In patients with spinal cord injury, the primary or mechanical trauma seldom causes total transection, even though the functional loss may be complete. In addition, biochemical and pathological changes in the cord may worsen after injury. To explain these phenomena, the concept of the secondary injury has evolved for which numerous pathophysiological mechanisms have been postulated. This paper reviews the concept of secondary injury with special emphasis on vascular mechanisms. Evidence is presented to support the theory of secondary injury and the hypothesis that a key mechanism is posttraumatic ischemia with resultant infarction of the spinal cord. Evidence for the role of vascular mechanisms has been obtained from a variety of models of acute spinal cord injury in several species. Many different angiographic methods have been used for assessing microcirculation of the cord and for measuring spinal cord blood flow after trauma. With these techniques, the major systemic and local vascular effects of acute spinal cord injury have been identified and implicated in the etiology of secondary injury. The systemic effects of acute spinal cord injury include hypotension and reduced cardiac output. The local effects include loss of autoregulation in the injured segment of the spinal cord and a marked reduction of the microcirculation in both gray and white matter, especially in hemorrhagic regions and in adjacent zones. The microcirculatory loss extends for a considerable distance proximal and distal to the site of injury. Many studies have shown a dose-dependent reduction of spinal cord blood flow varying with the severity of injury, and a reduction of spinal cord blood flow which worsens with time after injury. The functional deficits due to acute spinal cord injury have been measured electrophysiologically with techniques such as motor and somatosensory evoked potentials and have been found proportional to the degree of posttraumatic ischemia. The histological effects include early hemorrhagic necrosis leading to major infarction at the injury site. These posttraumatic vascular effects can be treated. Systemic normotension can be restored with volume expansion or vasopressors, and spinal cord blood flow can be improved with dopamine, steroids, nimodipine, or volume expansion. The combination of nimodipine and volume expansion improves posttraumatic spinal cord blood flow and spinal cord function measured by evoked potentials. These results provide strong evidence that posttraumatic ischemia is an important secondary mechanism of injury, and that it can be counteracted.

Review of the secondary injury theory of acute spinal cord trauma with emphasis on vascular mechanisms

Spinal cord injury occurs through various countries throughout the world with an annual incidence of 15 to 40 cases per million, with the causes of these injuries ranging from motor vehicle accidents and community violence to recreational activities and workplace-related injuries. Survival has improved along with a greater appreciation of patterns of presentation, survival, and complications. Despite much work having been done, the only treatment to date known to ameliorate neurologic dysfunction that occurs at or below the level of neurologic injury has been intravenous methylprednisolone therapy. Much research over the past 30 to 40 years has focused on elucidating the mechanisms of spinal cord injury, with the complex pathophysiologic processes slowly being unraveled. With a greater understanding of both primary and secondary mechanisms of injury, the roles of calcium, free radicals, sodium, excitatory amino acids, vascular mediators, and apoptosis have been elucidated. This review examines the epidemiology, demographics, and pathophysiology of acute spinal cord injury.

Epidemiology, demographics, and pathophysiology of acute spinal cord injury.

The distribution of microglia, macrophages, T-lymphocytes, and astrocytes was characterized throughout a spinal contusion lesion in Sprague-Dawley and Lewis rats by using immunohistochemistry. The morphology, spatial localization, and activation state of these inflammatory cells were described both qualitatively and quantitatively at 12 hours, 3, 7, 14, and 28 days after injury. By use of OX42 and ED1 antibodies, peak microglial activation was observed within the lesion epicenter of both rat strains between three and seven days post-injury preceding the bulk of monocyte influx and macrophage activation (seven days). Rostral and caudal to the injury site, microglial activation plateaued between two and four weeks post-injury in the dorsal and lateral funiculi as indicated by morphological transformation and the de-novo expression of major histocompatibility class II (MHC II) molecules. Similar to the timing of microglial reactions, T-lymphocytes maximally infiltrated the lesion epicenter between three and seven days post-injury. Reactive astrocytes, while present in the acute lesion, were more prominent at later survival times (7–28 days). These cells were interspersed with activated microglia but appeared to surround and enclose tissue sites occupied by reactive microglia and phagocytic macrophages. Thus, trauma-induced central nervous system (CNS) inflammation, regardless of strain, occurs rapidly at the site of injury and involves the activation of resident and recruited immune cells. In regions rostral or caudal to the epicenter, prolonged activation of inflammatory cells occurs preferentially in white matter and primarily consists of activated microglia and astrocytes.



Differences were observed in the magnitude and duration of macrophage activation between Sprague-Dawley (SD) and Lewis (LEW) rats throughout the lesion. Increased expression of complement type 3 receptors (OX42) and macrophage-activation antigens (ED1) persisted for longer times in LEW rats while expression of MHC class II molecules was attenuated in LEW compared to SD rats at all times examined. Variations in the onset and duration of T-lymphocyte infiltration also were observed between strains with twice as many T-cells present in the lesion epicenter of Lewis rats by 3 days post-injury. These strain-specific findings potentially represent differences in corticosteroid regulation of immunity and may help predict a range of functional neurologic consequences affected by neuroimmune interactions. J. Comp. Neurol. 377:443–464, 1997. © 1997 Wiley-Liss, Inc.

Cellular inflammatory response after spinal cord injury in Sprague-Dawley and Lewis rats.

http://www.student.oulu.fi/~taneliha/15min_Vertailevan_Endokrinologian_opiskelijaesitelma_Endokannabinoidit/Suurin%20osa%20k%E4ytetyist%E4%20artikkeleista/Cannabinoid%20physiology%20and%20pharmacology%2030%20years%20of%20progress.pdf

Cannabinoid physiology and pharmacology: 30 years of progress

I. Introduction: The Adrenal Functional Unit II. Interaction Between Adrenal Medulla and Adrenal Cortex A. Relationship between medullary and cortical cells B. Paracrine control of adrenocortical function by the adrenal medulla C. Gap junctions in the adrenal cortex D. Summary III. Innervation of the Adrenal Cortex A. Evidence for a nerve supply to the adrenal cortex B. The source of adrenocortical innervation C. Regulation of adrenocortical innervation D. Role of the splanchnic nerve in regulating adrenocortical neural function E. Influence of adrenal innervation on adrenocortical function F. Effects of neurotransmitter substances on adrenocortical function G. Summary IV. The Vascular System of the Adrenal Gland A. Regulation of blood flow B. Relationship between blood flow and steroid secretion C. Effects of vascular endothelial cell products on steroid secretion D. Summary V. The Intraadrenal CRH/ACTH System A. Extrapituitary effect of CRH B. Intraadrenal ACTH C. Intraadrenal CRH and CRH receptors D. F...

Intraadrenal Interactions in the Regulation of Adrenocortical Steroidogenesis

✓ The authors used indicator fractionation techniques to determine blood flow in normal and bluntly traumatized spinal cords of Macaca rhesus monkeys. Normal flow rates were determined for several levels of spinal cord as well as differential values for white and gray matter from representative areas. Flow rates in traumatized tissue, obtained at several different time intervals up to 4 hours after injury, demonstrated marked differences in regional perfusion of the white matter and gray matter after trauma. Gray matter perfusion was nearly obliterated while white matter blood flow persisted and in fact was higher than uninjured controls. The findings do not support the concept of ischemia as a factor in white matter failure. If toxic pathobiochemical alterations are induced by trauma, it may be possible to reverse these changes by exploiting the preserved white matter blood flow for chemotherapeutic intervention.

Blood flow in normal and injured monkey spinal cord.

Although duration of unconsciousness is commonly used as a prognostic index following traumatic brain injury (TBI), few controlled studies have statistically evaluated the relationship between unconsciousness and histologic pathology, particularly after moderate head injury. Using a pendulum-striker concussive device, a reproducible model of TBI in rats was developed. This model is uncomplicated by skull fractures, contusions, or experimenter-induced craniotomies. In the present study, the severity of the histopathology observed in this model of moderate closed-head injury at 48 h posttrauma is linearly related to the duration of unconsciousness (p < 0.0001). The pathology, assessed with a silver stain for neurodegeneration, is particularly striking if unconsciousness persists for 4 minutes or more. These data suggest that the initial period of unconsciousness may be a useful predictor of clinical brain histopathology associated with moderate closed-head injury, predicting either the degree of pa...

Histopathologic Consequences of Moderate Concussion in an Animal Model: Correlations with Duration of Unconsciousness

The cardiac output fractionation technique employing Rb 86 or iodoantipyrine (I 131 ) has been applied to the study of adrenal blood flow in the rat. Either indicator is suitable for the measurement of adrenal blood flow: this is indicated by constancy of label uptake during the first 30 seconds after its administration in a single intravenous injection; when given together the same fraction of each indicator is taken up by the gland. The adrenal flow fraction is 0.14% of the cardiac output in 200–275-gm female rats, corresponding to a flow of 0.078 ml/min. or 1.9 ml/gm/min. The value is increased 114% by ACTH. Ligation of one common carotid artery increases the value 80%. Laparotomy and dissection around the adrenal gland produce irregular changes in adrenal blood flow. The significance of these findings for the ‘normal’ adrenal blood flow is discussed.

Adrenal blood flow in the albino rat.

NUMEROUS cytological and histochemical observations indicate a secretory function for the pineal body of higher vertebrates1,2. Physiologically also, the pineal body of the rat satisfies most of the criteria for an endocrine organ3–5. Although anatomical evidence suggests that rat and mouse pineal vascularity is less than in some classical endocrine organs6,7, in view of the relatively high blood flow rate to endocrine structures in general8, it is reasonable to expect the pineal to be similarly well perfused. We have found that the minimum rate of rat pineal blood flow per g exceeds that of most endocrine organs, equals that of the neurohypophysis and is surpassed only by that of the kidney.

Harold Goldman

Papers

Blood flow in normal and injured monkey spinal cord.

Histopathologic Consequences of Moderate Concussion in an Animal Model: Correlations with Duration of Unconsciousness

Adrenal blood flow in the albino rat.

Flow of Blood to the Pineal Body of the Rat

The Effects of MSH and MIF on the Brain