Diffusion Tensor Imaging of the Spinal Cord: Insights From Animal and Human Studies

Diffusion tensor imaging (DTI) provides a measure of the directional diffusion of water molecules in tissues. The measurement of DTI indexes within the spinal cord provides a quantitative assessment of neural damage in various spinal cord pathologies. DTI studies in animal models of spinal cord injury indicate that DTI is a reliable imaging technique with important histological and functional correlates. These studies demonstrate that DTI is a noninvasive marker of microstructural change within the spinal cord. In human studies, spinal cord DTI shows definite changes in subjects with acute and chronic spinal cord injury, as well as cervical spondylotic myelopathy. Interestingly, changes in DTI indexes are visualized in regions of the cord, which appear normal on conventional magnetic resonance imaging and are remote from the site of cord compression. Spinal cord DTI provides data that can help us understand underlying microstructural changes within the cord and assist in prognostication and planning of therapies. In this article, we review the use of DTI to investigate spinal cord pathology in animals and humans and describe advances in this technique that establish DTI as a promising biomarker for spinal cord disorders

Neuroprotection by Chitosan and Chitosan Nanoparticles

In the U.S., about 200,000 people are currently living with spinal cord injury (SCI). An estimated of 50%-70% of all SCI cases occurs in the range of ages between 15-35 years old. The destructive neurotrauma results in the majority of adult disability, even after patients suffering with SCI survived from the acute death. There are two stages involved in the progression of SCI, the primary stage and the secondary stage. The primary stage is mainly the mechanical damage to the central nervous system. The rapid collapse of the integrity of cell membrane and tissue is often one of the initial onsets. Centered by the cascade of biochemical disruption, such as aldehyde toxins, the secondary injury is responsible for the major clinical deficits in sensory and motor functions. Available pharmacological treatment for SCI includes high doses of steroids. However, the side effects of steroid therapy leave patients more susceptible for complications, such as infections, chronic pain and blood clots. The absence of standard of care have triggered waves of intense research leading to finding a cure for SCI . Based on our previous successful explorations of the neuroprotection by chitosan and chitosan nanoparticles (Chi-NPs) in SCI related cell and tissue studies, we further investigated the neuroprotective effects based on two major characteristics of chitosan: (1) molecular weight (MW) and (2) degree of acetylation (DA). Our results demonstrated that chitosan polymer blocked the random exchange of a probe, tetramethyl-rodamine (TMR) and an endogenous protein, lactate dehydrogenase (LDH), across mechanically compromised cell membrane, while a significant difference of the membrane sealing effect was not suggested among different MWs and DAs of chitosan polymer. A similar affinity of FITC-chitosan polymer at intact and injured spinal tissues was also suggested. To push the use of chitosan a step towards clinical tests, we incorporated the advantage of nanomedicine with our promising chitosan material . Different factors were investigated during the formation and the storage of Chi F-NPs. Two types of Chi-NPs (chitosan-triphosphate, Chi-TPPNPs and chitosan-dextran sulfate, Chi-DSNPs) were synthesized, with a range of size at 100-300nm and zeta-potentials of 30.65mV and -47.4mV, based on an ionic gelation method. Chi-DSNPs were shown to rescue necrotic BV-2 cells induced by a short incubation of hydrogen peroxide at 5.5mM. In addition, the conduction of somatosensory evoked potentials (SSEPs) through the lesion produced by the compression injury was partially restored after 1 week of the subcutaneous administration of Chi-DSNPs. We also found that polyethylene glycol (PEG)-coated silica NPs were significantly accumulated at the compression injured spinal tissues. The affinity of NPs at severed cell membranes was guided by PEG. Our experimental findings suggested that chitosan and Chi-NPs provided neuroprotective effects using both in vitro and in vivo models

Value of micro-CT for monitoring spinal microvascular changes after chronic spinal cord compression

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Effects of diet and/or exercise in enhancing spinal cord sensorimotor learning.

Given that the spinal cord is capable of learning sensorimotor tasks and that dietary interventions can influence learning involving supraspinal centers, we asked whether the presence of omega-3 fatty acid docosahexaenoic acid (DHA) and the curry spice curcumin (Cur) by themselves or in combination with voluntary exercise could affect spinal cord learning in adult spinal mice. Using an instrumental learning paradigm to assess spinal learning we observed that mice fed a diet containing DHA/Cur performed better in the spinal learning paradigm than mice fed a diet deficient in DHA/Cur. The enhanced performance was accompanied by increases in the mRNA levels of molecular markers of learning, i.e., BDNF, CREB, CaMKII, and syntaxin 3. Concurrent exposure to exercise was complementary to the dietary treatment effects on spinal learning. The diet containing DHA/Cur resulted in higher levels of DHA and lower levels of omega-6 fatty acid arachidonic acid (AA) in the spinal cord than the diet deficient in DHA/Cur. The level of spinal learning was inversely related to the ratio of AA:DHA. These results emphasize the capacity of select dietary factors and exercise to foster spinal cord learning. Given the non-invasiveness and safety of the modulation of diet and exercise, these interventions should be considered in light of their potential to enhance relearning of sensorimotor tasks during rehabilitative training paradigms after a spinal cord injury

Nanomedicine for treating spinal cord injury

Spinal cord injury results in significant mortality and morbidity, lifestyle changes, and difficult rehabilitation. Treatment of spinal cord injury is challenging because the spinal cord is both complex to treat acutely and difficult to regenerate. Nanomaterials can be used to provide effective treatments; their unique properties can facilitate drug delivery to the injury site, enact as neuroprotective agents, or provide platforms to stimulate regrowth of damaged tissues. We review recent uses of nanomaterials including nanowires, micelles, nanoparticles, liposomes, and carbon-based nanomaterials for neuroprotection in the acute phase. We also review the design and neural regenerative application of electrospun scaffolds, conduits, and self-assembling peptide scaffolds

Acrolein involvement in sensory and behavioral hypersensitivity following spinal cord injury in the rat

Growing evidence suggests that oxidative stress, as associated with spinal cord injury (SCI), may play a critical role in both neuroinflammation and neuropathic pain conditions. The production of the endogenous aldehyde acrolein, following lipid peroxidation during the inflammatory response, may contribute to peripheral sensitization and hyperreflexia following SCI via the TRPA1-dependent mechanism. Here we report that there are enhanced levels of acrolein and increased neuronal sensitivity to the aldehyde for at least 14 days after SCI. Concurrent with injury-induced increases in acrolein concentration is an increased expression of TRPA1 in the lumbar (L3-L6) sensory ganglia. As proof of the potential pronociceptive role for acrolein, intrathecal injections of acrolein revealed enhanced sensitivity to both tactile and thermal stimuli for up to 10 days, supporting the compound’s pro-nociceptive functionality. Treatment of SCI animals with the acrolein scavenger hydralazine produced moderate improvement in tactile responses as well as robust changes in thermal sensitivity for up to 49 days. Taken together, these data suggests that acrolein directly modulates SCI-associated pain behavior, making it a novel therapeutic target for preclinical and clinical SCI as an analgesic

Acrolein as a novel therapeutic target for spinal cord injury induced neuropathic pain

Despite years of research, post-spinal cord injury (SCI) chronic neuropathic pain remains refractory to treatment and drastically impairs quality of life for SCI victims beyond paralysis. Although inflammation and free radicals contribute to neuropathic pain in SCI, the mechanism is not completely clear. We have recently demonstrated that acrolein, a product and catalyst of lipid peroxidation, induces a vicious cycle of oxidative stress, amplifying its effects and perpetuating oxidative stress and inflammation. In the current study, we have confirmed that acrolein is elevated significantly at least two weeks post-SCI which coincides with the emergence of hyperalgesia (mechanical, cold and thermal). Furthermore, anti-acrolein treatment hydalazine can reverse pain behavior. Consistent with this, acrolein is a known ligand that directly excites transient receptor potential ankyrin 1 receptor (TRPA1) in DRG nociceptive neurons to transmit pain sensation. In addition, we have observed a significant increase of monocyte chemoattractant protein-1 (MCP1), a pro-inflammatory chemokine that is also known be increased upon acrolein stimulation and capable of sensitizing TRPA1 following SCI. Similarly, we observed a heightened excitatory response of DRG sensory neurons to current stimulation in the presence of acrolein, indicating an enhanced sensitivity of DRG cells to acrolein post SCI. In summary, acrolein may play an important role in the post SCI hyperalgesia through greater direct binding to TRPA1 and enhanced sensitivity of DRG to acrolein via MCP1-mediated pathway