JOURNAL OF NEUROTRAUMA Volume 7, Number 3, 1990 Mary Ann Liebert, Inc., Publishers
Commentary
Methylprednisolone in Spinal Cord Injury: The Possible Mechanism of Action CHUNG Y. HSU and MILAN R. DIMITRIJEVIC of
methylprednisolone and naloxone, the Second National Spinal Cord Injury Study (NASCIS II), have Results been published (Bracken al., of this is manifold: it in well-coordinated multiof the multiCenter clinical trial
now
et
1990). The significance study (1) demonstrates, a center, double-blind, and placebo-controlled trial, that acute CNS injury in humans is treatable if an appropriate therapeutic agent is administered within a therapeutic window, (2) it supports the earlier hypothesis that a secondary injury process triggered by the initial trauma may contribute to the ultimate tissue damage and neurological deficit (Balentine, 1985; Young, 1985, 1988), (3) it reaffirms that therapeutic efficacy in animal models can be extended to patients and thus diminishes the pessimism expressed in recent editorials (Molinari, 1988; Wiebers et al., 1990) and legitimizes therapeutic trials in animal models, a research directive that has relatively low regard among NINDS peer review panels, and (4) it illustrates that selection of dosage for human trials based on results from animal studies is important (Means et al., 1981; Young and Flamm, 1982; Anderson et al., 1982, 1985; Braughler and Hall, 1982, 1984; Hall et al., 1984; Braughler et al, 1987a). An important issue, which was not and could not be addressed in this multicenter clinical trial, is the mechanism of action of methylprednisolone in spinal cord injury. It was discussed briefly in the NASCIS II article (Bracken et al., 1990) but was not elaborated on in the accompanying editorial (Ducker, 1990). The remainder of this commentary is devoted to this subject. Because of the high dose of methylprednisolone used in this study, Bracken et al. (1990) suggested that "methylprednisolone may act through mechanisms unrelated to corticosteroid receptors." They stated that the most likely mechanism is inhibition of lipid peroxidation. This hypothesis is attractive and supported by the recent demonstration of the beneficial effect of 21-aminosteroids, which are potent inhibitors of lipid peroxidation (Braughler et al., 1987b) in experimental spinal cord injury (Anderson et al., 1988). The lack of glucocorticoid effects among the 21-aminosteroids argues for the possible protective effect of methylprednisolone that may not be relevant to its glucocorticoid actions. However, recent studies in experimental spinal cord make it difficult to discard the role of glucocorti-
coid effect in the NASCIS II results. Methylprednisolone, like other glucocorticoids, is prescribed by clinicians for a variety of diseases. Indications as listed in the USP Drug Information fall into three major categories (U.S. Pharmacopeia Convention, 1990): (1) replacement therapy for adrenal insufficiency, (2) immunosuppression in certain autoimmune disorders, and (3) inhibition of inflammatory processes. Glucocorticoids, including methylprednisolone, are among the most potent of anti-inflammatory agents. Inflammation is a complex hormonal and cellular response by the body to microbial, immunological, chemical, and physical insults (Gallin et al., 1988; Hsu et al., 1990). The cellular reactions of an Division of Restorative Texas.
Neurology and Human Neurobiology, Baylor College of Medicine, Houston, 115
HSU AND DIMITRIJEVIC infiltration of polymorphonuclear cells, deposition of platelets, and alteration of endothelial cell function, leading to increased vascular permeability and edema formation. Eicosanoids, free radicals, kinins, proteolytic enzymes, and other inflammatory mediators are released following tissue injury and the subsequent activation of inflammatory cells and interaction between inflammatory cells and endothelial cells (Lewis, 1986; Gallin et al., 1988; Hsu et al., 1990). Free radicals in the inflammatory process may be generated during conversion of arachidonic acid to eicosanoids and following the activation of inflammatory cells (Gallin et al., 1988; Hsu et al., 1990). The exact mechanism of the anti-inflammatory action of glucocorticoids has yet to be fully characterized. However, recent studies have shown that glucocorticoids suppress inflammatory processes through the inhibition of inflammatory cell functions, including chemotaxis (Espersen et al., 1989; Schleimer et al., 1989), phagocytosis (Becker and Grasso, 1985), synthesis of inflammatory mediators (DiRosa and Pérsico, 1979; Schleimer et al., 1989), and release of lysosomal enzymes (Schleimer et al., 1989). The anti-inflammatory effects of glucocorticoids are at least partly due to induction of macrocortin synthesis (Blackwell et al., 1980), leading to the inhibition of phospholipase A2 (Hirata et al., 1980), which catalyzes the release of arachidonic acid from membrane phospholipids and the subsequent formation of eicosanoids and free radicals (Williams and Higgs, 1988). These anti-inflammatory effects of glucocorticoids also contribute to the reduction of endothelial permeability and edema formation (Chan et al., 1983). Immunosuppressive effects of glucocorticoids also play a role in the anti-inflammatory action of glucocorticoids (U.S. Pharmacopeia Convention, 1990). The cardinal features of inflammation as described have been illustrated in the spinal cord after impact injury in animal models. Infiltration of inflammatory cells, including polymorphonuclear cells (Balentine, 1978; Means and Anderson, 1983; Xu et al., 1990) and platelets (Balentine, 1978; Goodman et al., 1979), has been demonstrated in the acute phase of experimental spinal cord injury. Increased vascular permeability (Griffiths and Miller, 1974; Stewart and Wagner, 1979; Hsu et al., 1985b), with subsequent development of vasogenic edema (Stewart, 1985), also has been well studied in animal models. The progressive nature of the changes in endothelial injury and increased vascular permeability (Griffiths and Miller, 1974; Stewart and Wagner, 1979; Hsu et al., 1985b), together with delayed hypoperfusion (Senter and Venes, 1978; Young, 1985), are consistent with the hypothesis of a secondary injury mechanism (Balentine, 1985; Young, 1985, 1988). Eicosanoids, including prostaglandins, thromboxane, and leukotrienes, are the major lipid inflammatory mediators (Williams and Higgs, 1988). Accumulation of these inflammatory mediators in experimental spinal cord injury has been documented extensively (Demediuk et al., 1985; Hsu et al., 1985a; Xu et al., 1990). The progressive degradation of cytoskeletal proteins, especially neurofilament proteins, in experimental spinal cord injury indicates the release of proteolytic enzymes (Banik et al., 1982; Braughler and Hall, 1984). The kallikrein-kinin system is another major biochemical cascade leading to the generation of chemical mediators in inflammation (Lewis, 1986). Kinins and their precursor, kininogen, accumulate progressively in the spinal cord following injury (Chao et al., 1988). The role of kinins in the posttraumatic process may include activation of phospholipases, leading to the release of arachidonic acid and the production of free radicals and eicosanoids (Kontos et al., 1984, 1985). Kininogen also has been implicated in the second phase vascular changes following experimental traumatic head injury (Ellis et al., 1989). acute inflammation consist of the
DISCUSSION The prominence of inflammatory processes in experimental spinal cord injury suggests that the potent anti-inflammatory actions of methylprednisolone cannot be ignored as one additional mechanism of action. The potential benefit of 21-aminosteroids in spinal cord injury has been described previously. Whether 21-aminosteroids are broad-spectrum anti-inflammatory agents
116
MECHANISM OF MP IN SPINAL CORD INJURY that inhibit arachidonic acid metabolism and leukocyte function remains to be determined. In addition to inhibition of lipid peroxidation, the possible anti-inflammatory effect of methylprednisolone in spinal cord injury offers another perspective on the development of new therapeutic agents directed at inflammatory processes. To a large extent, tissue destruction and vascular injury in inflammation are caused by the release of inflammatory mediators and proteolytic enzymes from the inflammatory cells (Lewis, 1986; Gallin et al., 1988; Hsu et al., 1990). The future search for effective therapeutic regimens also should include attempts to block the actions of inflammatory cells and inflammatory mediators. Because of serious adverse effects, several potent anti-inflammatory regimens, including glucocorticoids, are not ideal for long-term administration in patients with chronic inflammatory disorders, such as rheumatoid arthritis. Since inflammatory reactions following trauma are restricted to a relatively short period of time, a more aggressive anti-inflammatory regimen over a short duration, such as high-dose methylprednisolone, is less likely to cause serious adverse reactions as shown in the NASCIS II study
(Bracken
et
al., 1990).
REFERENCES ANDERSON, D.K., BRAUGHLER, J.M., HALL, E.D., et al. (1988). Effects of treatment with U74006F on neurological recovery following experimental spinal cord injury. J. Neurosurg. 69, 562-567. ANDERSON, D.K., MEANS, E.D., WATERS, T.R., et al. (1982). Microvascular perfusion and metabolism in injured spinal cord after methylprednisolone treatment. J. Neurosurg. 56, 106-113. ANDERSON, D.K., SAUNDERS, R.D., DEMEDIUK, P., et al. (1985). Lipid hydrolysis and peroxidation in injured spinal cord: Partial protection with methylprednisolone or vitamin E and selenium. Cent. Nerv. System Trauma 2, 257-267. BALENTINE, J.D. (1978). Pathology of experimental spinal cord trauma. Lab. Invest. 39, 254-266. BALENTINE, J.D. (1985). Hypotheses in spinal cord trauma research, in: Central Nervous System Trauma Status Report. D.P. Becker and J.T. Povlishock (eds). National Institutes of Health: Bethesda, MD, pp. 455-461.
BANIK, N.L., HOGAN, E.L., POWERS, J.M., et al. (1982). Degradation of neurofilament proteins in spinal cord injury. Neurochem. Res. 7, 1465-1475. BECKER, J., and GRASSO, R.J. (1985). Suppression of phagocytosis by dexamethasone in macrophage cultures: Inability of arachidonic acid, indomethacin, and nordihydroguaiaretic acid to reverse the inhibitory response mediated by a steroid-inducible factor. Int. J. Immunopharmacol. 7, 839-847. BLACKWELL, G.J., CARNUCCIO, R., DiROSA, M., et al. (1980). Macrocortin: A polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature (Lond.) 287, 147-149. BRACKEN, M.B., SHEPARD, M.J., COLLINS, W.F., et al. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N. Engl. J. Med. 322, •
1405-1411.
BRAUGHLER, J.M., and HALL, E.D. (1982). Correlation of methylprednisolone levels in cat spinal cord with its effects on (Na2+ K+)-ATPase, lipid peroxidation, and alpha motor neuron function. J. Neurosurg. 56, 838-844. BRAUGHLER, J.M., and HALL, E.D. (1984). Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal cord neurofilament degration and energy metabolism. J. Neurosurg. 61, 290-295. BRAUGHLER, J.M., HALL, E.D., MEANS, E.D., et al. (1987a). Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury. J. Neurosurg. 67, 102-105. BRAUGHLER, J.M., PREGENZER, J.F., CHASE, R.L., et al (1987b). Novel 21-amino substituted steroids as potent inhibitors of iron-dependent lipid peroxidation. J. Biol. Chem. 262, 10438-10440. CHAN, P.H., FISHMAN, R.A., CARONNA, J., et al. (1983). Induction of brain edema following intracerebral injection of arachidonic acid. Ann. Neurol. 13, 625-632. 117
HSU AND DIMITRIJEVIC CHAO, J., XU, J., HSU, C.Y., et al. (1988). Kininogen and kinins in experimental spinal cord injury. FASEB J. 2, A1145. DEMEDIUK, P., SAUNDERS, R.D., ANDERSON, D.K., et al. (1985). Membrane lipid changes in laminectomized and traumatized cat spinal cord. Proc. Nati Acad. Sei. USA 82, 7071-7075. DiROSA, M., and PÉRSICO, P. (1979). Mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leukocytes. Br. J. Pharmacol. 66, 161-163. DUCKER, T.B. (1990). Treatment of spinal-cord injury. New Engl. J. Med. 322, 1459-1461. ELLIS, E.F., CHAO, J., and HEIZER, M.L. (1989). Brain kininogen following experimental brain injury: Evidence for a secondary event. J. Neurosurg. 71, 437-442. ESPERSEN, G.T., ERNST, E., VESTERGAARD, M., et al. (1989). Changes in PMN leukocyte migration activity and complement C3d levels in RA patients with high disease activity during steroid treatment. Scand. J. Rheumatol. 18, 51-56. GALLIN, J.I., GOLDSTEIN, I.M., and SNYDERMAN, R. (1988). Inflammation: Basic Principles and Clinical Correlates. Raven Press: New York.
GOODMAN, J.G., BINGHAM, W.G., and HUNT, W.E. (1979). Platelet aggregation in experimental spinal cord injury. Arch. Neurol. 30, 197-201. GRIFFITHS, I.R., and MILLER, R. (1974). Vascular permeability to protein and vasogenic oedema in experimental concussive injuries to the canine spinal cord. J. Neurol. Sei. 22, 291-304. HALL, E.D., WOLF, D.L., and BRAUGHLER, J.M. (1984). Effects of a single large dose of methylprednisolone sodium succinate on posttraumatic spinal cord ischemia: Dose-response and time-action analysis. J. Neurosurg. 61, 124-130. HIRATA, F., SCHIFFMAN, E., SUBRAMANIAN, V., et al. (1980). A phospholipase A2 inhibitory protein in rabbit neutrophils induced by glucocorticoids. Proc. Nati Acad. Sei. USA 77, 2533-2536. HSU, C.Y., HALUSHKA, P.V., HOGAN, E.L., et al. (1985a). Alteration of thromboxane and prostacycline levels in experimental spinal cord injury. Neurology 35, 1003-1009. HSU, C.Y., HOGAN, E.L., GADSDEN, R.H. Sr., et al. (1985b). Vascular permeability in experimental spinal cord injury. J. Neurol. Sei. 70, 275-282. HSU, C.Y., LIU, T.H., HOGAN, E.L., et al. (1990). Lipid inflammatory mediators in ischémie brain edema and injury; in: New Trends in Lipid Mediators. N.G. Bazan (ed). Karger: Basel, Vol. 4, 85-112. KONTOS, H.A., WEI, E.P., ELLIS, E.F., et al. (1985). Appearance of Superoxide anión radical in cerebral extracellular space during increased prostaglandin synthesis in cats. Circ. Res. 57, 142-151. KONTOS, H.A., WEI, E.P., POVLISHOCK, J.T., et al. (1984). Oxygen radicals mediate the cerebral arteriolar dilation from arachidonate and bradykinin in cats. Circ. Res. 55, 295-303. LEWIS, G.P. (1986). Mediators of Inflammation. Bristol: Wright. MEANS, E.D., and ANDERSON, D.K. (1983). Neuronophagia by leukocytes in experimental spinal cord injury. J. Neuropathol. Exp. Neurol. 42, 707-719. MEANS, E.D., ANDERSON, D.K., WATERS, T.R., et al. (1981). Effects of methylprednisolone in compression trauma to the feline spinal cord. J. Neurosurg. 55, 200-208. MOLINARI, G.F. (1988). Why model strokes? Stroke 19, 1195-1197. SCHLEIMER, R.P., FREELAND, H.S., PETERS, S.P., et al. (1989). An assessment of the effects of glucocorticoids on degranulation, chemotaxis, binding to vascular endothelium and formation of leukotriene B4 by purified human neutrophils. J. Pharmacol. Exp. Ther. 250, 598-605. SENTER, H.J., and VENES, J.L. (1978). Altered blood flow and secondary injury in experimental spinal cord trauma. J. Neurosurg. 49, 569-578. STEWART, W.B. (1985). Edema in spinal cord injury, in: Central Nervous System Trauma Status Report. D.P. Becker and J.T. Povlishock (eds). National Institutes of Health: Bethesda, MD, pp. 475-479. STEWART, W.B., and WAGNER, F.C. (1979). Vascular permeability changes in the contused feline spinal cord. Brain Res. 169, 163-167. 118
MECHANISM OF MP IN SPINAL CORD INJURY U.S. PHARMACOPEIA CONVENTION (1990). Adrenocorticoids/corticotropin, in: Drug Information for the Health Care Professional. U.S. Pharmacopeial Convention: Rockville, Maryland, Vol. 1A, pp. 87-119.
WIEBERS, D.O., ADAMS, H.P. Jr., and WHISNANT, J.P. (1990). Animal models of stroke: Are they relevant to human disease? Stroke 21, 1-3. WILLIAMS, K.I., and HIGGS, G.A. (1988). Eicosanoids and inflammation. J. Pathol. 156, 101-110. XU, J., HSU, C.Y., LIU, T.H., et al. (1990). Leukotriene B4 release and polymorphonuclear cell infiltration in spinal cord injury. J. Neurochem. Vol. 55, pp. 907-912. YOUNG, W. (1985). Blood flow, metabolic and neurophysiological mechanisms in spinal cord injury, in: Central Nervous System Trauma Status Report. D. Becker and J.T. Povlishock (eds). National Institutes of Health: Bethesda, MD, pp. 463-473 YOUNG, W. (1988). Secondary CNS injury. J. Neurotrauma 5, 219-221. YOUNG, W., and FLAMM, E.S. (1982). Effect of high-dose corticosteroid therapy on blood flow, evoked potentials, and extracellular calcium in experimental spinal injury. J. Neurosurg. 57, 667-673. Address reprint requests to: Chung Y. Hsu, M.D., Ph.D. Division of Restorative Neurology and Human Neurobiology
Baylor College of Medicine One Baylor Plaza, S815
Houston, TX 77030
119
Commentary
Methylprednisolone in Spinal Cord Injury: The Possible Mechanism of Action CHUNG Y. HSU and MILAN R. DIMITRIJEVIC of
methylprednisolone and naloxone, the Second National Spinal Cord Injury Study (NASCIS II), have Results been published (Bracken al., of this is manifold: it in well-coordinated multiof the multiCenter clinical trial
now
et
1990). The significance study (1) demonstrates, a center, double-blind, and placebo-controlled trial, that acute CNS injury in humans is treatable if an appropriate therapeutic agent is administered within a therapeutic window, (2) it supports the earlier hypothesis that a secondary injury process triggered by the initial trauma may contribute to the ultimate tissue damage and neurological deficit (Balentine, 1985; Young, 1985, 1988), (3) it reaffirms that therapeutic efficacy in animal models can be extended to patients and thus diminishes the pessimism expressed in recent editorials (Molinari, 1988; Wiebers et al., 1990) and legitimizes therapeutic trials in animal models, a research directive that has relatively low regard among NINDS peer review panels, and (4) it illustrates that selection of dosage for human trials based on results from animal studies is important (Means et al., 1981; Young and Flamm, 1982; Anderson et al., 1982, 1985; Braughler and Hall, 1982, 1984; Hall et al., 1984; Braughler et al, 1987a). An important issue, which was not and could not be addressed in this multicenter clinical trial, is the mechanism of action of methylprednisolone in spinal cord injury. It was discussed briefly in the NASCIS II article (Bracken et al., 1990) but was not elaborated on in the accompanying editorial (Ducker, 1990). The remainder of this commentary is devoted to this subject. Because of the high dose of methylprednisolone used in this study, Bracken et al. (1990) suggested that "methylprednisolone may act through mechanisms unrelated to corticosteroid receptors." They stated that the most likely mechanism is inhibition of lipid peroxidation. This hypothesis is attractive and supported by the recent demonstration of the beneficial effect of 21-aminosteroids, which are potent inhibitors of lipid peroxidation (Braughler et al., 1987b) in experimental spinal cord injury (Anderson et al., 1988). The lack of glucocorticoid effects among the 21-aminosteroids argues for the possible protective effect of methylprednisolone that may not be relevant to its glucocorticoid actions. However, recent studies in experimental spinal cord make it difficult to discard the role of glucocorti-
coid effect in the NASCIS II results. Methylprednisolone, like other glucocorticoids, is prescribed by clinicians for a variety of diseases. Indications as listed in the USP Drug Information fall into three major categories (U.S. Pharmacopeia Convention, 1990): (1) replacement therapy for adrenal insufficiency, (2) immunosuppression in certain autoimmune disorders, and (3) inhibition of inflammatory processes. Glucocorticoids, including methylprednisolone, are among the most potent of anti-inflammatory agents. Inflammation is a complex hormonal and cellular response by the body to microbial, immunological, chemical, and physical insults (Gallin et al., 1988; Hsu et al., 1990). The cellular reactions of an Division of Restorative Texas.
Neurology and Human Neurobiology, Baylor College of Medicine, Houston, 115
HSU AND DIMITRIJEVIC infiltration of polymorphonuclear cells, deposition of platelets, and alteration of endothelial cell function, leading to increased vascular permeability and edema formation. Eicosanoids, free radicals, kinins, proteolytic enzymes, and other inflammatory mediators are released following tissue injury and the subsequent activation of inflammatory cells and interaction between inflammatory cells and endothelial cells (Lewis, 1986; Gallin et al., 1988; Hsu et al., 1990). Free radicals in the inflammatory process may be generated during conversion of arachidonic acid to eicosanoids and following the activation of inflammatory cells (Gallin et al., 1988; Hsu et al., 1990). The exact mechanism of the anti-inflammatory action of glucocorticoids has yet to be fully characterized. However, recent studies have shown that glucocorticoids suppress inflammatory processes through the inhibition of inflammatory cell functions, including chemotaxis (Espersen et al., 1989; Schleimer et al., 1989), phagocytosis (Becker and Grasso, 1985), synthesis of inflammatory mediators (DiRosa and Pérsico, 1979; Schleimer et al., 1989), and release of lysosomal enzymes (Schleimer et al., 1989). The anti-inflammatory effects of glucocorticoids are at least partly due to induction of macrocortin synthesis (Blackwell et al., 1980), leading to the inhibition of phospholipase A2 (Hirata et al., 1980), which catalyzes the release of arachidonic acid from membrane phospholipids and the subsequent formation of eicosanoids and free radicals (Williams and Higgs, 1988). These anti-inflammatory effects of glucocorticoids also contribute to the reduction of endothelial permeability and edema formation (Chan et al., 1983). Immunosuppressive effects of glucocorticoids also play a role in the anti-inflammatory action of glucocorticoids (U.S. Pharmacopeia Convention, 1990). The cardinal features of inflammation as described have been illustrated in the spinal cord after impact injury in animal models. Infiltration of inflammatory cells, including polymorphonuclear cells (Balentine, 1978; Means and Anderson, 1983; Xu et al., 1990) and platelets (Balentine, 1978; Goodman et al., 1979), has been demonstrated in the acute phase of experimental spinal cord injury. Increased vascular permeability (Griffiths and Miller, 1974; Stewart and Wagner, 1979; Hsu et al., 1985b), with subsequent development of vasogenic edema (Stewart, 1985), also has been well studied in animal models. The progressive nature of the changes in endothelial injury and increased vascular permeability (Griffiths and Miller, 1974; Stewart and Wagner, 1979; Hsu et al., 1985b), together with delayed hypoperfusion (Senter and Venes, 1978; Young, 1985), are consistent with the hypothesis of a secondary injury mechanism (Balentine, 1985; Young, 1985, 1988). Eicosanoids, including prostaglandins, thromboxane, and leukotrienes, are the major lipid inflammatory mediators (Williams and Higgs, 1988). Accumulation of these inflammatory mediators in experimental spinal cord injury has been documented extensively (Demediuk et al., 1985; Hsu et al., 1985a; Xu et al., 1990). The progressive degradation of cytoskeletal proteins, especially neurofilament proteins, in experimental spinal cord injury indicates the release of proteolytic enzymes (Banik et al., 1982; Braughler and Hall, 1984). The kallikrein-kinin system is another major biochemical cascade leading to the generation of chemical mediators in inflammation (Lewis, 1986). Kinins and their precursor, kininogen, accumulate progressively in the spinal cord following injury (Chao et al., 1988). The role of kinins in the posttraumatic process may include activation of phospholipases, leading to the release of arachidonic acid and the production of free radicals and eicosanoids (Kontos et al., 1984, 1985). Kininogen also has been implicated in the second phase vascular changes following experimental traumatic head injury (Ellis et al., 1989). acute inflammation consist of the
DISCUSSION The prominence of inflammatory processes in experimental spinal cord injury suggests that the potent anti-inflammatory actions of methylprednisolone cannot be ignored as one additional mechanism of action. The potential benefit of 21-aminosteroids in spinal cord injury has been described previously. Whether 21-aminosteroids are broad-spectrum anti-inflammatory agents
116
MECHANISM OF MP IN SPINAL CORD INJURY that inhibit arachidonic acid metabolism and leukocyte function remains to be determined. In addition to inhibition of lipid peroxidation, the possible anti-inflammatory effect of methylprednisolone in spinal cord injury offers another perspective on the development of new therapeutic agents directed at inflammatory processes. To a large extent, tissue destruction and vascular injury in inflammation are caused by the release of inflammatory mediators and proteolytic enzymes from the inflammatory cells (Lewis, 1986; Gallin et al., 1988; Hsu et al., 1990). The future search for effective therapeutic regimens also should include attempts to block the actions of inflammatory cells and inflammatory mediators. Because of serious adverse effects, several potent anti-inflammatory regimens, including glucocorticoids, are not ideal for long-term administration in patients with chronic inflammatory disorders, such as rheumatoid arthritis. Since inflammatory reactions following trauma are restricted to a relatively short period of time, a more aggressive anti-inflammatory regimen over a short duration, such as high-dose methylprednisolone, is less likely to cause serious adverse reactions as shown in the NASCIS II study
(Bracken
et
al., 1990).
REFERENCES ANDERSON, D.K., BRAUGHLER, J.M., HALL, E.D., et al. (1988). Effects of treatment with U74006F on neurological recovery following experimental spinal cord injury. J. Neurosurg. 69, 562-567. ANDERSON, D.K., MEANS, E.D., WATERS, T.R., et al. (1982). Microvascular perfusion and metabolism in injured spinal cord after methylprednisolone treatment. J. Neurosurg. 56, 106-113. ANDERSON, D.K., SAUNDERS, R.D., DEMEDIUK, P., et al. (1985). Lipid hydrolysis and peroxidation in injured spinal cord: Partial protection with methylprednisolone or vitamin E and selenium. Cent. Nerv. System Trauma 2, 257-267. BALENTINE, J.D. (1978). Pathology of experimental spinal cord trauma. Lab. Invest. 39, 254-266. BALENTINE, J.D. (1985). Hypotheses in spinal cord trauma research, in: Central Nervous System Trauma Status Report. D.P. Becker and J.T. Povlishock (eds). National Institutes of Health: Bethesda, MD, pp. 455-461.
BANIK, N.L., HOGAN, E.L., POWERS, J.M., et al. (1982). Degradation of neurofilament proteins in spinal cord injury. Neurochem. Res. 7, 1465-1475. BECKER, J., and GRASSO, R.J. (1985). Suppression of phagocytosis by dexamethasone in macrophage cultures: Inability of arachidonic acid, indomethacin, and nordihydroguaiaretic acid to reverse the inhibitory response mediated by a steroid-inducible factor. Int. J. Immunopharmacol. 7, 839-847. BLACKWELL, G.J., CARNUCCIO, R., DiROSA, M., et al. (1980). Macrocortin: A polypeptide causing the anti-phospholipase effect of glucocorticoids. Nature (Lond.) 287, 147-149. BRACKEN, M.B., SHEPARD, M.J., COLLINS, W.F., et al. (1990). A randomized, controlled trial of methylprednisolone or naloxone in the treatment of acute spinal-cord injury. N. Engl. J. Med. 322, •
1405-1411.
BRAUGHLER, J.M., and HALL, E.D. (1982). Correlation of methylprednisolone levels in cat spinal cord with its effects on (Na2+ K+)-ATPase, lipid peroxidation, and alpha motor neuron function. J. Neurosurg. 56, 838-844. BRAUGHLER, J.M., and HALL, E.D. (1984). Effects of multi-dose methylprednisolone sodium succinate administration on injured cat spinal cord neurofilament degration and energy metabolism. J. Neurosurg. 61, 290-295. BRAUGHLER, J.M., HALL, E.D., MEANS, E.D., et al. (1987a). Evaluation of an intensive methylprednisolone sodium succinate dosing regimen in experimental spinal cord injury. J. Neurosurg. 67, 102-105. BRAUGHLER, J.M., PREGENZER, J.F., CHASE, R.L., et al (1987b). Novel 21-amino substituted steroids as potent inhibitors of iron-dependent lipid peroxidation. J. Biol. Chem. 262, 10438-10440. CHAN, P.H., FISHMAN, R.A., CARONNA, J., et al. (1983). Induction of brain edema following intracerebral injection of arachidonic acid. Ann. Neurol. 13, 625-632. 117
HSU AND DIMITRIJEVIC CHAO, J., XU, J., HSU, C.Y., et al. (1988). Kininogen and kinins in experimental spinal cord injury. FASEB J. 2, A1145. DEMEDIUK, P., SAUNDERS, R.D., ANDERSON, D.K., et al. (1985). Membrane lipid changes in laminectomized and traumatized cat spinal cord. Proc. Nati Acad. Sei. USA 82, 7071-7075. DiROSA, M., and PÉRSICO, P. (1979). Mechanism of inhibition of prostaglandin biosynthesis by hydrocortisone in rat leukocytes. Br. J. Pharmacol. 66, 161-163. DUCKER, T.B. (1990). Treatment of spinal-cord injury. New Engl. J. Med. 322, 1459-1461. ELLIS, E.F., CHAO, J., and HEIZER, M.L. (1989). Brain kininogen following experimental brain injury: Evidence for a secondary event. J. Neurosurg. 71, 437-442. ESPERSEN, G.T., ERNST, E., VESTERGAARD, M., et al. (1989). Changes in PMN leukocyte migration activity and complement C3d levels in RA patients with high disease activity during steroid treatment. Scand. J. Rheumatol. 18, 51-56. GALLIN, J.I., GOLDSTEIN, I.M., and SNYDERMAN, R. (1988). Inflammation: Basic Principles and Clinical Correlates. Raven Press: New York.
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