Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal cord neurofilament degradation and energy metabolism

1984 ◽  
Vol 61 (2) ◽  
pp. 290-295 ◽  
Author(s):  
J. Mark Braughler ◽  
Edward D. Hall
Keyword(s):  
Spinal Cord ◽  
Sodium Succinate ◽  
Energy Charge ◽  
Lumbar Spinal Cord ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Neurofilament Protein ◽  
Content Type ◽  
Methylprednisolone Sodium Succinate ◽  
Spinal Cord Segment

✓ Thirty minutes after experimental spinal cord contusion (500 gm-cm) injury, cats were treated with an initial intravenous dose of either vehicle (V) or 30 mg/kg of Solu-Medrol sterile powder (methylprednisolone sodium succinate; MPSS). Two hours later, cats received a second intravenous injection of either V or 15 mg/kg MPSS, giving three treatment groups: V/V; MPSS/V; MPSS/MPSS. At 4½ hours following injury of the cat lumbar spinal cord, the gray and white matter neurofilament protein content was reduced by over 70% within the injured segment of V/V-treated animals. The three major cat spinal cord neurofilament protein subunits of 200,000, 152,000, and 76,000 daltons were reduced in parallel by the injury. Treatment of cats with a single 30-mg/kg dose of MPSS (MPSS/V) provided a clear, although not significant, protection against neurofilament degradation compared with V/V-treated cats when measured at 4½ hours after injury. The lactic acid content of the injured spinal cord segment at 4½ hours after injury was significantly elevated in both V/V- and MPSS/V-treated cats, while the adenosine triphosphate (ATP) content, total adenylates, and energy charge were significantly reduced. The administration of a second intravenous 15-mg/kg dose of MPSS 2 hours after the initial 30-mg/kg dose (MPSS/MPSS) provided complete (p < 0.01) preservation of neurofilaments within the injured spinal cord segment measured at 4½ hours after injury. The levels of lactate, ATP, total adenylates, and tissue energy charge in MPSS/MPSS-treated cats were not different from those of uninjured spinal cords following laminectomy. The (Na+ + K+)-ATPase activity in the injured spinal segment was enhanced, although highly variable, in MPSS/V-treated animals. On the other hand, spinal cord enzyme activity was significantly and consistently elevated in the MPSS/MPSS-treated group. The results demonstrate that a 30-mg/kg dose of MPSS followed at 2 hours by a 15-mg/kg dose provides significantly better protection against injury-induced ischemia and Ca++-dependent neurofilament degradation than a single 30-mg/kg dose. These findings are in agreement with the spinal cord tissue pharmacokinetics and time-action characteristics of methylprednisolone observed in earlier studies.

Effects of a single large dose of methylprednisolone sodium succinate on experimental posttraumatic spinal cord ischemia

1984 ◽  
Vol 61 (1) ◽  
pp. 124-130 ◽  
Author(s):  
Edward D. Hall ◽  
Daniel L. Wolf ◽  
J. Mark Braughler
Keyword(s):  
Spinal Cord ◽  
Sodium Succinate ◽  
Spinal Cord Ischemia ◽  
Repeated Measurements ◽  
Intravenous Dose ◽  
Lumbar Spinal Cord ◽  
Spinal Cord Blood Flow ◽  
Content Type ◽  
Methylprednisolone Sodium Succinate ◽  
Fine Print

✓ The ability of a single large intravenous dose of methylprednisolone sodium succinate (MPSS: 15, 30, or 60 mg/kg) to modify the evolution of lumbar spinal cord ischemia in cats undergoing a contusion injury of 500 gm-cm is examined. Repeated measurements of spinal cord blood flow (SCBF) in the dorsolateral funiculus were made via the hydrogen clearance technique before and for 4 to 5 hours after injury. The mean preinjury SCBF for all animals was 12.29 ± 0.77 ml/100 gm/min. Following injury, SCBF began to decrease progressively in vehicle-treated animals to a level of 7.71 ml/100 gm/min, a fall of 37.3%. In contrast, cats that received a 30-mg/kg intravenous dose of MPSS at 30 minutes after injury maintained SCBF within normal limits (p < 0.05 at 3 and 4 hours after contusion). A 15-mg/kg MPSS dose was less effective at preventing posttraumatic white matter ischemia, and a 60-mg/kg dose was essentially ineffective. It was determined that the 30-mg/kg MPSS dose was optimal for supporting SCBF when the drug was given at 30 minutes after spinal trauma, and a second series of experiments was carried out to examine the ability of this dose, when given at longer latencies, to improve decreased flow. Methylprednisolone given at 1½ hours after injury in four cats produced a slight (12.7%) but transient improvement in SCBF, and when administered at 4½ hours in another three animals was totally ineffective. These results show that MPSS in a 30-mg/kg dose can prevent posttraumatic spinal cord ischemia. However, it would appear that the ability of the steroid to reverse the ischemia once it has developed is limited, and probably lost, within a few hours of onset. This further suggests that the ischemic process is irreversible and underscores the need for early treatment with a large MPSS dose in order to prevent full development of ischemia and to promote neurological recovery.

Uptake and elimination of methylprednisolone from contused cat spinal cord following intravenous injection of the sodium succinate ester

1983 ◽  
Vol 58 (4) ◽  
pp. 538-542 ◽  
Author(s):  
J. Mark Braughler ◽  
Edward D. Hall
Keyword(s):  
Spinal Cord ◽  
Drug Administration ◽  
Sodium Succinate ◽  
Elimination Rate ◽  
Lumbar Spinal Cord ◽  
Spinal Cord Tissue ◽  
Elimination Phase ◽  
Content Type ◽  
Rapid Elimination ◽  
Lumbar Spinal

✓ The uptake and elimination of methylprednisolone by the injured cat lumbar spinal cord were examined following a single 30-mg/kg intravenous bolus injection of the sodium succinate ester. The findings were considerably different from those previously reported for normal lumbar cord. When the glucocorticoid was administered 30 minutes after a 400 gm-cm contusion injury, peak tissue concentrations in both injured and uninjured segments of traumatized spinal cord were not achieved until 30 minutes following drug administration. The elimination of methylprednisolone from injured spinal cord tissue was biphasic in nature, with a rapid elimination phase occurring between 1 and 2 hours after drug administration. This rapid elimination phase was followed by a slower phase which paralleled the constant elimination rate from uninjured tissue of traumatized cord (approximate half-time = 6 hours). Significantly more methylprednisolone accumulated in the injured segment of traumatized spinal cord than in an uninjured segment adjacent to the injury site. This was only true, however, if the drug was administered at times up to 1 hour after injury. If injected after 1 hour, uptake by the injured segment decreased significantly with time after trauma and was no different from that observed for the uninjured segment in the same animal, which showed no significant variation with time after trauma. The probable basis for these differences and the possible clinical implications of these pharmacokinetic characteristics are discussed.

Presence and significance of CD-95 (Fas/APO1) expression after spinal cord injury

2001 ◽  
Vol 94 (2) ◽  
pp. 257-264 ◽  
Author(s):  
Mercedes Zurita ◽  
Jesús Vaquero ◽  
Isabel Zurita
Keyword(s):  
Spinal Cord ◽  
Spinal Cord Injury ◽  
White Matter ◽  
Gray Matter ◽  
Spinal Cord Tissue ◽  
Injured Spinal Cord ◽  
Content Type ◽  
Cord Injury ◽  
Positive Immunostaining ◽  
Fine Print

Object. A glycoprotein, CD95 (Fas/APO1) is widely considered to be implicated in the development of apoptosis in a number of tissues. Based on the hypothesis that apoptosis is related to cell death after spinal cord injury (SCI), the authors studied the presence and distribution of CD95 (Fas/APO1)-positive cells in injured spinal cord tissue for the purpose of determining the significance of this protein during the early phases of SCI. Methods. The presence and distribution of cells showing positive immunostaining for CD95 (Fas/APO1) were studied 1, 4, 8, 24, 48, and 72 hours and 1, 2, and 4 weeks after induction of experimental SCI in rats. Studies were conducted using a monoclonal antibody to the CD95 (Fas/APO1) protein. Positivity for CD95 (Fas/APO1) was observed in apoptotic cells, mainly in the gray matter, 1 hour after trauma, and the number of immunostained cells increased for the first 8 hours, at which time the protein was expressed in both gray and white matter. From 24 to 72 hours postinjury, the number of immunostained cells decreased in the gray matter, but increased in the white matter. From then on, there were fewer CD95 (Fas/APO1)-positive cells, but some cells in the white matter still exhibited positive immunostaining 1 and 2 weeks after injury. At 4 weeks, there remained no CD95 (Fas/APO1)-positive cells in injured spinal cord. Conclusions. These findings indicate that CD95 (Fas/APO1) is expressed after SCI, suggesting a role for this protein in the development of apoptosis after trauma and the possibility of a new therapeutic approach to SCI based on blocking the CD95 (Fas/APO1) system.

Norepinephrine levels in experimental spinal cord trauma

1977 ◽  
Vol 46 (3) ◽  
pp. 342-349 ◽  
Author(s):  
Stephen E. Rawe ◽  
Robert H. Roth ◽  
Margaret Boadle-Biber ◽  
William F. Collins
Keyword(s):  
Spinal Cord ◽  
Tyrosine Hydroxylase ◽  
Concentration Gradient ◽  
Neurological Function ◽  
Spinal Cord Tissue ◽  
Spinal Cord Trauma ◽  
Content Type ◽  
Spinal Cord Segment ◽  
Fine Print

✓ Levels of norepinephrine (NE) in the spinal cord tissue of nontraumatized cats are highest in the cervical and lumbar enlargements. A rather uniform but slightly increasing concentration gradient from cephalad to caudad is observed in the thoracic segments. A 500 gm-cm trauma at the T-5 or C-7 spinal cord segment did not demonstrate any significant increase in NE levels measured sequentially over a 4-hour period after trauma. Dopamine levels could not be detected in the nontraumatized or traumatized cat spinal cords. Four traumatized cats treated with alpha methyl tyrosine, a tyrosine hydroxylase inhibitor, and followed clinically for 5 months showed no improvement in neurological function when compared to untreated traumatized cats. This study does not support the norepinephrine hypothesis of experimental spinal cord trauma.

Effects of the 21-aminosteroid U74006F on posttraumatic spinal cord ischemia in cats

1988 ◽  
Vol 68 (3) ◽  
pp. 462-465 ◽  
Author(s):  
Edward D. Hall
Keyword(s):  
Spinal Cord ◽  
Blood Flow ◽  
Sodium Succinate ◽  
Spinal Cord Ischemia ◽  
Intravenous Dose ◽  
Content Type ◽  
Methylprednisolone Sodium Succinate ◽  
Surprising Effect ◽  
Surgical Preparation ◽  
Dorsolateral Funiculus

✓ The ability of a single intravenous dose of the 21-aminosteroid U74006F to affect the development of posttraumatic spinal cord ischemia was examined in pentobarbital-anesthetized cats. After surgical preparation, each animal received a 300 gm-cm contusion injury to the exposed L-3 vertebral segment, followed by a single bolus injection of vehicle or U74006F (3 or 10 mg/kg) at 30 minutes postinjury. Spinal cord white matter blood flow (SCBF) was measured by hydrogen clearance in the dorsolateral funiculus in the center of the injured segment before and at various times up to 4 hours after injury. In vehicle-treated cats, there was a progressive decline in SCBF over the course of the experiment. By 4 hours postinjury, SCBF had decreased from a preinjury value of 15.9 ± 2.4 ml/100 gm/min (mean ± standard error of the mean) to 5.8 ± 0.8 ml/100 gm/min, representing a decline of 63.5%. In contrast, the SCBF measured 4 hours postinjury in cats that were treated with a single 10-mg/kg dose of U74006F was 13.6 ± 1.7 ml/100 gm/min (p < 0.001 vs. vehicle). Animals that received a 3-mg/kg intravenous dose of U74006F displayed a drop in SCBF equal to that of vehicle-treated cats. However, when a 3-mg/kg dose of U74006F was given to four vehicle-treated cats at the end of the experiment, a partial reversal of ischemia was recorded. Blood flow increased within 30 minutes from a mean of 4.5 ± 0.8 to 7.4 ± 1.0 ml/100 gm/min or an increase of 64.4% (p < 0.05). This rather surprising effect of U74006F in reversing posttraumatic ischemia once it has developed significantly is not shared by a 30-mg/kg intravenous dose of methylprednisolone sodium succinate (MP), although MP has previously been shown to attenuate the posttraumatic drop in SCBF when given before the SCBF drop occurs. The mechanism of action of U74006F in antagonizing posttraumatic ischemia development is believed to involve the ability of the compound to inhibit iron-dependent lipid peroxidation in central nervous system tissue.

Localized delivery of methylprednisolone sodium succinate with polymeric nanoparticles in experimental injured spinal cord model

2016 ◽  
Vol 22 (8) ◽  
pp. 972-981 ◽  
Author(s):  
Yasemin Karabey-Akyurek ◽  
Ahmet Gurhan Gurcay ◽  
Oktay Gurcan ◽  
Omer Faruk Turkoglu ◽  
Samiye Yabanoglu-Ciftci ◽  
...  
Keyword(s):  
Spinal Cord ◽  
Polymeric Nanoparticles ◽  
Sodium Succinate ◽  
Injured Spinal Cord ◽  
Methylprednisolone Sodium Succinate ◽  
Localized Delivery

Control of blood flow in the cat spinal cord

1983 ◽  
Vol 58 (5) ◽  
pp. 742-748 ◽  
Author(s):  
Oscar U. Scremin ◽  
Emilio E. Decima
Keyword(s):  
Spinal Cord ◽  
Blood Flow ◽  
White Matter ◽  
Ventral Horn ◽  
Hydrogen Gas ◽  
Lumbar Spinal Cord ◽  
Spinal Cord Tissue ◽  
Spinal Cord Blood Flow ◽  
Content Type ◽  
Fine Print

✓ Spinal cord blood flow (SCBF) and the effect of end-tidal CO2 concentration (ETCO2) on SCBF (CO2 reactivity) were studied in the lumbar spinal cord of cats by means of the hydrogen-clearance technique. Hydrogen gas was administered by inhalation, and its level in spinal cord tissue was estimated amperometrically with small (75 µm) platinum electrodes. The average SCBF's at normocapnia (ETCO2 = 4%) of the ventral horn gray matter and of the white matter at several locations were 43.2 and 16.2 ml·100 gm−1·min−1, respectively. For gray and white matter, the values of CO2 reactivity, estimated by the coefficient of the regression of SCBF (ml·100 gm−1·min−1) on ETCO2 (ml·100 ml−1) were 11.6 and 2.1, respectively. No differences in SCBF or CO2 reactivity were observed between intact animals kept under N2O-O2 ventilation and decerebrated animals with no anesthesia. After an acute spinal section, ventral horn SCBF and CO2 reactivity (measured eight segments below the cordotomy) were not altered, in spite of the profound neural depression present (that is, spinal shock). Orthodromic (dorsal root) stimulation of the ventral horn neurons induced an average increase in blood flow of 128% above control values. Antidromic (ventral root) motoneuron activation failed to produce any significant changes in ventral horn blood flow.

Lactate and pyruvate metabolism in injured cat spinal cord before and after a single large intravenous dose of methylprednisolone

1983 ◽  
Vol 59 (2) ◽  
pp. 256-261 ◽  
Author(s):  
J. Mark Braughler ◽  
Edward D. Hall
Keyword(s):  
Spinal Cord ◽  
Blood Flow ◽  
Sodium Succinate ◽  
Pyruvate Metabolism ◽  
Early Therapy ◽  
Content Type ◽  
Methylprednisolone Sodium Succinate ◽  
Before And After ◽  
Lactate And Pyruvate ◽  
Lactate Levels

✓ The lactate content and the lactate/pyruvate ratio of the acutely traumatized cat spinal cord have been studied and were found to rise rapidly following a 400 gm-cm injury. Lactate levels rose nearly twofold within 5 minutes after injury, peaked at 2 hours after injury, and remained significantly elevated for at least 8 hours compared to an adjacent uninjured segment of traumatized cord. Pyruvate levels, on the other hand, fell acutely in the injured section of cord during the 1st hour after injury then rose slowly over an 8-hour period. The changes in tissue lactate and pyruvate metabolism in the spinal cord following injury are consistent with a marked injury-induced reduction in blood flow. The elevation in lactate and the fall in pyruvate levels observed at 1 hour after injury were completely prevented by the intravenous administration of a single 30-mg/kg dose of methylprednisolone sodium succinate at 30 minutes after injury. Lower or higher doses of methylprednisolone were far less effective. The effects of the 30-mg/kg dose of methylprednisolone on tissue lactate content were associated with high tissue levels of the glucocorticoid and were short-lived, paralleling the accumulation and elimination pattern of steroid from the injured tissue. The results suggest that, in addition to other reported beneficial actions of large intravenous doses (30 mg/kg) of methylprednisolone on the injured cord, the glucocorticoid may also improve blood flow to the injured segment as has been suggested by others. The use of high glucocorticoid doses, early therapy initiation, and rigorous maintenance dosing is discussed.

Effect of mexiletine on lipid peroxidation and early ultrastructural findings in experimental spinal cord injury

1999 ◽  
Vol 91 (2) ◽  
pp. 200-204 ◽  
Author(s):  
Erkan Kaptanoglu ◽  
Hakan H. Caner ◽  
H. Selçuk Sürücü ◽  
Filiz Akbiyik
Keyword(s):  
Spinal Cord ◽  
Lipid Peroxidation ◽  
Spinal Cord Injury ◽  
Sodium Succinate ◽  
Content Type ◽  
Methylprednisolone Sodium Succinate ◽  
Cord Injury ◽  
Group 3 ◽  
Ultrastructural Findings ◽  
Fine Print

Object. The purpose of this study was to investigate the effect of mexiletine on lipid peroxidation and on ultrastructural findings after induced spinal cord injury (SCI). The authors also compared the activity of mexiletine to that of the well-known antioxidant, methylprednisolone sodium succinate (MPSS). Methods. Wistar rats were divided into seven groups, (Groups 1–7). Those in Groups 1 and 2 were control animals that underwent laminectomy only, after which nontraumatized spinal cord samples were obtained immediately (Group 1) and 2 hours postsurgery (Group 2). Spinal cord injury was induced in all other groups, and cord samples were obtained at 2 hours postsurgery. The rats in Group 3 underwent SCI alone; those in Group 4 received 30 mg/kg of MPSS intraperitoneally immediately after trauma was induced; and those in Groups 5, 6, and 7 received 1, 10, and 50 mg/kg of mexiletine, respectively, by intraperitoneal injection immediately after trauma was induced. Compared with the levels in control animals, lipid peroxidation was significantly elevated in rats in Groups 3 and 5, but there were no statistical differences among those in Groups 1, 2, 4, 6 and 7 in this regard. Compared with the findings in rats in Group 3, ultrastructural damage post-SCI was minor in rats in Groups 4 and 5, and there was even less damage evident in rats in Group 7. Conclusions. Analysis of these findings showed that administration of 50 mg/kg mexiletine significantly decreased the level of lipid peroxidation and protected spinal cord ultrastructure following SCI.

Correlation of methylprednisolone levels in cat spinal cord with its effects on (Na+ + K+)-ATPase, lipid peroxidation, and alpha motor neuron function

1982 ◽  
Vol 56 (6) ◽  
pp. 838-844 ◽  
Author(s):  
J. Mark Braughler ◽  
Edward D. Hall
Keyword(s):  
Spinal Cord ◽  
Motor Neuron ◽  
Sodium Succinate ◽  
Lipid Peroxide ◽  
High Dose ◽  
Spinal Cord Tissue ◽  
Content Type ◽  
Beneficial Effects ◽  
Therapeutic Value ◽  
Cord Injury

✓ Large intravenous doses of methylprednisolone sodium succinate are associated with biochemical and electrophysiological effects in the cat spinal cord which may be of therapeutic value in the treatment of spinal cord injury. The potentially beneficial effects of large doses of the glucocorticoid include: 1) an enhancement of spinal cord (Na+ + K+)-ATPase activity; 2) an attenuation of lipid peroxide formation; 3) a hyperpolarization of motor neuron resting membrane potentials; and 4) an accelerated impulse conduction along the myelinated portion of the motor axon. Each of these is apparent with spinal cord tissue levels of methylprednisolone around 1.3 µg/gm wet weight, which are rapidly obtained following a single intravenous dose of 30 mg/kg. The half-life of methylprednisolone in cat spinal cord following a single intravenous administration, as well as the duration of its pharmacological actions, is roughly 3 hours. The data suggest that, in order to be of therapeutic value in the treatment of acute spinal cord trauma, early intervention with high-dose intravenous methylprednisolone (30 to 40 mg/kg) is necessary, followed by intravenous maintenance dosing of 15 to 20 mg/kg every 2 to 3 hours. The rationale and duration for this regimen are discussed.

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