Ching Hsia Hung

Exercise Training Attenuates Neuropathic Pain and Cytokine Expression After Chronic Constriction Injury of Rat Sciatic Nerve

BACKGROUND: The underlying mechanism of exercise on neuropathic pain is not well understood. We investigated whether physical exercise regulates the functional recovery and heat shock protein 72 (Hsp72), tumor necrosis factor-&agr; (TNF-&agr;), and interlukin-1&bgr; (IL-1&bgr;) expression after chronic constriction injury (CCI) of the sciatic nerve. METHODS: Male Sprague–Dawley rats were divided into 7 groups: control, sham operated (SO), SO with swimming or treadmill exercise (SOSE or SOTE), CCI, CCI with swimming or treadmill exercise (CCISE or CCITE). We recorded body weight, thermal withdrawal latency, and mechanical withdrawal threshold as well as Hsp72, TNF-&agr;, and IL-1&bgr; expression in sciatic nerve. RESULTS: The body weights in the control and SO groups were heavier than those in the SOSE, SOTE, CCI, CCISE, and CCITE groups. CCI rats with swimming or treadmill exercise showed significant increase in thermal withdrawal latency and mechanical withdrawal threshold when compared with CCI rats without exercise on day 21 after CCI. Both CCISE and CCITE groups demonstrated greater Hsp72 expression and lower TNF-&agr; or IL-1&bgr; level than did the CCI group in sciatic nerve on day 21 after CCI. CONCLUSIONS: These results suggest that progressive exercise training decreases peripheral neuropathic pain as well as TNF-&agr; and IL-1&bgr; overproduction and increases HSP72 expression after CCI of the sciatic nerve.

Progressive exercise preconditioning protects against circulatory shock during experimental heatstroke

Heat shock protein (HSP) 72 expression protects against arterial hypotension in rat heatstroke. HSP72 can also be induced in multiple organs, including hearts from rats with endurance exercise. We validated the hypothesis that progressive exercise preconditioning may confer cardiovascular protection during heatstroke by inducing the overexpression of HSP72 in multiple organs. To deal with the matter, we assessed the effects of heatstroke on mean arterial pressure, heart rate, cardiac output, stroke volume, total peripheral vascular resistance, colonic temperature, blood gases, and serum or tissue levels of tumor necrosis factor-α (TNF-α) in urethane-anesthetized rats pretreated without or with progressive exercise training for 1, 2, or 3 weeks. In addition, HSP72 expression in multiple organs was determined in different groups of animals. Heatstroke was induced by exposing the rats to a high blanket temperature (43°C); the moment at which mean arterial pressure decreased from the peak value was taken as the time of heatstroke onset. Previous exercise training for 3 weeks, but not 1 or 2 weeks, conferred significant protection against hyperthermia, arterial hypotension, decreased cardiac output, decreased stroke volume, decreased peripheral vascular resistance, and increased levels of serum or tissue TNF-α during heatstroke and correlated with overexpression of HSP72 in multiple organs, including heart, liver, and adrenal gland. However, 10 days after 3 weeks of progressive exercise training, when HSP72 expression in multiple organs returned to basal values, the beneficial effects exerted by 3 weeks of exercise training were no longer observed. These results strongly suggest that HSP72 preconditioning with progressive exercise training protects against hyperthermia, circulatory shock, and TNF-α overproduction during heatstroke.

Physical exercise induces excess hsp72 expression and delays the development of hyperalgesia and allodynia in painful diabetic neuropathy rats.

BACKGROUND:The underlying mechanism of exercise on the development of diabetes-associated neuropathic pain is not well understood. We investigated in rats whether exercise regulates the functional recovery and heat shock protein 72 (Hsp72), tumor necrosis factor (TNF)-&agr;, and interleukin (IL)-6 expression in streptozotocin (STZ)-induced diabetes. METHODS:Male Wistar rats were divided into 4 groups: normal sedentary rats, normal rats with exercise, sedentary STZ-diabetic (SS) rats, and STZ-diabetic rats with exercise. Diabetes was induced with STZ (65 mg/kg IV). The trained rats ran daily on a treadmill 30 to 60 min/d with an intensity of 20 to 25 m/min. We monitored thermal withdrawal latency and mechanical withdrawal threshold as well as Hsp72, TNF-&agr;, and IL-6 expression in the spinal cord and peripheral nerves. RESULTS:Two weeks after STZ injection, sedentary rats exhibited a marked and sustained hypersensitivity to von Frey tactile and heat stimuli. In contrast, diabetic rats undergoing exercise demonstrated delayed progress of tactile and thermal hypersensitivity. Exercise significantly suppressed diabetes-induced blood glucose levels and body weight loss, although they were not restored to control levels. Compared with normal sedentary rats, SS rats displayed significantly higher TNF-&agr; and IL-6 levels in the spinal cord and peripheral nerves. The STZ-diabetic rats with exercise group showed greater Hsp72 expression and similar TNF-&agr; or IL-6 level compared with the SS group in the spinal cord and peripheral nerves on day 14 after STZ treatment. CONCLUSIONS:These results suggest that progressive exercise training markedly decreases diabetes-associated neuropathic pain, including thermal hyperalgesia and mechanical allodynia. In rats, this protective effect is related to the increase of Hsp72, but not TNF-&agr; and IL-6, expression in the spinal cord and peripheral nerves of STZ-induced diabetes.

Diphenidol inhibited sodium currents and produced spinal anesthesia.

The aim of this study was to evaluate the effect of diphenidol on blocking Na(+) currents and spinal anesthesia. We used the patch-clamp method to examine if diphenidol blocked Na(+) currents. Lidocaine, a common used local anesthesia, was used as control. We also evaluated the potencies and durations of diphenidol and lidocaine on spinal blockades of motor function, proprioception, and nociception in rats. Lidocaine exhibited a concentration- and state-dependent effect on tonic blockade of voltage-gated Na(+) currents in mouse neuroblastoma N2A cells (IC(50) of 8.1 and 138.9 microM at holding potentials of -70 and -100 mV, respectively). Diphenidol was more potent (IC(50) of 0.77 and 62.6 microM at holding potentials of -70 and -100 mV, respectively). However, unlike lidocaine, block of Na(+) currents by diphenidol lacked use-dependence. We also found that diphenidol acted like lidocaine and produced dose-related spinal blockades of motor function, proprioception and nociception. Although diphenidol had similar potencies of spinal anesthesia compared with lidocaine it produced a much longer duration of spinal blockades than lidocaine. Our results demonstrated that intrathecal diphenidol produced a long duration and similar potency on spinal anesthesia compared with lidocaine in rats. The anesthetic effect of diphenidol could be in part due to its blockade of Na(+) currents.

The Local Anesthetic Effect of Memantine on Infiltrative Cutaneous Analgesia in the Rat

BACKGROUND: Memantine blocks N-methyl-D-aspartate receptors and the Na+ current, one principal mechanism of local anesthesia. Until now, no study mentioned that memantine had a local anesthetic effect, and therefore we investigated the local anesthetic effect of memantine. METHODS: After blockade of cutaneous trunci muscle reflex with subcutaneous injections, we evaluated the cutaneous analgesic effect of memantine, lidocaine, and dizocilpine (MK-801) in rats. The dose-dependent response of memantine on cutaneous analgesia was compared with lidocaine and MK-801 in rats. The duration of action for each drug was evaluated and compared on an equipotent basis (20% effective dose [ED20], ED50, and ED80). Lidocaine, a frequently used local anesthetic, was used as control. RESULTS: We demonstrated that memantine, lidocaine, and MK-801 produced dose-dependent local anesthetic effects as infiltrative cutaneous analgesia. The relative potency was MK-801 (10.4 [9.7–11.1]) > memantine (17.6 [15.2–20.4]) > lidocaine (25.9 [23.8–28.1 ]) (P < 0.01). On an equipotent basis, memantine showed longer duration than lidocaine (P = 0.012) and MK-801 (P = 0.008). Coadministration of memantine (13.3 &mgr;mol/kg) and MK-801 (1.3 &mgr;mol/kg) produced greater blockade and duration than memantine (13.3 &mgr;mol/kg) or MK-801 (1.3 &mgr;mol/kg) alone. Neither local injection of saline nor intraperitoneal administration of a large dose of memantine, lidocaine, or MK-801 produced cutaneous analgesia (data not shown). CONCLUSIONS: This study indicated that memantine is less potent than MK-801, and that memantine elicits longer analgesic duration than both lidocaine and MK-801. When combined with MK-801, memantine demonstrates a synergetic effect of cutaneous analgesia. We conclude that memantine produces better local analgesia than lidocaine and that N-methyl-D-aspartate receptors also contribute to the analgesic effect of memantine.

Quercetin is a potent anti‐atherosclerotic compound by activation of SIRT1 signaling under oxLDL stimulation

SCOPE Atherosclerosis is believed to be an independent predictor of cardiovascular diseases. A growing body of evidence suggests that quercetin is a potent antioxidant and anti-inflammatory compound. The molecular mechanisms underlying its protective effects against oxidative stress in human endothelial cells remain unclear. This study was designed to confirm the hypothesis that quercetin inhibits oxidized LDL (oxLDL) induced endothelial oxidative damage by activating sirtuin 1 (SIRT1) and to explore the role of adenosine monophosphate activated protein kinase (AMPK), which is a negative regulator of Nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) and free radicals. METHODS AND RESULTS Human umbilical vein endothelial cells were treated with oxLDL with or without quercetin pretreatment. We found that quercetin pretreatment increased SIRT1 mRNA expression. In fact, quercetin protected against oxLDL-impaired SIRT1 and AMPK activities and reduced oxLDL-activated NOX2 and NOX4. However, silencing SIRT1 and AMPK diminished the protective function of quercetin against oxidative injuries. The results also indicated that oxLDL suppressed AKT/endothelial NO synthase, impaired mitochondrial dysfunction, and enhanced reactive oxygen species formation, activating the Nuclear Factor Kappa B (NF-κB) pathway. CONCLUSION These results provide new insight regarding the possible molecular mechanisms of quercetin. Quercetin suppresses oxLDL-induced endothelial oxidative injuries by activating SIRT1 and modulating the AMPK/NADPH oxidase/AKT/endothelial NO synthase signaling pathway.

Intrathecal oxybuprocaine and proxymetacaine produced potent and long-lasting spinal anesthesia in rats.

Proxymetacaine and oxybuprocaine were clinically used for topical ocular anesthesia but never for spinal anesthesia, and therefore spinal anesthetic effects of proxymetacaine and oxybuprocaine were performed and compared with bupivacaine and lidocaine. After rats were injected intrathecally with proxymetacaine, oxybuprocaine, bupivacaine, and lidocane, dose-response curves were constructed. We evaluated the potencies (ED(50)) and durations (time to full recovery) of proxymetacaine and oxybuprocaine on spinal blockades of motor function, proprioception, and nociception and compared with bupivacaine and lidocaine in rats. We found that proxymetacaine and oxybuprocaine acted like bupivacaine or lidocaine and produced dose-related spinal blockades of motor function, proprioception and nociception. On the ED(50) basis, the ranks of potencies in motor, proprioception, and nociception were proxymetacaine>oxybuprocaine>bupivacaine>lidocaine (P<0.01 for the differences). On an equipotent basis (ED(20), ED(50), ED(80)), oxybuprocaine and bupivacaine produced similarly longer spinal blockades than did proxymetacaine or lidocaine (P<0.05 for the differences). Intrathecal proxymetacaine, oxybuprocaine, and bupivacaine also produced longer sensory blockade than motor blockade. These data demonstrated that oxybuprocaine and proxymetacaine produced more potent spinal blockades, when compared with bupivacaine or lidocaine. Oxybuprocaine and bupivacaine with a more sensory-selective action over motor blockade produced longer spinal blockade than did proxymetacaine or lidocaine.

Exercise pretraining protects against cerebral ischaemia induced by heat stroke in rats

Background: In the rat brain, heat-stroke-induced damage to cerebral neurons is attenuated through heat-shock-induced overexpression of heat-shock protein 72 (HSP72). Objective: To ascertain whether progressive exercise preconditioning induces HSP72 expression in the rat brain and prevents heat-stroke-induced cerebral ischaemia and injury. Methods: Male Wistar rats were randomly assigned to either a sedentary group or an exercise group. Those in the exercise group progressively ran on a treadmill 5 days/week, for 30–60 min/day at an intensity of 20–30 m/min for 3 weeks. The effects of heat stroke on mean arterial pressure, cerebral blood flow, brain ischaemia markers (glutamate, lactate/pyruvate ratio and nitric oxide), a cerebral injury marker (glycerol) and brain neuronal damage score in the preconditioned animals were compared with effects in unexercised controls. Heat stroke was induced by exposing urethane-anaesthetised animals to a temperature of 43°C for 55 min, which caused the body temperature to reach 42°C. Results: Three weeks of progressive exercise pretreatment induced HSP72 preconditioning in the brain and conferred significant protection against heat-stroke-induced hyperthermia, arterial hypotension, cerebral ischaemia and neuronal damage; it also prolonged survival. Conclusions: Exercise for 3 weeks can improve heat tolerance as well as attenuate heat-stroke-induced cerebral ischaemia in rats. The maintenance of mean arterial pressure and cerebral blood flow at appropriate levels in the rat brain may be related to overexpression of HSP72.

isobolographic Analysis of Epinephrine With Bupivacaine, Dextromethorphan, 3-methoxymorphinan, or Dextrorphan on Infiltrative Anesthesia in Rats : dose-response Studies

Background and Objectives: The aims of this study were to establish the potencies of epinephrine, bupivacaine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan and evaluate interactions of epinephrine with bupivacaine, dextromethorphan, 3‐methoxymorphinan, or dextrorphan as an infiltrative anesthetic. Bupivacaine, a common and long‐acting local anesthetic, was used as control. Methods: Dose‐dependent responses of epinephrine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan on cutaneous analgesia were compared with bupivacaine in rats. The interactions of drugs were evaluated via an isobolographic analysis. Results: We found that epinephrine, bupivacaine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan produced a dose‐dependent local anesthetic effect as infiltrative cutaneous analgesia. Relative potencies were epinephrine > bupivacaine > dextromethorphan > 3‐methoxymorphinan > dextrorphan (P < .01 for each comparison). Coadministration of bupivacaine with epinephrine produced a synergistic effect, and coadministration of dextromethorphan, 3‐methoxymorphinan, or dextrorphan with epinephrine produced an additive effect. Conclusions: Epinephrine, dextromethorphan, 3‐methoxymorphinan, and dextrorphan are known to have local anesthetic effects as infiltrative cutaneous analgesia in rats. Epinephrine increased the potency of bupivacaine, but not dextromethorphan, 3‐methoxymorphinan, or dextrorphan as an infiltrative anesthetic. The cutaneous analgesic effects of adding epinephrine to dextromethorphan, 3‐methoxymorphinan, or dextrorphan, are similar to combinations of 2 local anesthetics.

Cutaneous Analgesia and Systemic Toxicity of Carbetapentane and Caramiphen in Rats

Background Caramiphen produces spinal anesthesia; caramiphen and carbetapentane have never been tested as infiltrative cutaneous analgesic. The aim of this study was to compare cutaneous analgesia of caramiphen and carbetapentane with bupivacaine and evaluated their central nervous system and cardiovascular toxicity. Methods After the blockade of cutaneous trunci muscle reflex with subcutaneous drug injections in rats, we evaluated the local anesthetic effect of carbetapentane and caramiphen on infiltrative cutaneous analgesia. After continuous intravenous infusion of equipotent doses of bupivacaine, carbetapentane, caramiphen, and saline, we observed mean arterial blood pressure and heart rate and monitored the onset time of seizure, apnea, and impending death. Results Carbetapentane and caramiphen acted like bupivacaine and elicited cutaneous analgesia in a dose-related fashion. On a 50% effective dose (ED50) basis, the ranks of potencies were bupivacaine (1.78 [1.52–2.07]) > carbetapentane (2.53 [2.38–2.77]) > caramiphen (3.60 [3.41–3.99]) (P < 0.01). At equianalgesic doses (ED25, ED50, ED75), the duration caused by carbetapentane or caramiphen was similar to that caused by bupivacaine. Under equipotent doses, the infusion time of carbetapentane or caramiphen required to cause seizure, apnea, and impending death was longer than that of bupivacaine (P < 0.05). The decline in mean arterial blood pressure and heart rate was slower with carbetapentane or caramiphen when compared with bupivacaine (P < 0.01 for the differences) at equipotent doses. Conclusions Carbetapentane and caramiphen were similar to bupivacaine at producing durations of cutaneous analgesia but were less likely than bupivacaine to induce central nervous system and cardiovascular systemic toxicity.