Therapeutic Approach For Spinal Cord Injury Research Articles

Amelioration of functional and histopathological consequences after spinal cord injury through phosphodiesterase 4D (PDE4D) inhibition

Spinal cord injury (SCI) is a life-changing event that severely impacts the patient's quality of life. Modulating neuroinflammation, which exacerbates the primary injury, and stimulating neuro-regenerative repair mechanisms are key strategies to improve functional recovery. Cyclic adenosine monophosphate (cAMP) is a second messenger crucially involved in both processes. Following SCI, intracellular levels of cAMP are known to decrease over time. Therefore, preventing cAMP degradation represents a promising strategy to suppress inflammation while stimulating regeneration. Intracellular cAMP levels are controlled by its hydrolyzing enzymes phosphodiesterases (PDEs). The PDE4 family is most abundantly expressed in the central nervous system (CNS) and its inhibition has been shown to be therapeutically relevant for managing SCI pathology. Unfortunately, the use of full PDE4 inhibitors at therapeutic doses is associated with severe emetic side effects, hampering their translation toward clinical applications. Therefore, in this study, we evaluated the effect of inhibiting specific PDE4 subtypes (PDE4B and PDE4D) on inflammatory and regenerative processes following SCI, as inhibitors selective for these subtypes have been demonstrated to be well-tolerated. We reveal that administration of the PDE4D inhibitor Gebr32a, even when starting 2 dpi, but not the PDE4B inhibitor A33, improved functional as well as histopathological outcomes after SCI, comparable to results obtained with the full PDE4 inhibitor roflumilast. Furthermore, using a luminescent human iPSC-derived neurospheroid model, we show that PDE4D inhibition stabilizes neural viability by preventing apoptosis and stimulating neuronal differentiation. These findings strongly suggest that specific PDE4D inhibition offers a novel therapeutic approach for SCI.

Sensory-motor coupling electrical stimulation driven by a bionic Z‐structured triboelectric nanogenerator improves functional recovery from spinal cord injury

Spinal cord injury (SCI) disrupts the neuronal relay circuits and causes limb paralysis. Although epidural electrical stimulation is a therapeutic approach for SCI, electrical stimulation pattern and continuous self-power capability are critical aspects that affect its effectiveness and clinical translation. Based on the triboelectrification principle, we developed a novel bionic Z-structured triboelectric nanogenerator (BZ-TENG) which can convert the kinetic energy of joint flexion and extension into electricity after implantation adjacent to posterior side of the rat elbow joint. The BZ-TENG had an excellent electrical potential of up to 15 V and stability after 14,000 repeated compressions and it stimulated axonal regeneration without interfering with dorsal root ganglion neuronal activity in vitro. Additionally, we designed an innovative electrical stimulation pattern by transferring BZ-TENG generated currents to both sciatic nerves and the lateral spinal cord, which we named sensory-motor coupling electrical stimulation (SMCS). In vivo, BZ-TENG-SMCS significantly improved the recovery of motor and sensory functions in SCI rats compared to spinal epidural stimulation alone (BZ-TENG-ESA) by promoting motor and sensory tract regeneration, axonal neogenesis, myelination, synapse formation, and inhibition of glial scar formation. The proposed BZ-TENG strategy provides a smart bio-adaptive and sustainable power source in vivo and is in combination with an SMCS pattern a promising novel approach for SCI therapy.

P.235 Differences in Human, Pig, and Rat Spinal Cord Stem Cells in Response to Inflammatory and Regenerative Factors In Vitro

Background: While the use of neural stem/progenitor cells has been reported as a promising therapeutic approach for spinal cord injury, direct comparison of adult primary animal spinal cord NSPCs have not been compared to human NSPCs under the same conditions to characterize intrinsic differences between human/animal NSPC response to inflammatory/regenerative factors. Methods: To mimic post-injury inflammation, primary-derived NSPCs from adult humans, pigs, and rats were treated with pro-inflammatory factors.To direct regeneration, NSPCs were treated with retinoic acid, platelet-derived growth factor or bone morphogenic protein-(BMP4) to induce neurons, oligodendrocytes or astrocytes, respectively.Cultures were treated for 7 or 14 days and characterized by immunocytochemistry. Results: Pro-inflammatory factors promoted more astrogenesis in rat and pig NSPCs compared to human NSPCs and induced neuronal differentiation in human NSPCs. RA increased neurogenesis of human and rat NSPCs, PDGFα increased oligodendrocyte differentiation of rat NSPCs, and BMP4 increased astrogenesis of human and rat NSPCs Conclusions: For the first time, differences in response of human, pig and rat primary NSPCs to inflammatory and regenerative factors have been identified. Better understanding of these differences is essential to improving the successful translation of regenerative therapies to humans.

Delayed administration of high dose human immunoglobulin G enhances recovery after traumatic cervical spinal cord injury by modulation of neuroinflammation and protection of the blood spinal cord barrier

Background/introductionThe neuroinflammatory response plays a major role in the secondary injury cascade after traumatic spinal cord injury (SCI). To date, systemic anti-inflammatory medications such as methylprednisolone sodium succinate (MPSS) have shown promise in SCI. However, systemic immunosuppression can have detrimental side effects. Therefore, immunomodulatory approaches including the use of human immunoglobulin G (hIgG) could represent an attractive alternative. While emerging preclinical data suggests that hIgG is neuroprotective after SCI, the optimal time window of administration and the mechanism of action remain incompletely understood. These knowledge gaps were the focus of this research study. MethodsFemale adult Wistar rats received a clip compression-contusion SCI at the C7/T1 level of the spinal cord. Injured rats were randomized, in a blinded manner, to receive a single intravenous bolus of hIgG (2 g/kg) or control buffer at 15 minutes (min), 1 hour (h) or 4 h post-SCI. At 24 h and 8 weeks post-SCI, molecular, histological and neurobehavioral analyses were undertaken. ResultsAt all 3 administration time points, hIgG (2 g/kg) resulted in significantly better short-term and long-term outcomes as compared to control buffer. No significant differences were observed when comparing outcomes between the different time points of administration. At 24 h post-injury, hIgG (2 g/kg) administration enhanced the integrity of the blood spinal cord barrier (BSCB) by increasing expression of tight junction proteins and reducing inflammatory enzyme expression. Improvements in BSCB integrity were associated with reduced immune cell infiltration, lower amounts of albumin and Evans Blue in the injured spinal cord and greater expression of anti-inflammatory cytokines. Furthermore, hIgG (2 g/kg) increased expression of neutrophil chemoattractants in the spleen and sera. After hIgG (2 g/kg) treatment, there were more neutrophils in the spleen and fewer neutrophils in the blood. hIgG also co-localized with endothelial cell ligands that mediate neutrophil extravasation into the injured spinal cord. Importantly, short-term effects of delayed hIgG (2 g/kg) administration were associated with enhanced tissue and neuron preservation, as well as neurobehavioral and sensory recovery at 8 weeks post-SCI. Discussion and conclusionhIgG (2 g/kg) shows promise as a therapeutic approach for SCI. The anti-inflammatory effects mediated by hIgG (2 g/kg) in the injured spinal cord might be explained in twofold. First, hIgG might antagonize neutrophil infiltration into the spinal cord by co-localizing with endothelial cell ligands that mediate various steps in neutrophil extravasation. Second, hIgG could traffic neutrophils towards the spleen by increasing expression of neutrophil chemoattractants in the spleen and sera. Overall, we demonstrate that delayed administration of hIgG (2 g/kg) at 1 and 4-h post-injury enhances short-term and long-term benefits after SCI by modulating local and systemic neuroinflammatory cascades.

Heme Oxygenase-1 Inhibits Neuronal Apoptosis in Spinal Cord Injury through Down-Regulation of Cdc42-MLK3-MKK7-JNK3 Axis

The mechanism by which spinal cord injury (SCI) induces neuronal death has not been thoroughly understood. Investigation on the molecular signal pathways involved in SCI-mediated neuronal apoptosis is important for development of new therapeutics for SCI. In the current study, we explore the role of heme oxygenase-1 (HO-1) in the modulation of mixed lineage kinase 3/mitogen-activated protein kinase kinase/cJUN N-terminal kinase 3 (MLK3/MKK7/JNK3) signaling, which is a pro-apoptotic pathway, after SCI. We found that MLK3/MKK7/JNK3 signaling was activated by SCI in a time-dependent manner, demonstrated by increase in activating phosphorylation of MLK3, MKK7, and JNK3. SCI also induced HO-1 expression. Administration of HO-1-expressing adeno-associated virus before SCI introduced expression of exogenous HO-1 in injured spinal cords. Exogenous HO-1 reduced phosphorylation of MLK3, MKK7, and JNK3. Consistent with its inhibitory effect on MLK3/MKK7/JNK3 signaling, exogenous HO-1 decreased SCI-induced neuronal apoptosis and improved neurological score. Further, we found that exogenous HO-1 inhibited expression of cell division cycle 42 (Cdc42), which is crucial for MLK3 activation. In vitro experiments indicated that Cdc42 was essential for neuronal apoptosis, while transduction of neurons with HO-1-expressing adeno-associated virus significantly reduced neuronal apoptosis to enhance neuronal survival. Therefore, our study disclosed a novel mechanism by which HO-1 exerted its neuroprotective efficacy. Our discovery might be valuable for developing a new therapeutic approach for SCI.

Grafted Bone Marrow Stromal Cells

In the CNS, astrocytes, oligodendrocytes and microglias are involved in not only development but also pathology such as spinal cord injury (SCI). Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Bone marrow stromal cells (BMSCs) represent a new therapeutic approach for SCI by enabling improved sensory and motor functions in animal models. Although transdifferentiation to spinal neurons was poor, because of their pleiotropic nature, the protective effects of BMSCs are broad and are primarily mediated through modulation of transdifferentiation into host spinal glial components. Transplantation of BMSCs can positively alter the spinal microenvironment and enhance recovery. The objective of this review is to discuss these and other related mechanisms. Since BMSCs transplantation has been applied in other clinical fields, we hope to provide useful clues for the clinical application of BMSCs to treat the SCI in the near future.