mechanisms by which it attenuates pain associated with central sensitization are poorly understood. We find that fentanyl and the α2-adrenoceptor agonist dexmedetomidine (Dex) differ significantly in their modulatory actions on noxious mechanical and noxious heat-evoked nociception in vivo. Unlike fentanyl, Dex modified descending control of nociception by decreasing the threshold for descending inhibition and/or increasing the threshold for descending facilitation. Dex exhibited after-actions on activities of thalamus in prolongation of noxious heat-evoked paw withdrawal latency that persisted for at least 7 days. This study provides insight into the organization of thalamic modulation in pre-emptive analgesia. ⋯ We investigated and compared the antinociceptive effects of intraperitoneal administration of fentanyl (2-60 μg kg(-1)) and dexmedetomidine (Dex, 1-10 μg kg(-1); a highly selective α2-adrenoceptor agonist) in the regulation of nociception assessed by measuring noxious paw withdrawal reflexes in rats. Fentanyl elevated noxious mechanical paw withdrawal threshold and prolonged paw withdrawal heat latency within 1-1.5 h (P < 0.05). Dex failed to affect the mechanical paw withdrawal threshold, yet significantly prolonged the paw withdrawal heat latency in a bi-phasic manner; a short transient 1-1.5 h period followed by a second, slowly developing increase in latency that persisted for at least 7 days (P < 0.05). Lesion of the dorsolateral funiculus (DLF) did not influence fentanyl-induced antinociceptive effects, indicating peripheral and spinal antinociceptive mechanisms. By contrast, the Dex-induced second, but not the first, phase of the prolonged paw withdrawal heat latency was significantly blocked by the lesion of either DLF or thalamic ventromedial (VM) nuclei, and was attenuated by intracerebral administration of either atipamezole (α2-adrenoceptor antagonist) or WAY-100635 (5-HT1A receptor antagonist) into the VM nuclei (P < 0.05). Upon intramuscular 5.8% saline-induced muscle nociception, pre-emptive injection of fentanyl enhanced mechanical hyperalgesia and blocked heat hypoalgesia, whereas Dex significantly prevented the occurrence of mechanical hyperalgesia and enhanced heat hypoalgesia. It is suggested that Dex, but not fentanyl, significantly enhances descending inhibition and/or decreases descending facilitation to modulate pain and nociception. The present study provides novel insight into thalamus-mediated mechanisms in pre-emptive analgesia.
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The Journal of physiology · Mar 2016
Dopamine modulation of transient receptor potential vanilloid type 1 (TRPV1) receptor in dorsal root ganglia neurons.
The transient receptor potential vanilloid type 1 (TRPV1) receptor plays a key role in the modulation of nociceptor excitability. To address whether dopamine can modulate the activity of TRPV1 channels in nociceptive neurons, the effects of dopamine and dopamine receptor agonists were tested on the capsaicin-activated current recorded from acutely dissociated small diameter (<27 μm) dorsal root ganglia (DRG) neurons. Dopamine or SKF 81297 (an agonist at D1/D5 receptors), caused inhibition of both inward and outward currents by ∼60% and ∼48%, respectively. ⋯ The inhibitory effect of SKF 81297 on the capsaicin-activated current was not affected when the protein kinase A (PKA) activity was blocked with H89, or when the protein kinase C (PKC) activity was blocked with bisindolylmaleimide II (BIM). In contrast, when the calcium-calmodulin-dependent protein kinase II (CaMKII) was blocked with KN-93, the inhibitory effect of SKF 81297 on the capsaicin-activated current was greatly reduced, suggesting that activation of D1/D5 dopamine receptors may be preferentially linked to CaMKII activity. We suggest that modulation of TRPV1 channels by dopamine in nociceptive neurons may represent a way for dopamine to modulate incoming noxious stimuli.