A gastric hormone to treat spinal cord injury?

Worldwide there are at least 130,000 traumatic spinal cord injuries each year. In the United States alone, traumatic spinal cord injury (SCI) affects 12,000 individuals annually, and as many as 1,275,000 people in the United States live with some form of SCI (1, 2). SCI costs the American health system an estimated $40.5 billion annually (2). Depending on the severity and location of the injury, patients present with a range of sensory, motor, and autonomic impairments due both to damage to the local spinal cord circuitry and disruption of ascending and descending fiber tracts (3). The resultant paraparesis or tetraplegia, bowel and bladder incontinence, and sexual dysfunction have a devastating effect on the quality of life. At present there are no therapies proven to be of benefit for either acute or chronic spinal cord injury.

In this issue of Endocrinology, Lee et al. (4) reported that systemic administration of the gastric hormone, ghrelin, improved functional recovery after a moderate SCI in rodents. The authors demonstrated that ghrelin administration reduced apoptosis of neurons and oligodendroglia, decreased lesion volume, and limited loss of axons and myelin, and they suggested that ghrelin could potentially be a therapy for acute SCI in humans. It might initially seem surprising that a protein viewed as a gastric hormone would be a reasonable candidate for treatment of SCI. However, it has been clear since the 1970s that gut hormones signal to the central nervous system in numerous profound ways and that central nervous system neurons widely express receptors for these hormones. Furthermore, the authors found that both neurons and oligodendroglia in the spinal cord express receptors for ghrelin. There have also been several prior studies cited by the authors that demonstrate a protective effect for ghrelin on neuronal survival after ischemic or toxic insults to cortex, hypothalamus, substantia nigra, and cerebellum. There was thus a good rationale for considering ghrelin as a potential therapeutic agent for SCI.

Lee et al. demonstrated very clear benefits of ghrelin administration on both anatomic and functional outcomes in their rodent model of SCI. However, it is important to put these findings in context with numerous prior studies of experimental SCI that have demonstrated equivalent or greater benefits with a large variety of different therapeutic interventions (5). In fact, the authors themselves found comparable results with administration of extracts of Scutellaria baicalensis, PEP-1-superoxide dismutase-1 fusion protein, or minocycline (6–8). However, there is great variability in SCI models and the way they are done in different laboratories, and the reproducibility of findings with different therapeutic interventions has been distressingly poor. A recent National Institutes of Health-supported effort to independently replicate published studies in SCI failed to replicate the findings in all eight attempts thus far reported. For example, one of these efforts failed to replicate prior findings on the neuroprotective effects of minocycline (9).

Why has it been so difficult to find an intervention that reliably improves outcome after SCI? SCI is an exceedingly complex biological problem with a complicated pathology. There is direct damage induced by the trauma due to membrane disruption, breakdown of the blood brain barrier, vascular damage, and hemorrhage. There are then a number of secondary processes that occur acutely after the injury including apoptosis of neurons and oligodendroglia, release of molecules that inhibit regenerative responses, invasion of peripheral immune cells, and activation of microglia (10–13). There is subsequently an additional wave of cell death accompanied by formation of a glial scar that limits axon outgrowth, by both acting as a physical barrier and accumulating molecules that inhibit axon outgrowth such as chondroitin sulfate proteoglycans (12–16). No single intervention including ghrelin administration can easily address all of these issues, and recovery from SCI will likely require a multifaceted approach using a combination of different methodologies. Many studies including the one by Lee et al. therefore studied moderate rather than severe injuries to limit the hurdles that must be overcome to achieve a favorable outcome. This obviously limits conclusions about relevance to severe human injuries. Many studies examine the effects of therapeutic interventions at the time of SCI, which also clearly does not correlate with clinical realities. In fact, all but one figure in the study by Lee et al. reflect the results of treatment at the time of injury, which limits the relevance to human SCI. To their credit Lee et al. did examine the effects of delayed dosing on one behavioral test and reported benefits with treatment given as long as 12 h after the injury.

Is ghrelin a good candidate for treatment of human SCI? Answering this question will require replication of the findings of this study in other laboratories as well as studies using different models of SCI. Even if the results can be replicated, findings with rodent models have not historically extrapolated well to human SCI. The complex pathological picture after SCI reflects a multitude of changes affecting several different cell types. Recovery from SCI will therefore likely require a multifaceted approach using a combination of different methodologies (5).