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ABSTRACT: Human umbilical cord blood cells (HUCBCs) have been shown to be beneficial in reducingneurological deficits in rats with brain fluid percussion injury (FPI). This study aimed toassess the basic mechanisms underlying the neuroprotective effects of HUCBCs derivedCD34+ cells. Rats were divided into three major groups: (i) sham-operated controls; (ii) FPIrats treated with PBS (phosphate buffered saline); (iii) FPI rats treated with 0.2%, 50%, or95% CD+ cells (in 5x105 cord blood lymphocytes and monocytes). Intravenous administrationof 0.3 ml of PBS, 0.2% CD34+ cells, 50% CD34+ cells, or 95% CD34+ cells was conductedimmediately after FPI. It was found that, 4 days post-FPI, CD34+ cells could be detected inthe ischemic brain tissues for 50% CD34+ cells- or 95% CD+ cells-treated FPI rats, but not forthe PBS-treated FPI rats or the 0.2% CD34+ cells-treated FPI rats. CD34+ cells (0.2%)-treatedFPI rats or PBS-treated FPI rats displayed neurological and motor deficits, cerebral contusionand apoptosis (e.g., increased numbers of both TUNEL-positive cells and caspase-3-positivecells), and activated inflammation (e.g., increased serum levels of tumor necrosis factoralpha).FPI-induced neurological motor dysfunction, cerebral contusion and apoptosis, andactivated inflammation could be attenuated by 50% CD34+ cells or 95% CD34+ cells therapy.In addition 50% or 95% CD34+ cells, but not PBS or 0.2% CD34+ cells, therapy significantlypromoted angiogenesis (e.g., increased numbers of both vasculoendothelial growth factorpositivecells and BrdU-endothelial double positive cells), neurogenesis (e.g., increasednumbers of both glial cell lines-derived neurotrophic factor-positive cells and BrdU/NeuNdouble positive cells) in the ischemic brain after FPI, and migration of endothelial progenitorcells from the bone marrow. Our data suggest that i.v. administration of HUCBCs-derivedCD34+ cells may improve outcomes of FPI in rats by stimulating both angiogenesis andneurogenesis.
Cell Transplantation 04/2013; · 5.13 Impact Factor
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ABSTRACT: OBJECTIVE: We studied the effects of tetramethylpyrazine (TMP) on the fever, increased plasma levels of tumor necrosis factor-α (TNF-α) and increased hypothalamic levels of glutamate, hydroxyl radicals and prostaglandin-E2 (PGE2) induced by lipopolysaccharide (LPS). MATERIALS AND METHODS: The microdialysis probes were stereotaxically and chronically implanted into the hypothalamus of rabbit brain for determining extracellular levels of glutamate, hydroxyl radials, and PGE2. In addition, both the body core temperature and plasma levels of TNF-α were measured. RESULTS: All the body core temperature, plasma levels of TNF-α, and hypothalamic levels of glutamate, hydroxyl radicals, and PGE2 were up-graded by an intravenous dose of LPS (2 μg/kg). Pretreatment with intravenous TMP (10-40 mg/kg) or intracerebroventricular TMP (130 μg in 20 μl per animal) 1 h before LPS administration significantly attenuated the LPS-induced fever as well as the increased hypothalamic levels of glutamate, hydroxyl radicals, and PGE2. LPS-induced fever could also be attenuated by intravenous or intracerebroventricular TMP 1 h after LPS injection. CONCLUSION: TMP preconditioning may cause its antipyretic action by reducing plasma levels of TNF-α as well as hypothalamic levels of glutamate, hydroxyl radicals, and PGE2 in rabbits.
Agents and Actions 03/2013; · 1.59 Impact Factor
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ABSTRACT: Flutamide has been used as an adjunct for decreasing the mortality from subsequent sepsis. Heatstroke resembles septic shock in many aspects. We hypothesized that heat-induced multiple organ dysfunction syndromes and lethality could be reduced by flutamide therapy. In heatstroke groups, mice were exposed to whole body heating (41.2°C, for 1h) in a controlled-environment chamber. The heat-stressed mice were returned to normal room temperature (24°C) after whole body heating. Mice still alive on day 4 of WBH treatment were considered survivors. Physiological and biochemical parameters were monitored for 2.5h post-WBH. Heatstroke mice were subcutaneously treated with flutamide (12.5-50mg/kg body weight in 0.05 ml) or vehicle solution (0.05 ml/kg body weight) once daily for 3 consecutive days post-WBH. We evaluated the effect of flutamide in heatstroke mice and showed that flutamide significantly (i) attenuated hypothermia, (ii) reduced the number of apoptotic cells in the hypothalamus, the spleen, the liver, and the kidney, (iii) attenuated the plasma index of toxic oxidizing radicals (e.g., nitric oxide metabolites and hydroxyl radicals), (iv) diminished the plasma index of the organ injury index (e.g., lactate dehydrogenase), (v) attenuated plasma systemic inflammation response molecules (e.g., tumor necrosis factor-α and interleukin-6), (vi) reduced the index of infiltration of polymorphonuclear neutrophils in the lung (e.g., myeloperoxidase activity), and (vii) allowed three times the fractional survival compared with vehicle. Thus, flutamide appears to be a novel agent for the treatment of mice with heatstroke or patients in the early stage of heatstroke.
European journal of pharmacology 05/2012; 688(1-3):62-7. · 2.59 Impact Factor
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ABSTRACT: Heatstroke is a form of excessive hyperthermia associated with a systemic inflammatory response that leads to multi-organ dysfunction in which central nervous system disorders predominate. Herein we determined to ascertain whether heat-induced multi-organ dysfunction in rats could be attenuated by granulocyte-colony stimulating factor (G-CSF) preconditioning. Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline, 0.3 ml, subcutaneously) or G-CSF (50-200 μg/kg body weight in 0.3 ml normal saline, subcutaneously) daily and consecutively for 5 days before the start of thermal experiments. They were exposed to an ambient temperature of 43°C for 68 min to induce heatstroke. G-CSF preconditioning significantly prolonged the survival time in heatstroke rats in a dose-related way (82-98 min vs 127-243 min). The non-preconditioning heatstroke animals showed hyperthermia, arterial hypotension, increased serum levels of systemic inflammatory response molecules, increased hypothalamic apoptotic cell numbers as well as neuronal damage scores, and increased serum levels of renal and hepatic dysfunction indicators. These heatstroke syndromes could be significantly reduced by G-CSF preconditioning. Thus our results revealed a potential for G-CSF used as a prophylactic agent for heatstroke in rats.
European journal of pharmacology 07/2011; 661(1-3):109-17. · 2.59 Impact Factor
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ABSTRACT: Our previous studies showed that electrical stimulation of the nuclei ambiguous (NA) or dorsomotor nuclei of the vagus (DMV) complex in the brain stem of spontaneously breathing pond turtles (Cyclemys fiavomarginata), anesthetized with chloralose (4 mg/100 g) and urethane (40 mg/100 g), produced a marked slowing or even cessation of the heart rate, and resulted in an immediate fall of blood pressure. Results of the present study further demonstrated that the cardioinhibitory responses could also be elicited by microinjection of monosodium glutamate (0.2-20 nl, 50 mM) into the NA/DMV complex in turtles. A two-barrel glass micropipette held in a manipulator was connected to a pneumatic pressure pump for microinjection. The glutamate-induced cardioinhibitory responses could be significantly reduced in a dose-dependent manner by pretreatment with AP-5 (a NMDA receptor antagonist, at 1-8 nmole) or CNQX (a non-NMDA receptor antagonist; at 0.1-0.8 nmole) 20 min before glutamate administration. Histochemical verification by injecting horseradish peroxidase into the cervical vagus nerves revealed that retrogradely labeled glutamatergic neurons in the NA/DMV complex were observed. These results suggest that glutamatergic receptors in the caudal medulla may mediate vagal cardioinhibitory responses in the turtle.
The Chinese journal of physiology 02/2011; 54(1):47-54. · 0.56 Impact Factor
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ABSTRACT: To assess whether systemic delivery of kynurenic acid improves the outcomes of heatstroke in rats.
Anesthetized rats were divided into 2 major groups and given vehicle solution (isotonic saline 0.3 mL/kg rat weight) or kynurenic acid (30-100 mg in 0.3 mL saline/kg) 4 h before the start of thermal experiments. They were exposed to an ambient temperature of 43 °C for 68 min to induce heatstroke. Another group of rats were exposed to room temperature (26 °C) and used as normothermic controls. Their core temperatures, mean arterial pressures, serum levels of systemic inflammatory response molecules, hypothalamic values of apoptotic cells and neuronal damage scores, and spleen, liver, kidney and lung values of apoptotic cells were determined.
The survival time values during heatstroke for vehicle-treated rats were decreased from the control values of 475-485 min to new values of 83-95 min. Treatment with KYNA (30-100 mg/kg, iv) 4 h before the start of heat stress significantly and dose-dependently decreased the survival time to new values of 152-356 min (P<0.05). Vehicle-treated heatstroke rats displayed hypotension, hypothalamic neuronal degeneration and apoptosis, increased serum levels of tumor necrosis factor-α (TNF-α), intercellular adhesion molecule-1 (ICAM-1), and interleukin-10 (IL-10), and spleen, liver, kidney, and lung apoptosis. KYNA preconditioning protected against hypotension but not hyperthermia and attenuated hypothalamic neuronal degeneration and apoptosis during heatstroke. KYNA preconditioning attenuated spleen, kidney, liver, and lung apoptosis and up-regulated serum IL-10 levels but down-regulated serum TNF-α and ICAM-1 levels during heatstroke.
Our results suggest that systemic delivery of kynurenic acid may attenuate multiorgan dysfunction in rats after heatstroke.
Acta Pharmacologica Sinica 02/2011; 32(2):167-74. · 1.95 Impact Factor
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ABSTRACT: To ascertain whether Premarin improves spinal cord injury outcomes in male rats by stimulating both angiogenesis and neurogenesis.
Chi Mei Medical Center research laboratory.
Male Sprague-Dawley rats 240-258 g.
Anesthetized rats, after the onset of spinal cord injury, were divided into two groups and given the vehicle solution (1 mL/kg of body weight) or Premarin (1 mg/kg of body weight). Saline or Premarin solutions were administered intravenously and immediately after spinal cord injury.
Premarin (an estrogen sulfate) causes attenuation of spinal cord injury-induced spinal cord infarction and hind limb locomotor dysfunction. Spinal cord injury-induced apoptosis as well as activated inflammation was also significantly Premarin-reduced. In injured spinal cord, angiogenesis, neurogenesis, and production of an antiinflammatory cytokine were all Premarin therapy-promoted.
Our results indicate that Premarin therapy may protect against spinal cord apoptosis after spinal cord injury through mechanisms stimulating both angiogenesis and neurogenesis in male rats.
Critical care medicine 10/2010; 38(10):2043-51. · 6.37 Impact Factor
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Taiwanese journal of obstetrics & gynecology 03/2010; 49(1):112-4.
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ABSTRACT: When the vehicle-treated, sham-operated mice underwent heat stress, the fraction survival and core temperature at +4 h of body heating were found to be 5 of 15 and 34.4 degrees C +/- 0.3 degrees C, respectively. Castration 2 weeks before the start of heat stress decreased the plasma levels of testosterone almost to zero, protected the mice from heat-induced death (fraction survival, 13/15) and reduced the hypothermia (core temperature, 37.3 degrees C). The beneficial effects of castration in ameliorating lethality and hypothermia can be significantly reduced by testosterone replacement. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl- transferase- mediatedalphaUDP-biotin nick end-labeling staining, were significantly prevented by castration. In addition, heat-induced neuronal damage, as indicated by cell shrinkage and pyknosis of nucleus, to the hypothalamus was also castration-prevented. Again, the beneficial effects of castration in reducing neuronal damage to the hypothalamus as well as apoptosis in multiple organs during heatstroke, were significantly reversed by testosterone replacement. The data indicate that testosterone depletion by castration may protect mice from heatstroke-induced multiple organ damage and lethality.
Journal of Biomedicine and Biotechnology 01/2010; 2010:485306. · 2.44 Impact Factor
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ABSTRACT: Intravenous administration of human umbilical cord blood cells (HUCBC) has been shown to improve heatstroke by reducing arterial hypotension as well as cerebral ischemia and damage in a rat model. To extend these findings, we assessed both hypothalamic neuronal apoptosis and systemic inflammatory responses in the presence of HUCBCs or vehicle medium immediately after initiation of heatstroke.
Anesthetized rats, immediately after the initiation of heat stress, were divided into two groups and given either serum-free lymphocyte medium (0.3mL per rat, intravenously) or HUCBCs (5 x 10(6) in 0.3 mL serum-free lymphocyte medium, intravenously). Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Heatstroke was induced by exposing the anesthetized rats to a high ambient temperature of 43 degrees C for 68 minutes.
After the onset of heatstroke, animals treated with serum-free lymphocyte medium displayed hyperthermia, hypotension, bradycardia, hypothalamic neuronal apoptosis and degeneration, and up-regulation of systemic inflammatory response molecules including serum tumor necrosis factor-alpha, soluble intercellular adhesion molecule-1 and E-selectin. Heatstroke-induced hypotension, bradycardia, hypothalamic neuronal apoptosis and degeneration, and increased systemic inflammatory response molecules were significantly inhibited by HUCBC treatment. Although heatstroke-induced hyperthermia was not affected by HUCBC treatment, the serum levels of the anti-inflammatory cytokine interleukin-10 were significantly increased by HUCBC therapy during hyperthermia.
These findings suggest that HUCBC transplantation may prevent the occurrence of heatstroke by reducing hypothalamic neuronal damage and the systemic inflammatory responses.
Pediatrics & Neonatology 10/2009; 50(5):208-16. · 0.75 Impact Factor
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ABSTRACT: To establish mechanisms of neuroprotective actions induced by Premarin (an estrogen sulfate) during traumatic brain injury.
Chi Mei Medical Center research laboratory.
Male Sprague-Dawley rats 244 to 268 g.
Anesthetized rats, immediately after the onset of fluid percussion injury, were divided into three major groups and given the vehicle solution (1 mL/kg of body weight), Premarin (1 mg/kg of body weight), or Premarin (1 mg/kg of body weight) plus the nonselective estrogen receptor-alpha antagonist ICI 182, 780 (0.25 mg/kg of body weight) intravenously and immediately after fluid percussion injury.
Premarin, in addition to inducing pharmacologic levels of estradiol, causes attenuation of fluid percussion injury-induced cerebral infarction and motor and cognitive function deficits. Fluid percussion injury-induced apoptosis (e.g., increased numbers of both terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive and caspase-3-positive cells) as well as activated inflammation (e.g., increased levels of tumor necrosis factor-alpha) was also significantly Premarin-reduced. In peri-ischemic areas of hippocampus, both angiogenesis (e.g., increased numbers of both 5-bromodeoxyuridine-positive endothelial and vascular endothelial growth factor-positive cells) and neurogenesis (e.g., increased numbers of both 5-bromodeoxyuridine/neuronal-specific nuclear protein double-positive and glial cell line-derived neurotrophic factor-positive cells) were Premarin therapy-promoted. In estrogen receptor-alpha blockade rats, Premarin therapy had less or no effect on fluid percussion injury-induced behavioral deficits, cerebral infarction and apoptosis, and activated inflammation. Furthermore, Premarin-induced angiogenesis and neurogenesis were estrogen receptor-alpha blockade-reduced.
Our results indicate that pharmacologic levels of Premarin therapy-induced estradiol protect against cortical and hippocampal programmed cell death after fluid percussion injury through mechanisms stimulating estrogen receptor-alpha in the male rats.
Critical care medicine 09/2009; 37(12):3097-106. · 6.37 Impact Factor
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Taiwanese journal of obstetrics & gynecology 01/2009; 47(4):438-40.
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ABSTRACT: The aim of present study was to examine whether systemically delivered glial cell-derived neurotrophic factor (GDNF) was beneficial in reversing the spinal cord injury (SCI) in a spinal cord compression model. Rats were divided into three major groups: (1) sham operation (laminectomy only); (2) laminectomy+SCI+normal saline (1 ml/kg, i.v.); (3) laminectomy+SCI+GDNF (50 ng/kg, i.v.). Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. GDNF or saline was administered immediately after SCI via the tail vein. Behavioral tests of motor function measured by maximal angle an animal could hold to the inclined plane were conducted at days 1-7 after SCI. The triphenyltetrazolium chloride staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay were also conducted after SCI to evaluate spinal cord infarction and apoptosis, respectively. Both GDNF and vascular endothelial growth factor (VEGF) in the injured spinal cord were assayed by immunofluorescence. It was found that systemically delivered GDNF, but not vehicle solution, significantly attenuated the SCI-induced hind limb dysfunction and spinal cord infarction and apoptosis. Both GDNF and VEGF could be detected in the injury spinal cord after GDNF, but not vehicle solution, therapy. The results indicate that GDNF treatment may be beneficial in reversing hind limb dysfunction by reducing spinal cord infarction and apoptosis in a spinal cord compression model.
Resuscitation 07/2008; 77(3):395-400. · 3.60 Impact Factor
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ABSTRACT: Human umbilical cord blood cells (HUCBCs) were used to investigate the mechanisms underlying the beneficial effects of cord blood cells in spinal cord injury (SCI).
Rats were divided into three groups: (1) sham operation (laminectomy only); (2) Laminectomy+SCI+human adult peripheral blood mononucleocytes (PBMCs) (5 x 10(6)/0.3 mL); and (3) Laminectomy+SCi+HUCBCs (5 x 10(6)/0.3 mL). SCI was induced by compressing the spinal cord for 1 minute with an aneurysm clip calibrated to 55 g closing pressure. HUCBCs were infused immediately after SCI via the tail vein. Behavioral function tests measuring the maximal angle at which an animal could hold onto the inclined plane were conducted on days 1, 4 and 7 after SCI. Serum levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-10, were assayed. Furthermore, to determine if glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) could be detected in the spinal cord injured area after systemic HUCBC infusion, analysis of these two molecules was conducted by immunofluorescence.
Systemic HUCBC infusion significantly attenuated SCI-induced hind limb dysfunction. The serum IL-10 levels were increased, but TNF-alpha levels were decreased after HUCBC infusion. Both VEGF and GDNF could be detected in the injured spinal cord after transplantation of HUCBC, but not PBMC, cells.
Our results demonstrate that HUCBC therapy may be beneficial for the recovery of SCI-induced hind limb dysfunction by increasing serum levels of IL-10, VEGF and GDNF in SCI rats.
Pediatrics & Neonatology 07/2008; 49(3):77-83. · 0.75 Impact Factor
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ABSTRACT: The present study was conducted to assess whether Premarin, a water-soluble estrogen sulfate, can act via estrogen receptors (ERs) to rescue mice from heat-induced lethality. Unanesthetized, unrestrained mice were exposed to ambient temperature of 42.4 degrees C to induce heatstroke (HS). Another group of mice was exposed to room temperature (24 degrees C) and used as normothermic controls. They were given isotonic sodium chloride solution, Premarin (0.1 - 1.0 mg/kg of body weight, i.p.), or Premarin (1 mg/kg of body weight, i.p.) plus the nonselective ER antagonist ICI 182, 780 (0.25 mg/kg of body weight, i.p.) 1 h after the termination of heat stress. Their physiologic and biochemical parameters were continuously monitored. Mice that survived on day 4 of heat treatment were considered survivors. When the vehicle-treated mice underwent heat, the fraction survival and core temperature at +4 h of body heating were found to be 0 of 12 and 34.4 degrees C +/- 3 degrees C, respectively. Administration of Premarin (1 mg/kg) 1 h after the cessation of heat stress rescued the mice from heat-induced death (fraction survival, 12/12) and reduced the hypothermia (core temperature, 37.3 degrees C). The beneficial effects of Premarin in ameliorating lethality and hypothermia can be abolished by simultaneous administration of ICI 182, 780. Both IL-10 (an anti-inflammatory cytokine) and estradiol in the serum were increased significantly in heat-stressed mice administered Premarin compared with vehicle-treated HS group. Heat-induced apoptosis, as indicated by terminal deoxynucleotidyl-transferase-mediated alpha UDP-biotin nick end-labeling staining, in the spleen, liver, and kidney were significantly reduced by Premarin. The increased levels of cellular ischemia (e.g., glutamate, lactate-to-pyruvate ratio, and nitrite) and damage (e.g., glycerol) markers and iNOS expression in the hypothalamus during HS were decreased significantly by Premarin therapy. The levels of proinflammatory cytokines (e.g., IL-1 beta and TNF-alpha) and renal and hepatic dysfunction markers in plasma that are up-regulated in heat stressed mice were significantly lower in Premarin-administered mice. The data indicate that Premarin may act via ERs to rescue mice form HS-induced lethality.
Shock (Augusta, Ga.) 06/2008; 30(6):668-74. · 2.87 Impact Factor
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ABSTRACT: We attempted to assess the prophylactic effect of human umbilical cord blood-derived CD34(+) cells in experimental heatstroke. Anesthetized rats, 1 day before heat stress, were divided into 2 major groups and given CD34(-) cells (defined by 1 x 10(6) human cord blood lymphocytes and monocytes that contained <0.2% CD34(+) cells) or CD34(+) cells (defined by 1 x 10(6) human cord blood lymphocytes and monocytes that contained >95% CD34(+) cells). They were exposed to ambient temperature of 43 degrees C for 70 min to induce heatstroke. When the CD34(-) cells-treated or untreated rats underwent heat stress, their survival time values were found to be 20-24 min. Pretreatment with CD34(+) cells significantly increased survival time (123-351 min). As compared with normothermic controls, all CD34(-) cells-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, these heatstroke reactions all were significantly suppressed by CD34(+) cells pretreatment. In addition, the levels of interleukin-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34(+) cell administration during heatstroke. Our data indicate that human umbilical cord-derived CD34(+) cells can be used as a prophylactic agent for experimental heatstroke.
Journal of Pharmacological Sciences 01/2008; 106(1):46-55. · 2.08 Impact Factor
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ABSTRACT: Human umbilical cord blood-derived CD34(+) cells were used to elucidate the mechanisms underlying the beneficial effects exerted by cord blood cells in spinal cord injury (SCI). Rats were divided into four groups: (1) sham operation (laminectomy only); (2) laminectomy + SCI + CD34(-) cells (5 x 10(5) human cord blood lymphocytes and monocytes that contained <0.2% CD34(+) cells); (3) laminectomy + SCI + CD34(+) cells (5 x 10(5) human cord blood lymphocytes and monocytes that contained approximately 95% CD34(+) cells); and (4) laminectomy + SCI + saline (0.3 mL). Spinal cord injury was induced by compressing the spinal cord for 1 min with an aneurysm clip calibrated to a closing pressure of 55 g. CD34 cells or saline was administered immediately after SCI via the tail vein. Behavioral tests of motor function measured by maximal angle an animal could hold to the inclined plane were conducted at days 1 to 7 after SCI. The triphenyltetrazolium chloride staining and terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay were also conducted after SCI to evaluate spinal cord infarction and apoptosis, respectively. To elucidate whether glial cell line-derived neurotrophic factor (GDNF) or vascular endothelial growth factor (VEGF) can be secreted in spinal cord-injured area by the i.v. transplanted CD34(+) cells, analysis of spinal cord homogenate supernatants by specific enzyme-linked immunosorbent assay for GDNF or immunofluorescence for VEGF was conducted. It was found that systemic administration of CD34(+), but not CD34(-), cells significantly attenuated the SCI-induced hind limb dysfunction and spinal cord infarction and apoptosis. Both GDNF and VEGF could be detected in the injured spinal cord after transplantation of CD34(+), but not CD34(-), cells. The results indicate that CD34(+) cell therapy may be beneficial in reversing the SCI-induced spinal cord infarction and apoptosis and hindlimb dysfunction by stimulating the production of both VEGF and GDNF in a spinal cord compression model.
Shock 01/2008; 29(1):49-55. · 2.85 Impact Factor
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ABSTRACT: In the rat brain, heat-stroke-induced damage to cerebral neurons is attenuated through heat-shock-induced overexpression of heat-shock protein 72 (HSP72).
To ascertain whether progressive exercise preconditioning induces HSP72 expression in the rat brain and prevents heat-stroke-induced cerebral ischaemia and injury.
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 degrees C for 55 min, which caused the body temperature to reach 42 degrees C.
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.
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.
British journal of sports medicine 10/2007; 41(9):597-602. · 2.55 Impact Factor
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ABSTRACT: Multiorgan dysfunction ensuing from severe heatstroke includes hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. We attempted to assess whether human umbilical cord blood-derived CD34+ cell therapy improves survival during experimental heatstroke by attenuating multiorgan dysfunction. Anesthetized rats, immediately after the onset of heatstroke, were divided into 2 major groups and given CD34- or CD34+ cells (1 x 10(5)-5 x 10(5)/mL/kg body weight) i.v. They were exposed to ambient temperature of 43 degrees C to induce heatstroke. Another group of rats were exposed to room temperature (26 degrees C) and used as normothermic controls. Hypotension, hepatic and renal failure (evidenced by increased serum urea nitrogen, creatinine, aspartate aminotransferase, alanine aminotransferase, and alkaline phosphatase levels in plasma), hypercoagulable state (evidenced by increased prothrombin time, activated partial thromboplastin time, and D-dimer, and decreased platelet count and protein C in plasma), activated inflammation (evidence by increased TNF-alpha levels in serum), and cerebral dysfunction (evidenced by intracranial hypertension, cerebral hypoperfusion and hypoxia, and cerebral ischemia and injury) were monitored. When the CD34- cell-treated or untreated rats underwent heat stress, their survival time values were found to be 19 to 23 min. Resuscitation with CD34+ cells significantly improved survival time (duration, 63-291 min). As compared with normothermic controls, all CD34- cell-treated heatstroke animals displayed hypotension, hepatic and renal failure, hypercoagulable state, activated inflammation, and cerebral ischemia and injury. However, CD34+ cell therapy significantly caused attenuation of all the above-mentioned heatstroke reactions. In addition, the levels of IL-10 in plasma and glial cell line-derived neurotrophic factors in brain were all significantly increased after CD34+ cell therapy during heatstroke. Our data indicate that CD34+ cell therapy may resuscitate persons who had a heatstroke by reducing multiorgan dysfunction or failure.
Shock 07/2007; 27(6):663-71. · 2.85 Impact Factor
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ABSTRACT: This current review summarized animal models of heatstroke experimentation that promote our current knowledge of therapeutic effects on cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation with human umbilical cord blood cells (HUCBCs) or estrogen in the setting of heatstroke. Accumulating evidences have demonstrated that HUCBCs provide a promising new therapeutic method against neurodegenerative diseases, such as stroke, traumatic brain injury, and spinal cord injury as well as blood disease. More recently, we have also demonstrated that post- or pretreatment by HUCBCs may resuscitate heatstroke rats with by reducing circulatory shock, and cerebral nitric oxide overload and ischemic injury. Moreover, CD34+ cells sorted from HUCBCs may improve survival by attenuating inflammatory, coagulopathy, and multiorgan dysfunction during experimental heatstroke. Many researchers indicated pro- (e.g. tumor necrosis factor-alpha [TNF-alpha]) and anti-inflammatory (e.g. interleukin-10 [IL-10]) cytokines in the peripheral blood stream correlate with severity of circulatory shock, cerebral ischemia and hypoxia, and neuronal damage occurring in heatstroke. It has been shown that intravenous administration of CD34+ cells can secrete therapeutic molecules, such as neurotrophic factors, and attenuate systemic inflammatory reactions by decreasing serum TNF-alpha but increasing IL-10 during heatstroke. Another line of evidence has suggested that estrogen influences the severity of injury associated with cerebrovascular shock. Recently, we also successfully demonstrated estrogen resuscitated heatstroke rats by ameliorating systemic inflammation. Conclusively, HUCBCs or estrogen may be employed as a beneficial therapeutic strategy in prevention and repair of cerebrovascular dysfunction, coagulopathy, and/or systemic inflammation during heatstroke.
Taiwanese journal of obstetrics & gynecology 04/2007; 46(1):15-25.
