Research reportCombined treatment with αMSH and methylprednisolone fails to improve functional recovery after spinal injury in the rat
Introduction
In the pathophysiology of traumatic spinal cord injury (SCI), two mechanisms can be distinguished: the primary and the secondary damage 1, 11. The initial mechanical damage to the spinal cord, which includes both the kinetic impact to the cord and the persistent compression of the cord by shifted bone fragments, is referred to as the primary damage 14, 15. This initiates a cascade of events, the so called secondary damage, which promotes further destruction of the spinal cord. This sequence in time provides a window of opportunity for intervention. Pharmacological intervention in the acute phase of SCI may counteract the secondary neurotoxic events and further destruction of viable tissue.
For example, treatment with high doses of methylprednisolone (MP) has been shown to be a successful intervention in SCI, both in animal 3, 12, 29, 43 and man. In the NASCIS-2 and NASCIS-3 studies, statistically significant improvement in function was found in spinal-injured humans when MP was administered within 8 h after SCI [8]. The underlying mechanism is not fully understood, but experimental data point to protection against membrane peroxidation and edema 9, 29. Further research has shown that the high doses of MP required to inhibit lipid peroxidation also exert a number of other actions on the injured spinal cord that almost certainly contribute to an attenuation of post-traumatic neuronal damage (e.g., reduction in ischemic area and neurofilament degradation, preserved evoked potentials and improved spinal cord blood flow) 10, 25, 43, 44.
Melanocortins, peptides related to melanotropin (αMSH) and adrenocorticotropin (ACTH), are known to improve axonal regeneration following sciatic nerve injury 6, 7, 17, 18, 21, 35, 36, 37, 42 and to enhance compensation after damage to the CNS 20, 40, 41. In vitro, melanocortins also exert trophic effects on the outgrowth of neurites from CNS neurons 2, 39. Moreover, Joosten et al. [28] showed that implantation of collagen containing αMSH in a spinal transection injury site stimulates corticospinal tract axons to grow into the collagen graft. In addition, we showed that subcutaneous and intrathecally administered αMSH, as well as intravenously administered MP, had beneficial effects on functional recovery after experimental spinal cord injury (ESCI) 31, 38. Since both αMSH and MP have shown their value in intervention studies after (E)SCI and most likely act via a different mechanism of action, we decided to study the effects of the combined treatment with MP and αMSH on functional outcome after experimental spinal cord contusion injury in the rat.
Section snippets
Animals
All procedures in this study involving animals were approved by the Ethics Committee on Animal Experiments of the University of Utrecht. Forty-eight adult female Wistar rats (UWU:CPB), 11 weeks of age (200–240 g) at the start of the experiment, were used in this study. Animals were housed in pairs in a 12-h light–dark cycle, with water and food available ad libitum.
Animals were randomly divided into four groups and treated with either intracisternal (i.c.) αMSH (3.75 μg kg−1 h−1 for 10 days [31]
Exclusion of animals and mortality
Animals were excluded from the study in case of incorrect injury (as determined by the MASCIS-device), or when animals did not survive the entire study. In the present study, two animals were excluded because of incorrect injury, and one animal was excluded because of death during the course of the study.
Body weight
After induction of ESCI, body weight decreased during the first few days (from 232.2±3.0 to 220.0±3.1 g), stabilized and increased from DPO-07 onward in all groups (to 280.3±4.3 g at DPO-56).
Discussion
To date, relatively little progress has been made in the treatment of SCI-related neurological impairments. Since many different pathogenic processes are involved in SCI, it is unlikely that treatment with a single agent will result in maximum recovery. Until now, MP is the only drug shown to have at least some beneficial effects in treatment of human SCI. Therefore, MP seems to be the logical choice to include in combination therapy studies. To our knowledge, only two papers reported on the
Acknowledgements
This work was supported by a grant from the Glaxo Research Fund (GRN 95016). The authors would like to thank Simone Duis and Ruth Verzijl for their excellent technical assistance.
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