Ischemia and reperfusion (IR) of the spinal cord has resulted in devastating complications after surgery for thoracoabdominal aortic disease.1 Postsurgical paraplegia is still high despite recent modification of surgical and anesthetic approaches.1 Reduced cord blood flow as a result of the aortic cross-clamp, followed by reperfusion, induces a significant neuronal injury in the spinal cord, presumably due to a cascade of events, such as a reactive oxygen species storm and inflammatory response. A number of adjunctive measures have been deployed to ameliorate spinal cord IR injury, such as hypothermia, cerebrospinal fluid drainage (to lower pressure), electrophysiological monitoring (somatosensory and motor evoked potentials), ischemia/anesthetic pre- and postconditioning, and a variety of neuroprotective pharmacological agents.1 While the incidence of significant spinal cord injury has decreased after thoracoabdominal aortic surgery, it is safe to conclude that the success has been limited.
PHARMACOLOGICAL EFFECT OF A ROCK INHIBITOR
In this issue, Ohbuchi et al2 have applied fasudil, a medication commonly used to treat vasospasm in vascular disorders, such as subarachnoid hemorrhage or pulmonary hypertension, in a rat model of spinal cord IR injury. Fasudil is a selective inhibitor of Rho kinases (ROCK), which are enzymes (protein serine/threonine kinases) in the cytoplasm that can be activated by GTP-bound Rho and phosphorylate downstream substrates.3 There are 2 isoforms of ROCK: ROCK I (expressed in nonneuronal tissues) and ROCK II (mainly in brain tissue). ROCKs are important in fundamental cellular processes, such as proliferation, migration, and survival. Under pathological conditions (eg, brain and spinal cord disorders), ROCKs are abnormally activated, impairing neurite growth and sprouting. In addition, ROCKs are also able to regulate vascular tone. Therefore, ROCK inhibitors have great potential in treating a variety of medical conditions, including cardiovascular disorders and neurological diseases.4,5
Fasudil has proven to be effective in reducing vasospasm and vascular remodeling, even in human studies.6,7 In a rat model of subarachnoid hemorrhage, fasudil effectively decreases the development of cerebral aneurysm.8 Fasudil is proregenerative for dopaminergic neurons in a mouse model of Parkinson disease and decreases pathogenic tau levels in Drosophila.9,10 Further, it has also been reported that fasudil improves neuronal survival and functional recovery in different animal models of neurological disorders.11–13 Thus, the scientific premise for salutary effects in spinal cord IR injury is strong.
NEUROPROTECTION BY FASUDIL IN SPINAL IR INJURY
Although a variety of pharmacological agents, including different anesthetics, have been tested and have shown variable benefits in animal models of spinal cord IR injury, the Ohbuchi et al2 study is the first to report effects of fasudil in such a model for as long as 2 weeks after injury. They found that optimal functional and histopathologic outcomes occurred after fasudil was given both before and after the injury, and that only histological improvement occurred when given just after the injury. As previous study has suggested, white matter damage is as important as gray matter damage to outcomes after spinal IR injury,14 and this study is the first to indicate that both are spared as the histological basis for the observed neuroprotection. However, the authors underscored the lack of correlation between histopathology (ie, number of intact neurons) and neurologic outcomes,15 which disappointingly weakens the case for fasudil efficacy. Potential solutions might lie in the use of more specific markers for motor neurons (eg, choline acetyl transferase) and the application of motor function analyses with more granularity (eg, Basso, Beattie, and Bresnahan score of 21 points,16 as compared to the neuropathology disability score of 8 points that is also mixed with sensory assessment). In this type of preclinical study, it is critical to choose the right methodology in both the histology and (multiple) behavior tests to have the most representative assessment of drug efficacy.
Although ROCK pathways are implicated, the Ohbuchi et al2 study could not provide further mechanistic detail. As both treatment paradigms (before and after versus after only) reduce tissue damage, it seems that fasudil is capable of inhibiting IR-induced downstream cascades, such as apoptosis, inflammation, and oxidative stress, thus promoting tissue repair and functional recovery. The fact that pre- and posttreatments produced even better neurologic outcomes may be attributed to the vasodilatory effect of fasudil, as well as other direct consequences of ROCK inhibition.17 It is possible that pretreatment before IR injury could “precondition” the spinal cord tissue to improve tolerance (eg, increased regional spinal blood flow) of subsequent ischemic and reperfusion stress. As the authors suggested, it is also likely that hydroxyl fasudil (the active metabolite) has a longer half-life and may contribute to the subsequent protection against spinal IR injury if used as a pretreatment. Further, as most of the thoracoabdominal surgical patients are elderly and of both sexes, preclinical studies in aged and female animals should be considered.
PROMISING CANDIDATE FOR PERIOPERATIVE SPINAL CORD PROTECTION
Fasudil has been studied in a wide variety of preclinical models, as well as in clinical trials. In this study, it benefits functional outcomes with both pre- and posttreatments up to 2 weeks, making it potentially attractive for cases where spinal cord ischemia can be predicted. Previous study also suggested it has wide therapeutic window even at 6 or 24 hours after brain ischemia. It is also noteworthy that Ohbuchi et al2 demonstrated the protective effect of fasudil in normothermic conditions, further enhancing its attractiveness for clinical use. Although it is clear that further mechanistic study is needed in preclinical models of spinal cord IR, the Ohbuchi et al2 results suggest that human clinical trials on spinal cord protection should be considered to directly evaluate the efficacy of fasudil, an already approved drug in some countries.
DISCLOSURES
Name: Jonathan Z. Pan, MD, PhD.
Contribution: This author helped write and edit the manuscript.
Name: Roderic G. Eckenhoff, MD.
Contribution: This author helped write and edit the manuscript.
This manuscript was handled by: Ken B. Johnson, MD.
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