Spinal cord injury (SCI) is an incapacitating condition that affects motor, sensory, and autonomic functions. Since 1990, the only treatment administered in the acute phase of SCI has been methylprednisolone (MP), a synthetic corticosteroid that has anti-inflammatory effects; however, its efficacy remains controversial. Although MP has been thought to help in the resolution of edema, there are no scientific grounds to support this assertion. Aquaporin 4 (AQP4), the most abundant component of water channels in the CNS, participates in the formation and elimination of edema, but it is not clear whether the modulation of AQP4 expression by MP plays any role in the physiopathology of SCI. We studied the functional expression of AQP4 modulated by MP following SCI in an experimental model in rats along with the associated changes in the permeability of the blood-spinal cord barrier. We analyzed these effects in male and female rats and found that SCI increased AQP4 expression in the spinal cord white matter and that MP diminished such increase to baseline levels. Moreover, MP increased the extravasation of plasma components after SCI and enhanced tissue swelling and edema. Our results lend scientific support to the increasing motion to avoid MP treatment after SCI.

Study design: Experimental laboratory investigations in paraplegic rats. Objective: In order to understand why acute spinal cord injury (SCI) changes the disposition of some, but not all drugs given intravenously (i.v.), pharmacokinetic parameters of drugs with different pharmacological properties were evaluated to determine the influence of SCI on physiological processes such as distribution, metabolism and excretion. Setting: Mexico City, Mexico. Methods: Rats were subjected to severe SCI (contusion) at T-9 level; pharmacokinetic studies of phenacetin, naproxen or gentamicin were performed 24 h after. These drugs were not chosen as markers because of their therapeutic properties, but because of their pharmacokinetic characteristics. Additional studies including plasma proteins, liver and renal function tests, and micro-vascular hepatic blood flow, were also performed at the same time after injury. Results: Acute SCI significantly reduced distribution of drugs with intermediate and low binding to plasma proteins (phenacetin 30% and gentamicin 10%, respectively), but distribution did not change when naproxen -a drug highly bound to plasma proteins (99%) -was used, in absence of changes in plasma proteins. Metabolism was significantly altered only for a drug with liver blood flow -limited clearance (phenacetin) and not for a drug with liver capacity-limited clearance (naproxen). The liver function test did not change, whereas the hepatic micro-vascular blood flow significantly decreased after SCI. Renal excretion, evaluated by gentamicin clearance, was significantly reduced as a consequence of SCI, without significant changes in serum creatinine. Conclusions: Changes in drug disposition associated to acute SCI are complex and generalization is not possible. They are highly dependent on each drug properties as well as on the altered physiological processes. Results motivate the quest for strategies to improve disposition of selective i.v. drugs during spinal shock, in an effort to avoid therapeutic failure.

Spinal cord injury (SCI) produces multiple systemic and metabolic alterations. Although some systemic alterations could be associated with ischemic organ damage, little is known about microvascular blood flow (MVBF) in organs other than the spinal cord after acute SCI. We used laser Doppler flowmetry in anesthetized rats to assess MVBF in several tissues before and after complete T-2 and T-9 SCI at 1 h and on days 1, 3, and 7 post-SCI. Mean arterial blood pressure (MAP), heart rate and hematologic variables also were recorded. MAP changes after T-2 injury were not significant, while MAP decreased significantly 1 h after T-9 injury. Statistically significant bradycardia occurred after T-2 injury at 7 days; statistically significant tachycardia occurred after T-9 injury at 1, 3, and 7 days. Hematocrit significantly increased at day 1 and decreased at days 3 and 7 after T-2 injury. SCI was associated with significant decreases in MVBF in liver, spleen, muscle and fore footpad skin. Changes in MVBF in hind footpad skin and kidney were not significant. Changes were more pronounced at 1 h and 1 day post-SCI. Significant differences between MVBF after T-2 and T-9 SCI occurred only in liver. MVBF significantly correlated with regional peripheral vascular resistances (assessed using the MAP/MVBF ratio), but not with MAP. In conclusion, organ-specific changes in systemic MVBF that are influenced by the level of SCI, could contribute to organ dysfunction.

Spinal cord injury (SCI) produces multiple systemic and metabolic alterations. Although some systemic alterations could be associated with ischemic organ damage, little is known about microvascular blood flow (MVBF) in organs other than the spinal cord after acute SCI. We used laser Doppler flowmetry in anesthetized rats to assess MVBF in several tissues before and after complete T-2 and T-9 SCI at 1 h and on days 1, 3, and 7 post-SCI. Mean arterial blood pressure (MAP), heart rate and hematologic variables also were recorded. MAP changes after T-2 injury were not significant, while MAP decreased significantly 1 h after T-9 injury. Statistically significant bradycardia occurred after T-2 injury at 7 days; statistically significant tachycardia occurred after T-9 injury at 1, 3, and 7 days. Hematocrit significantly increased at day 1 and decreased at days 3 and 7 after T-2 injury. SCI was associated with significant decreases in MVBF in liver, spleen, muscle and fore footpad skin. Changes in MVBF in hind footpad skin and kidney were not significant. Changes were more pronounced at 1 h and 1 day post-SCI. Significant differences between MVBF after T-2 and T-9 SCI occurred only in liver. MVBF significantly correlated with regional peripheral vascular resistances (assessed using the MAP/MVBF ratio), but not with MAP. In conclusion, organ-specific changes in systemic MVBF that are influenced by the level of SCI, could contribute to organ dysfunction.

Spontaneous repair or treatment-induced recovery after spinal cord injury (SCI) is very limited and might be related to extramedullary alterations that have only briefly been documented. Here we report on the morphological changes of the spinal subarachnoid space (SAS) in a clinically relevant model of SCI. Anesthetized rats were subjected either to mild or severe spinal cord contusion at T9. Spine blocks from the site of injury and adjacent segments were harvested at acute (1 h and 1 day [d]), subacute (3 and 7 d), and chronic (1 and 3 months) stages post-injury. Histopathology and morphometry at each decalcified vertebral level were assessed. At acute and subacute stages, reduction of SAS lumen was observed after both mild and severe injuries. Acutely, after severe injuries, SAS occlusion was associated mainly with cord swelling and subarachnoid hematomas; a trend for dural sac constriction was observed for mild injuries. At 7 d, cord swelling diminished in both instances, but dural sac constriction increased for severe injuries. At early stages, in the epicenter and vicinity, histopathology revealed compression of neurovascular elements within the SAS, which was more intense in severe than in mild injuries. In the chronic stage, SAS lumen increased notably, mostly from cord atrophy, despite dural sac constriction. Myelograms complemented observations made on SAS lumen permeability. Post-traumatic arachnoiditis occurred mainly in animals with severe injury. In conclusion, early extramedullary SAS changes described here might be expected to produce alterations in cerebrospinal fluid (CSF) dynamics and cord blood perfusion, thereby contributing to the pathophysiology of SCI and becoming novel targets for treatment.