Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (ΔmJOA, ≤-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration-approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone.

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Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.

Central nervous system pericytes (perivascular stromal cells) have recently gained significant attention within the scientific community. In addition to being recognized as major players in neurotrauma, pericytes have been discovered to share a common origin and potentially function with traditionally defined mesenchymal stromal cells (MSCs). Although there have been several in vitro comparisons, the in vivo therapeutic application of human brain-derived stromal cells has not been previously evaluated. This study demonstrates that these cells not only display a MSC phenotype in vitro but also have similar in vivo immunomodulatory effects after spinal cord injury that are more potent than those of non-central nervous system tissue-derived cells. Therefore, these cells are of great interest for therapeutic use in spinal cord injury.

Propriospinal interneurons (INs) communicate information over short and long distances within the spinal cord. They act to coordinate different parts of the body by linking motor circuits that control muscles across the forelimbs, trunk, and hindlimbs. Their role in coordinating locomotor circuits near and far may be invaluable to the recovery of locomotor function lost due to injury to the spinal cord where the flow of motor commands from the brain and brainstem to spinal motor circuits is disrupted. The formation and activation of circuits established by spared propriospinal INs may promote the re-emergence of locomotion. In light of progress made in animal models of spinal cord injury (SCI) and in human patients, we discuss the role of propriospinal INs in the intact spinal cord and describe recent studies investigating the assembly and/or activation of propriospinal circuits to promote recovery of locomotion following SCI.

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Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy patients present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the subacute and chronic neuroinflammatory environment following spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male: 33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity, and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity, and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, von Frey filament, and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by approximately 50% relative to wild type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased following exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory), and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra, and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.