Protocatechuic acid improves functional recovery after spinal cord injury by attenuating blood-spinal cord barrier disruption and hemorrhage in rats.

After spinal cord injury (SCI), blood-spinal cord barrier (BSCB) disruption and hemorrhage lead to blood cell infiltration and progressive secondary injuries including inflammation. Inflammatory response is one of the major events resulting in apoptosis, scar formation and neuronal dysfunction after SCI. Here, we investigated whether protocatechuic acid (PCA), a natural phenolic compound, would attenuate BSCB disruption and hemorrhage, leading to functional improvement after SCI. After a moderate contusion injury at T9, PCA (50 mg/kg) was administrated via intraperitoneal injection immediately, 6 h, and 12 h after SCI, and the same dose of PCA once a day until 7 d after injury. Our data show that PCA inhibited apoptotic cell death of neurons and oligodendrocytes and improved functional recovery after injury. PCA also attenuated BSCB disruption and hemorrhage and reduced the infiltration of neutrophils and macrophages compared to vehicle control. Moreover, PCA inhibited the expression and activation of matrix metalloprotease-9, which is well known to disrupt BSCB after SCI. Furthermore, PCA treatment significantly inhibited the expression of sulfonylurea receptor 1 and transient receptor potential melastatin 4, which are known to mediate hemorrhage at an early stage after SCI. Consistent with these findings, the mRNA and protein expression of inflammatory mediators such as tumor necrosis factor alpha, interleukin 1 beta, cyclooxygenase-2, inducible nitric oxide synthase, and chemokines was significantly alleviated by PCA treatment. Thus, our results suggest that PCA improved functional recovery after SCI in part by inhibiting BSCB disruption and hemorrhage through the down-regulation of sulfonylurea receptor 1/transient receptor potential melastatin 4 and matrix metalloprotease-9.

Engaging pain fibers after a spinal cord injury fosters hemorrhage and expands the area of secondary injury.

In humans, spinal cord injury (SCI) is often accompanied by additional tissue damage (polytrauma) that can engage pain (nociceptive) fibers. Prior work has shown that this nociceptive input can expand the area of tissue damage (secondary injury), undermine behavioral recovery, and enhance the development of chronic pain. Here, it is shown that nociceptive input given a day after a lower thoracic contusion injury in rats enhances the infiltration of red blood cells at the site of injury, producing an area of hemorrhage that expands secondary injury. Peripheral nociceptive fibers were engaged 24 h after injury by means of electrical stimulation (shock) applied at an intensity that engages unmyelinated pain (C) fibers or through the application of the irritant capsaicin. Convergent western immunoblot and cyanmethemoglobin colorimetric assays showed that both forms of stimulation increased the concentration of hemoglobin at the site of injury, with a robust effect observed 3-24 h after stimulation. Histopathology confirmed that shock treatment increased the area of hemorrhage and the infiltration of red blood cells. SCI can lead to hemorrhage by engaging the sulfonylurea receptor 1 (SUR1) transient receptor potential melastatin 4 (TRPM4) channel complex in neurovascular endothelial cells, which leads to cell death and capillary fragmentation. Histopathology confirmed that areas of hemorrhage showed capillary fragmentation. Co-immunoprecipitation of the SUR1-TRPM4 complex showed that it was up-regulated by noxious stimulation. Shock-induced hemorrhage was associated with an acute disruption in locomotor performance. These results imply that noxious stimulation impairs long-term recovery because it amplifies the breakdown of the blood spinal cord barrier (BSCB) and the infiltration of red blood cells, which expands the area of secondary injury.

XXXIII Reunión de la Sociedad Valenciana de Neurología. Comunicaciones: Valencia 19-20 de febrero de 2016 / No disponible

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