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Because of the complex, multifaceted nature of spinal cord injury (SCI), it is widely believed that a combination of approaches will be superior to individual treatments. Therefore, we employed a rat model of cervical SCI to evaluate the combination of four noninvasive treatments that individually have been reported to be effective for acute SCI during clinically relevant therapeutic time windows. These treatments included ghrelin, ibuprofen, C16, and ketogenic diet (KD). These were selected not only because of their previously reported efficacy in SCI models but also for their potentially different mechanisms of action. The administration of ghrelin, ibuprofen, C16, and KD several hours to days postinjury was based on previous observations by others that each treatment had profound effects on the pathophysiology and functional outcome following SCI. Here we showed that, with the exception of a modest improvement in performance on the Montoya staircase test at 8-10 weeks postinjury, the combinatorial treatment with ghrelin, ibuprofen, C16, and KD did not result in any significant improvements in the rearing test, grooming test, or horizontal ladder. Histologic analysis of the spinal cords did not reveal any significant differences in tissue sparing between treatment and control groups. Although single approaches of ghrelin, ibuprofen, C16, and KD have been reported to be beneficial after SCI, our results show that the combination of the four interventions did not confer significant functional or histological improvements in a cervical model of SCI. Possible interactions among the treatments may have negated their beneficial effects, emphasizing the challenges that have to be addressed when considering combinatorial drug therapies for SCI.

Functional recovery after spinal cord injury (SCI) is limited, and the injury results in a dramatic reduction in long-term lifespan. Prophylactic dietary restriction (DR) robustly extends animal lifespan, and is beneficial in models of neuronal insult. In rats, we found that one form of DR, every-other-day-fasting (EODF), which started 1 month prior to a cervical SCI improved functional recovery, resulted in greater numbers of neurons surrounding the injury site, and a approximately 45% reduction in lesion size compared to the control group. In the light of the low-risk implementation of prophylactic EODF, the clinical translation as a treatment prior to elective subacute or chronic interventions is attractive. There are numerous secondary complications after human SCI, including a 13- to 25-year reduction in lifespan. DR consistently increases median and maximal lifespan in a large range of organisms, including non-human primates. Animal research suggests that EODF might reduce many of the secondary complications people with SCI suffer from. Dietary interventions may provide the possibility to improve the quality and span of life for individuals with SCI.