Browsing by Subject "Lactate"

Now showing 1 - 4 of 4
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    Etiology, triggers and neurochemical circuits associated with unexpected, expected, and laboratory-induced panic attacks
    (Elsevier, 2014-10) Johnson, Philip L.; Federici, Lauren M.; Shekhar, Anantha; Department of Psychiatry, IU School of Medicine
    Panic disorder (PD) is a severe anxiety disorder that is characterized by recurrent panic attacks (PA), which can be unexpected (uPA, i.e., no clear identifiable trigger) or expected (ePA). Panic typically involves an abrupt feeling of catastrophic fear or distress accompanied by physiological symptoms such as palpitations, racing heart, thermal sensations, and sweating. Recurrent uPA and ePA can also lead to agoraphobia, where subjects with PD avoid situations that were associated with PA. Here we will review recent developments in our understanding of PD, which includes discussions on: symptoms and signs associated with uPA and ePAs; Diagnosis of PD and the new DSM-V; biological etiology such as heritability and gene×environment and gene×hormonal development interactions; comparisons between laboratory and naturally occurring uPAs and ePAs; neurochemical systems that are associated with clinical PAs (e.g. gene associations; targets for triggering or treating PAs), adaptive fear and panic response concepts in the context of new NIH RDoc approach; and finally strengths and weaknesses of translational animal models of adaptive and pathological panic states.
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    Lactate secreted via MCT4 from bone‑colonizing breast cancer excites sensory neurons via GPR81
    (Spandidos Publications, 2023) Okui, Tatsuo; Hiasa, Masahiro; Hasegawa, Kazuaki; Nakamura, Tomoya; Ono, Kisho; Ibaragi, Soichiro; Kanno, Takahiro; Sasaki, Akira; Yoneda, Toshiyuki; Medicine, School of Medicine
    Breast cancer (BC) bone metastasis causes bone pain (BP), which detrimentally damages the quality of life and outcome of patients with BC. However, the mechanism of BC-BP is poorly understood, and effective treatments are limited. The present study demonstrated a novel mechanism of BC-BP using a mouse model of bone pain, in which mouse (EO771) and human (MDA-MB-231) BC cells were injected in the bone marrow cavity of tibiae. Western blot analysis using sensory nerves, in vivo assessment of cancer pain and in vitro calcium flux analysis were performed. These mice developed progressive BC-BP in tibiae in conjunction with an upregulation of phosphorylated pERK1/2 and cAMP-response element-binding protein (pCREB), which are molecular indicators of neuron excitation, in the dorsal root ganglia (DRG) of sensory nerves. Importantly, mice injected with BC cells, in which the expression of the lactic acid transporter monocarboxylate transporter 4 (MCT4) was silenced, exhibited decreased BC-BP with downregulated expression of pERK1/2 and pCREB in the DRG and reduced circulating levels of lactate compared with mice injected with parental BC cells. Further, silencing of the cell-surface orphan receptor for lactate, G protein-coupled receptor 81 (GPR81), in the F11 sensory neuron cells decreased lactate-promoted upregulation of pERK1/2 and Ca2+ influx, suggesting that the sensory neuron excitation was inhibited. These results suggested that lactate released from BC cells via MCT4 induced BC-BP through the activation of GPR81 of sensory neurons. In conclusion, the activation of GPR81 of sensory neurons by lactate released via MCT4 from BC was demonstrated to contribute to the induction of BC-BP, and disruption of the interactions among lactate, MCT4 and GPR81 may be a novel approach to control BC-BP.
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    Panic-prone state induced in rats with GABA dysfunction in the dorsomedial hypothalamus is mediated by NMDA receptors
    (Society for Neuroscience, 2006-06-28) Johnson, Philip L.; Shekhar, Anantha; Psychiatry, School of Medicine
    Rats with chronic inhibition of GABA synthesis and consequently enhanced glutamatergic excitation in the dorsomedial hypothalamus (DMH) develop panic-like responses, defined as tachycardia, tachypnea, hypertension, and increased anxiety as measured by a social interaction (SI) test, after intravenous sodium lactate infusions, a phenomenon similar to patients with panic disorder. Therefore, the present studies tested the role of the postsynaptic NMDA and AMPA type glutamatergic receptors in the lactate-induced panic-like responses in these rats. Rats were fit with femoral arterial and venous catheters and Alzet pumps [filled with the GABA synthesis inhibitor L-allylglycine (L-AG; 3.5 nmol/0.5 microl per hour) or its inactive isomer D-AG] into the DMH. After 4-5 d of recovery only those rats with L-AG pumps exhibited panic-like responses to lactate infusions. Using double immunocytochemistry, we found that rats exhibiting panic-like responses (e.g., L-AG plus lactate) had increased c-Fos immunoreactivity in DMH neurons expressing the NMDA receptor 1 (NR1) subunit, but not those expressing the glutamate receptor 2 and 3 subunits of the AMPA receptors. To confirm this pharmacologically, we tested another group of rats implanted with l-AG pumps with intravenous lactate infusions preceded by injections of either NMDA [aminophosphonopentanoic acid (AP-5) or (+)-5-methyl-10,11-dihydro-5H-dibenzo [a,d]cyclohepten-5,10-imine maleate (MK-801)] or non-NMDA [CNQX or 4-(8-methyl-9H-1,3-dioxolo[4,5-h][2,3]benzodazepin-5-yl)-benzenamine dihydrochloride (GYKI52466)] antagonists into the DMH. Injections of NMDA, but not non-NMDA, antagonists into the DMH resulted in dose-dependent blockade of the tachycardia, tachypnea, hypertension, and SI responses after lactate infusions. These results suggest that NMDA, and not non-NMDA, type glutamate receptors regulate lactate-induced panic-like responses in rats with GABA dysfunction in the DMH.
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    Pediatric Malaria with Respiratory Distress: Prognostic Significance of Point-of-Care Lactate
    (MDPI, 2023-04-02) Mitran, Catherine; Opoka, Robert O.; Conroy, Andrea L.; Namasopo, Sophie; Kain, Kevin C.; Hawkes, Michael T.; Pediatrics, School of Medicine
    Respiratory distress (RD) in pediatric malaria portends a grave prognosis. Lactic acidosis is a biomarker of severe disease. We investigated whether lactate, measured at admission using a handheld device among children hospitalized with malaria and RD, was predictive of subsequent mortality. We performed a pooled analysis of Ugandan children under five years of age hospitalized with malaria and RD from three past studies. In total, 1324 children with malaria and RD (median age 1.4 years, 46% female) from 21 health facilities were included. Median lactate level at admission was 4.6 mmol/L (IQR 2.6-8.5) and 586 patients (44%) had hyperlactatemia (lactate > 5 mmol/L). The mortality was 84/1324 (6.3%). In a mixed-effects Cox proportional hazard model adjusting for age, sex, clinical severity score (fixed effects), study, and site (random effects), hyperlactatemia was associated with a 3-fold increased hazard of death (aHR 3.0, 95%CI 1.8-5.3, p < 0.0001). Delayed capillary refill time (τ = 0.14, p < 0.0001), hypotension (τ = -0.10, p = 0.00049), anemia (τ = -0.25, p < 0.0001), low tissue oxygen delivery (τ = -0.19, p < 0.0001), high parasite density (τ = 0.10, p < 0.0001), and acute kidney injury (p = 0.00047) were associated with higher lactate levels. In children with malaria and RD, bedside lactate may be a useful triage tool, predictive of mortality.