Richard J. Zeman, Xialing Wen, Chitti R. Moorthy and Joseph D. Etlinger
X-irradiation has been shown to be beneficial to recovery from spinal cord injury (SCI); however, the optimal therapeutic target has not been defined. Experiments were designed to determine the optimal target volume within the injured spinal cord for improving functional recovery and sparing tissue with stereotactic x-irradiation.
SCI was produced in rats at the T10 level. A 20-Gy dose of radiation was delivered with a single, 4-mm-diameter, circular radiation beam centered either on the injury epicenter or 4 or 8 mm caudal or rostral to the injury epicenter. Locomotor function was determined for 6 weeks with the Basso, Beattie, and Bresnahan locomotor scale and tissue sparing by histological analysis of transverse sections along the spinal cords.
X-irradiation of spinal cord segments at 4 mm, but not 8 mm, caudal or rostral to the contusion epicenter resulted in increases in locomotor recovery. Consistently, significant tissue sparing also occurred with x-irradiation centered at those sites, although irradiation centered 4 mm rostral to the epicenter led to tissue sparing along the greatest length of the spinal cord. Interestingly, regression analysis of these variables demonstrated that the quantitative relationship between the amount of tissue spared and the improvement in locomotion recovery was greatest in a region several millimeters rostral to the injury epicenter.
These results indicate that x-irradiation in a region rostral to the injury epicenter is optimal for recovery from SCI. This minimal target should be attractive for therapeutic application since it allows a greatly reduced target volume so that uninjured tissue is not needlessly irradiated.
Abraham Brown, Anna Nabel, William Oh, Joseph D. Etlinger and Richard J. Zeman
Traumatic injury to the spinal cord results in considerable delayed tissue loss. The authors investigated the extent to which ischemia occurs following contusion-induced spinal cord injury and whether ischemia exacerbates tissue damage that leads to the loss of locomotor function. They also determined if ischemia is reversed with β2–adrenoceptor agonist treatment, which has been established to be neuroprotective following contusion injury.
The extent and role of circulation loss in spinal cord injury was determined in an established experimental model of contusion injury. The spinal cord dura mater of Wistar rats was exposed by performing a laminectomy at T-8 to T-11. Laser Doppler perfusion imaging was then used to measure microcirculation in the exposed spinal cord. After imaging, a moderately severe contusion injury was produced using a weight-drop device unto the exposed dura at T-10. Perfusion imaging was again performed, scans were quantitated, and integrated intensities were compared.
Postinjury imaging revealed an 18%–27% reduction in perfusion in regions rostral and caudal to the injury site, and a 68% reduction was observed at the contusion epicenter. These perfusion losses persisted for at least 48 hours. At 24 hours after injury, some rats were intraperitoneally injected with 2 mg/kg of the β2–adrenoceptor agonist clenbuterol, which has been shown to promote the partial recovery of locomotor function and spare spinal cord tissue when administered within 2 days after contusion injury. Clenbuterol injection caused a gradual increase in perfusion, which was detectable at 30 minutes postinjection and continued over time, resulting in an 127% overall increase in perfusion at the epicenter 24 hours after treatment.
These results suggest that the occurrence of chronic perfusion loss after contusion contributes to delayed damage and tissue loss. In contrast, β2–adrenoceptor agonist treatment may exert neuroprotection by restoring perfusion, thereby preventing ischemic neurodegeneration. The ability of laser Doppler imaging to measure the loss of perfusion and its restoration upon treatment suggests that it may have clinical utility in the assessment and treatment of spinal cord injury.
Virany H. Hillard, Hong Peng, Kaushik Das, Raj Murali, Chitti R. Moorthy, Joseph D. Etlinger and Richard J. Zeman
Hyperbaric oxygen (HBO), the nitroxide antioxidant tempol, and x-irradiation have been used to promote locomotor recovery in experimental models of spinal cord injury. The authors used x-irradiation of the injury site together with either HBO or tempol to determine whether combined therapy offers greater benefit to rats.
Contusion injury was produced with a weight-drop device in rats at the T-10 level, and recovery was determined using the 21-point Basso-Beattie-Bresnahan (BBB) locomotor scale. Locomotor function recovered progressively during the 6-week postinjury observation period and was significantly greater after x-irradiation (20 Gy) of the injury site or treatment with tempol (275 mg/kg intraperitoneally) than in untreated rats (final BBB Scores 10.6 [x-irradiation treated] and 9.1 [tempol treated] compared with 6.4 [untreated], p < 0.05). Recovery was not significantly improved by HBO (2 atm for 1 hour [BBB Score 8.2, p > 0.05]). Interestingly, the improved recovery of locomotor function after x-irradiation, in contrast with antiproliferative radiotherapy for neoplasia, was inhibited when used together with either HBO or tempol (BBB Scores 8.2 and 8.3, respectively). The ability of tempol to block enhanced locomotor recovery by x-irradiation was accompanied by prevention of alopecia at the irradiation site. The extent of locomotor recovery following treatment with tempol, HBO, and x-irradiation correlated with measurements of spared spinal cord tissue at the contusion epicenter.
These results suggest that these treatments, when used alone, can activate neuroprotective mechanisms but, in combination, may result in neurotoxicity.