losartan-potassium and Paraplegia

Paraplegia remains a significant complication of thoracoabdominal aortic intervention. We previously reported that diazoxide (DZ), enhances the neuroprotective efficacy of erythropoietin (EPO). We hypothesized that DZ and EPO combined treatment attenuates spinal cord ischemic injury through upregulation of nerve growth factor (NGF).. DZ (pretreatment) was given to adult male C57/BL6 mice by oral gavage and EPO (before surgery) was intraperitoneally injected 32 h after administration of DZ. Spinal cords were harvested 0, 2, 4, and 6 h after injection of EPO. NGF expression was analyzed by western blot. After determining the optimal time, NGF expression was compared between DZ (pretreatment) + EPO (before surgery), DZ + PBS, PBS + EPO, and PBS + PBS (ischemic control). Four groups were studied to compare the motor function after ischemia: DZ + EPO (n = 11), ischemic control (n = 9), DZ + EPO + tropomyosin receptor kinase A receptor inhibitor (n = 9), and sham (without cross-clamp, n = 4). Spinal cord ischemia was induced by a 4-min thoracic aortic cross-clamp. Functional scoring (Basso Mouse Score) was done at 12-h intervals until 48 h, and spinal cords were harvested for evaluation of NGF expression and histological changes.. NGF expression was significantly upregulated 4 h after administration of EPO. At 4 h after injection of EPO, NGF expression in the DZ + EPO group was significantly higher than that in the other groups. DZ + EPO significantly preserved motor function compared with all other groups. At 48 h after reperfusion, the level of NGF expression in the DZ + EPO group, was significantly higher than in all other groups.. DZ + EPO attenuates spinal cord ischemic injury through upregulation of NGF. Better understanding of this mechanism may serve to further prevent ischemic complications for aortic intervention.

Topics: Animals; Aortic Aneurysm, Thoracic; Diazoxide; Disease Models, Animal; Drug Synergism; Erythropoietin; Humans; Male; Mice; Nerve Growth Factor; Paraplegia; Recombinant Proteins; Spinal Cord; Spinal Cord Ischemia; Up-Regulation; Vascular Surgical Procedures

Topics: Diazoxide; Erythropoietin; Humans; Paraplegia; Spinal Cord

This study examined effects and functional outcome of recombinant human erythropoietin (rhEPO) and carbamylated erythropoietin fusion protein (cEPO-FC) preconditioning in a rabbit model for spinal cord ischemia and resulting paraplegia. This model was chosen because only a small surgical effect is needed to cause paraplegia in rabbits, which facilitates postoperative observation of animals.. Anesthetized but spontaneously breathing New Zealand White rabbits randomly received cEPO-FC (50 μg/kg; n = 8), rhEPO (5000 IU/kg; n = 10), or vehicle (control; n = 10) 30 minutes before and after infrarenal aortic clamping. Ideal clamping time of 22 minutes was identified from preceding clamping tests (15-25 minutes). Postoperative observation time was 96 hours. Spinal cord function was assessed by neurologic evaluation of hind limb motor function every 12 hours using a modified Tarlov score. Spinal cord tissue damage was evaluated after 96 hours using hematoxylin and eosin, elastica van Gieson, Nissl, Masson-Goldner, and hemosiderin staining. Plasma levels of cell senescence markers stathmin, chitinase 1/3, elongation factor 1-α were determined.. Rabbits that received rhEPO showed significant improvement of spontaneous lower limb movements until 36 hours of reperfusion and improved histologic scores upon examination of the lumbar spinal cord compared with the control group. In contrast, cEPO-FC treatment showed comparable outcome to the control group concerning movements of the lower limbs and histology. Senescence markers were elevated in the control group, but not in the treatment groups, except for chitinase 3 in the rhEPO group. Only stathmin showed no significant effect. Markers for senescence might increase after acute ischemic injury. Attenuation of senescence markers might not come alone from improvement of the spinal cord.. Preconditioning with rhEPO attenuates ischemia/reperfusion injury of the spinal cord, whereas the carbamylated derivative (cEPO-FC) showed no positive effect on spinal cord function.

Topics: Animals; Biomarkers; Cellular Senescence; Chitinases; Disease Models, Animal; Erythropoietin; Male; Motor Activity; Neurologic Examination; Neuroprotective Agents; Paraplegia; Peptide Elongation Factor 1; Rabbits; Recombinant Proteins; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Stathmin; Time Factors

Paraplegia remains a devastating complication of complex aortic surgery. Erythropoietin (EPO) has been shown to prevent paraplegia after ischemia reperfusion, but the protective mechanism remains poorly described in the spinal cord. We hypothesized that EPO induces the CREB (cAMP [adenosine 3'5' cyclic monophosphate] response element-binding protein) pathway and neurotrophin production in the murine spinal cord, attenuating functional and cellular injury.. Adult male mice were subjected to 4 minutes of spinal cord ischemia via an aortic and left subclavian cross-clamp. Experimental groups included EPO treatment 4 hours before incision (n = 7), ischemic control (n = 7), and shams (n = 4). Hind-limb function was assessed using the Basso motor score for 48 hours after reperfusion. Spinal cords were harvested and analyzed for neuronal viability using histology and staining with a fluorescein derivative. Expression of phosphorylated (p)AKT (a serine/threonine-specific kinase), pCREB, B-cell lymphoma 2, and brain-derived neurotrophic factor were determined using immunoblotting.. By 36 hours of reperfusion, EPO significantly preserved hind-limb function after ischemia-reperfusion injury (P < .01). Histology demonstrated preserved cytoarchitecture in the EPO treatment group. Cords treated with EPO expressed significant increases in pAKT (P = .021) and pCREB (P = .038). Treatment with EPO induced expression of both of the neurotrophins, B-cell lymphoma 2, and brain-derived neurotrophic factor, beginning at 12 hours.. Erythropoietin-mediated induction of the CREB pathway and production of neurotrophins is associated with improved neurologic function and increased neuronal viability following spinal cord ischemia reperfusion. Further elucidation of EPO-derived neuroprotection will allow for expansion of adjunct mechanisms for spinal cord protection in high-risk thoracoabdominal aortic intervention.

Topics: Animals; Brain-Derived Neurotrophic Factor; CREB-Binding Protein; Disease Models, Animal; Erythropoietin; Male; Mice, Inbred C57BL; Motor Activity; Paraplegia; Phosphorylation; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-bcl-2; Reperfusion Injury; Signal Transduction; Spinal Cord; Spinal Cord Ischemia; Time Factors

Topics: Animals; CREB-Binding Protein; Erythropoietin; Male; Paraplegia; Reperfusion Injury; Signal Transduction; Spinal Cord; Spinal Cord Ischemia

Paraplegia remains a devastating complication for patients undergoing thoracic aortic procedures. Although surgical adjuncts have evolved to reduce the risk of paraplegia, no pharmacologic therapies have proven efficacious in attenuating spinal cord ischemia-reperfusion injury. Effects of erythropoietin in spinal cord ischemia-reperfusion injury, however, have not yet been elucidated. We hypothesized that pretreatment with erythropoietin would attenuate functional and cytoarchitectural spinal cord injury related to high-risk aortic procedures.. Adult male mice were subjected to ischemia-reperfusion. Aortic arch and proximal left subclavian arteries were clamped for 5 minutes; animals were observed for 48 hours. Neurologic scores of hind limb function were assessed every 12 hours. Experimental groups consisted of treatment with erythropoietin 4 hours before crossclamping (n = 7), ischemic controls (n = 7), and sham ischemia (operation without crossclamping, n = 6). Thoracolumbar sections of spinal cord were removed after 48 hours and preserved for cytoarchitectural analysis.. Mice pretreated with erythropoietin exhibited significant preservation of hind limb motor function. All mice without pretreatment were paralyzed at 48 hours. Mice with erythropoietin pretreatment had improved motor function; 3 had no measurable neurologic deficit at 48 hours. Histologic analysis in mice treated with erythropoietin showed markedly reduced neuronal cell injury.. Erythropoeitin preserves both function and histologic appearance in mice undergoing spinal cord ischemia-reperfusion. With further elucidation of mechanisms of protection and optimal administration, erythropoietin could become an important adjunct in reducing the incidence and severity of spinal cord injury related to aortic interventions.

Topics: Animals; Aorta, Thoracic; Constriction; Disease Models, Animal; Erythropoietin; Hindlimb; Male; Mice; Mice, Inbred C57BL; Motor Activity; Muscle, Skeletal; Neuroprotective Agents; Paraplegia; Recombinant Proteins; Reperfusion Injury; Spinal Cord; Spinal Cord Ischemia; Subclavian Artery; Time Factors

Topics: Accidental Falls; Adult; Blood Transfusion; Blood Transfusion, Autologous; Chest Tubes; Crystalloid Solutions; Erythropoietin; Hemoglobins; Hemothorax; Humans; Isotonic Solutions; Jehovah's Witnesses; Male; Multiple Trauma; Paraplegia; Plasma Substitutes; Religion and Medicine; Ringer's Lactate; Thoracic Injuries; Thoracic Vertebrae; Thoracotomy; Treatment Refusal; Wounds, Penetrating

The origin of the temporary reduction in hematocrit and hemoglobin occurring after spinal cord injury (SCI) may be related to the neurologic dysfunction and to a change in erythropoietin (Ep) synthesis and/or secretion. Serum Ep, vital capacities, and numerous hematologic profiles were obtained in 12 cervical SCI patients during the first 12 weeks and 13th to 27th post-injury weeks, and in 8 thoracic SCI patients during the first 8 weeks and 9th to 28th weeks. Serum iron, iron binding, and saturation were obtained in 4 cervical SIC patients and blood gases in 10 patients with cervical SCI and in 6 with thoracic SCI. The results in all patients showed increased Ep values, returning to normal after 8 weeks in the thoracic SCI patients only. The few results on iron kinetics showed a tendency to low values, suggesting the necessity for further investigation. In an attempt to explain the Ep increase in SCI patients, the relative influence of the renal pelvic nerves and of the sympathetic nerves on its secretion, are examined.

Topics: Adolescent; Adult; Erythropoietin; Hematocrit; Hemoglobins; Humans; Male; Paraplegia; Quadriplegia; Spinal Cord Injuries; Vital Capacity