Browsing by Subject "hyperthermia"

Now showing 1 - 4 of 4
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    Core Body Temperature Regulation and Locomotor Activity
    (Office of the Vice Chancellor for Research, 2014-04-11) Yoo, Yeonjoo; Kelley, Maire; Zaretsky, Dmitry; Molkov, Yaroslav
    Methamphetamine (Meth) enhances locomotor activity, and is known to cause life-threatening hyperthermia. There has been much debate about whether the locomotion plays a major role in hyperthermia caused by Meth or other stimulants. The existing model of the neural circuitry putatively involved in this phenomenon [1] accurately reproduces the temperature response to the different doses of Meth. We compared locomotor activity observed in the same experiments with activation patterns of neuronal populations as predicted by the model. We found that time-courses of locomotor activity closely resembles the activity of one particular node in the model putatively representing the medullary level. However, the data on locomotion did not match the model in the initial phase of the response within 1 hour after the injection. Therefore, we hypothesized that there were some changes in thermogenesis and heat exchange mechanisms that largely control temperature response during the first hour and make the influence of locomotion relatively small. The objective of the study was to measure the temperature dynamics in rats running on a treadmill at different speeds and to construct a mathematical model explaining the mechanism of their core body temperature response to such an intervention that takes into account potential changes in heat exchange, sensory input and feedback control mechanisms. In the experiments for every speed of 0, 6, 12, and 18 m/min we had 4 rats running for 15 min. For each speed we averaged the temperature over 4 rats to get the average temperature response curve. First, we found that the temperature response curves for different treadmill speeds were not different statistically. Second, every response curve starts with a short but profound (~0.25 deg C in the first 5 min) drop in the body temperature followed by virtually linear rise of the temperature which significantly (by ~1 deg C) overshoots the baseline temperature. To explain these findings we set up a model in a form of a system of two differential equations that described the change in the body temperature and the change in the body heat production under the hypothesis that there are contributions of varying heat exchange, sensory input and feedback mechanisms in thermogenesis. All parameters in the system were subject to fitting experimental time series of temperature response of rats to 4 consistent speeds of 0, 6, 12, and 18 m/min on treadmills. We found, that a sudden drop of the body temperature below the baseline in the first five minutes after rats were removed from their cages and placed on a treadmill was a result of the increased heat dissipation caused by changes in the body position and movement of rats. The following fast recovery of the body temperatures to the normal level was provided by the feedback mechanisms activated by the temperature drop and changed sensory input. Meth continues to stimulate thermogenesis even after the baseline temperature is achieved from feedback mechanisms. Estimated contribution of the locomotion was negligible as compared to the latter and hence played a relatively small role in the temperature change. We predict that varying locomotion might manifest itself in temperature dynamics after much longer (~1 hour) exposure to running. The suggested system, which considers major factors defining body temperature response, can help to uncover the mechanisms of hyperthermia elicited by Meth, but also can be used to understand the thermoregulatory mechanisms which underlie the responses to simultaneous changes in environmental and physical conditions.
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    Meth math: modeling temperature responses to methamphetamine
    (American Physiological Society (APS), 2014-04-15) Molkov, Yaroslav I.; Zaretskaia, Maria V.; Zaretsky, Dmitry V.; Department of Emergency Medicine, IU School of Medicine
    Methamphetamine (Meth) can evoke extreme hyperthermia, which correlates with neurotoxicity and death in laboratory animals and humans. The objective of this study was to uncover the mechanisms of a complex dose dependence of temperature responses to Meth by mathematical modeling of the neuronal circuitry. On the basis of previous studies, we composed an artificial neural network with the core comprising three sequentially connected nodes: excitatory, medullary, and sympathetic preganglionic neuronal (SPN). Meth directly stimulated the excitatory node, an inhibitory drive targeted the medullary node, and, in high doses, an additional excitatory drive affected the SPN node. All model parameters (weights of connections, sensitivities, and time constants) were subject to fitting experimental time series of temperature responses to 1, 3, 5, and 10 mg/kg Meth. Modeling suggested that the temperature response to the lowest dose of Meth, which caused an immediate and short hyperthermia, involves neuronal excitation at a supramedullary level. The delay in response after the intermediate doses of Meth is a result of neuronal inhibition at the medullary level. Finally, the rapid and robust increase in body temperature induced by the highest dose of Meth involves activation of high-dose excitatory drive. The impairment in the inhibitory mechanism can provoke a life-threatening temperature rise and makes it a plausible cause of fatal hyperthermia in Meth users. We expect that studying putative neuronal sites of Meth action and the neuromediators involved in a detailed model of this system may lead to more effective strategies for prevention and treatment of hyperthermia induced by amphetamine-like stimulants.
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    Orexinergic Neurotransmission in Temperature Responses to Amphetamines
    (Office of the Vice Chancellor for Research, 2014-04-11) Behrouzvaziri, Abolhassan; Fu, Daniel; Tan, Patrick; Zaretskaia, Maria; Rusyniak, Daniel; Zaretsky, Dmitry; Molkov, Yaroslav
    Derivatives of amphetamines are widely abused all over the world. After long-term use cognitive, neurophysiological, and neuroanatomical deficits have been reported. Neurophysiological deficits are enhanced by hyperthermia, which itself is major mortality factor in drug abusers. Temperature responses to injections of methamphetamine are multiphasic and include both hypothermic and hyperthermic phases, which are highly dependent on ambient temperature and previous exposure to the drug. Also, amphetamine derivatives differentially affect various neuromediator systems, such as dopaminergic, noradrenergic and serotonergic. Temperature responses to methamphetamine (Meth) at room temperature have non-trivial dose-dependence, which is far from being understood. Intermediate doses of Meth cause less hyperthermia than both low and high doses of the drug. Also, maxima of all responses have different latency responses to low and high doses are virtually immediate, while a response to an intermediate dose appears to be delayed. In our previous modeling study we demonstrated that such dose-dependence could be explained by interaction of inhibitory and excitatory drives induced by Meth [1]. Recently, we have published data on the involvement of orexinergic neurotransmission in Meth-induced temperature responses [2] where the low dose (10 mg/kg, i.p.) of SB-334867 (SB), an antagonist of the first type of orexin receptors (ORX1), was injected 30 min prior to various doses of Meth. While this dose of antagonist clearly suppressed the response to low (1 mg/kg) and intermediate (5 mg/kg) doses of Meth, the effect was statistically significant only at the late phase (t > 60 min) of the response to intermediate dose. At the early phase (t < 60 min) any drug-related changes were marred by stress-induced temperature fluctuations resulting from two intraperitoneal injections. In a separate set of experiments a high dose of the same antagonist (30 mg/kg, i.p.) suppressed the effect of low doses of Meth even more, but in contrast, it significantly amplified the responses to the higher doses (5 and 10 mg/kg) of Meth. Understanding the mechanism that differentially affect excitatory and inhibitory components of temperature responses can have profound importance for explaining cases of life-threatening hyperthermia after Meth administration. Therefore, we performed a mathematical modeling study to provide mechanistic interpretation of SB action. Our previous model [1] was created to describe Meth-sensitive compartments and dynamics of the neural populations defining temperature responses for various doses of Meth. We hypothesized that a specific distribution of orexin receptors over the structures involved in the neural control of temperature is responsible for the complex dependence of the Meth-induced responses on the dose of orexin antagonist. To test this hypothesis we extended the model by incorporating ORX receptors that mediated Meth- and stress-dependent inputs. We showed that the low dose of antagonist almost fully suppresses the responses to both stress and intermediate doses of Meth by disruption of the corresponding inputs to the control structures. This allows hypothesizing that the excitatory component in temperature response to both stress and low dose of Meth is mediated by ORX1 receptors. Amplification of the response to the high dose of Meth at high dose of the antagonist points out to the involvement of a mechanism different from ORX1 receptor blockade. We speculate that at high doses SB becomes non-specific to ORX1 receptors and starts affecting ORX2 receptors. Further, ORX2 activation disinhibits the structure activated by high doses of Meth, which underlies the exaggerated responses to high doses of Meth at the presence of a high dose of SB. We conclude that both excitatory and inhibitory components in temperature responses to Meth administration and stress are mediated by orexinergic pathways. Non-specificity of SB at high doses to ORX1 receptors manifests itself in additional suppression of inhibition resulting in facilitation of the responses to high-doses of Meth.
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    Role of Ape1 and Base Excision Repair in the Radiation Response and Heat-radiosensitization of HeLa Cells
    (2009-04) Batuello, Christopher N.; Kelley, Mark R.; Dynlacht, Joseph R.
    Background: The mechanism by which heat sensitizes mammalian cells to ionizing radiation remains to be elucidated. We determined whether base excision repair (BER) is involved in heat-radiosensitization and report novel findings that provide insight regarding the role of BER in the radiation response of HeLa cells. Materials and Methods: An siRNA approach was utilized to suppress expression of AP endonuclease (Ape1), a critical enzyme of BER. Clonogenic survival curves were obtained for HeLa cells expressing normal or reduced Ape1 content and which had been irradiated, and these were compared to survival curves from cells that were irradiated prior to hyperthermia treatment. Results: The amount of heat-radiosensitization observed in Ape1-suppressed cells was similar to or slightly greater than that observed in cells expressing near-normal levels of Ape1. Interestingly, we also found that for unheated HeLa cells, suppressed expression of Ape1 resulted in enhanced resistance to X-rays. Conclusion: The data suggest that Ape1, and therefore BER, is not involved in heat-radiosensitization. However, the observation that suppressed expression of Ape1 results in enhanced radioresistance supports the notion that BER may be detrimental to the survival of irradiated cells.