Axonal Remyelination Research Articles

A shape-persistent plasticine-like conductive hydrogel with self-healing properties for peripheral nerve regeneration

In recent years, electrically conductive hydrogel-based nerve guidance conduits (NGCs) have yielded promising results for treating peripheral nerve injuries (PNIs). However, developed ones are generally pre-manufactured and exhibit a limited ability to achieve good contact with nerve tissue with irregular surfaces. Herein, we developed a plasticine-like electrically conductive hydrogel consisting of gelatin, conducting polypyrrole, and tannic acid (named GPT) and assessed its ability to promote peripheral nerve regeneration. The shape-persistent GPT hydrogel exhibited good self-healing properties and could easily be molded to form a conduit that could match any injured nerve tissue. Their electrical properties could be tuned by changing the PPy concentration. In vitro, the improved conductivity of the hydrogel promoted dorsal root ganglion (DRG) axonal extension. More importantly, we found that the GPT hydrogel enhanced axonal regeneration and remyelination in vivo, preventing denervation atrophy and enhancing functional recovery in a mice model of sciatic nerve injury. These results suggest that our plasticine-like NGC has huge prospects for clinical application in the repair of PNI.

Tail nerve electrical stimulation promoted the efficiency of transplanted spinal cord-like tissue as a neuronal relay to repair the motor function of rats with transected spinal cord injury

Following transected spinal cord injury (SCI), there is a critical need to restore nerve conduction at the injury site and activate the silent neural circuits caudal to the injury to promote the recovery of voluntary movement. In this study, we generated a rat model of SCI, constructed neural stem cell (NSC)-derived spinal cord-like tissue (SCLT), and evaluated its ability to replace injured spinal cord and repair nerve conduction in the spinal cord as a neuronal relay. The lumbosacral spinal cord was further activated with tail nerve electrical stimulation (TNES) as a synergistic electrical stimulation to better receive the neural information transmitted by the SCLT. Next, we investigated the neuromodulatory mechanism underlying the action of TNES and its synergism with SCLT in SCI repair. TNES promoted the regeneration and remyelination of axons and increased the proportion of glutamatergic neurons in SCLT to transmit brain-derived neural information more efficiently to the caudal spinal cord. TNES also increased the innervation of motor neurons to hindlimb muscle and improved the microenvironment of muscle tissue, resulting in effective prevention of hindlimb muscle atrophy and enhanced muscle mitochondrial energy metabolism. Tracing of the neural circuits of the sciatic nerve and tail nerve identified the mechanisms responsible for the synergistic effects of SCLT transplantation and TNES in activating central pattern generator (CPG) neural circuits and promoting voluntary motor function recovery in rats. The combination of SCLT and TNES is expected to provide a new breakthrough for patients with SCI to restore voluntary movement and control their muscles.

Schwann cell-specific RhoA knockout accelerates peripheral nerve regeneration via promoting Schwann cell dedifferentiation.

Our previous studies indicated that RhoA knockdown or inhibition could alleviate the proliferation, migration, and differentiation of Schwann cells. However, the role of RhoA in Schwann cells during nerve injury and repair is still unknown. Herein, we developed two lines of Schwann cells conditional RhoA knockout (cKO) mice by breeding RhoAflox / flox mice with PlpCre -ERT2 or DhhCre mice. Our results indicate that RhoA cKO in Schwann cells accelerates axonal regrowth and remyelination after sciatic nerve injury, which enhances the recovery of nerve conduction and hindlimb gait, and alleviates the amyotrophy in gastrocnemius muscle. Mechanistic studies in both in vivo and in vitro models revealed that RhoA cKO could facilitate Schwann cell dedifferentiation via JNK pathway. Schwann cell dedifferentiation subsequently promotes Wallerian degeneration by enhancing phagocytosis and myelinophagy, as well as stimulating the production of neurotrophins (NT-3, NGF, BDNF, and GDNF). These findings shed light on the role of RhoA in Schwann cells during nerve injury and repair, indicating that cell type-specific RhoA targeting could serve as a promising molecular therapeutic strategy for peripheral nerve injury.

Inflammatory stimulation of astrocytes affects the expression of miRNA-22-3p within NSCs-EVs regulating remyelination by targeting KDM3A

BackgroundEndogenous neural stem cells (NSCs) are critical for the remyelination of axons following spinal cord injury (SCI). Cell–cell communication plays a key role in the regulation of the differentiation of NSCs. Astrocytes act as immune cells that encounter early inflammation, forming a glial barrier to prevent the spread of destructive inflammation following SCI. In addition, the cytokines released from astrocytes participate in the regulation of the differentiation of NSCs. The aim of this study was to investigate the effects of cytokines released from inflammation-stimulated astrocytes on the differentiation of NSCs following SCI and to explore the influence of these cytokines on NSC–NSC communication.ResultsLipopolysaccharide stimulation of astrocytes increased bone morphogenetic protein 2 (BMP2) release, which not only promoted the differentiation of NSCs into astrocytes and inhibited axon remyelination in SCI lesions but also enriched miRNA-22-3p within extracellular vesicles derived from NSCs. These miRNA-22 molecules function as a feedback loop to promote NSC differentiation into oligodendrocytes and the remyelination of axons following SCI by targeting KDM3A.ConclusionsThis study revealed that by releasing BMP2, astrocytes were able to regulate the differentiation of NSCs and NSC–NSC communication by enriching miRNA-22 within NSC-EVs, which in turn promoted the regeneration and remyelination of axons by targeting the KDM3A/TGF-beta axis and the recovery of neurological outcomes following SCI.

Implantation with SHED sheet induced with homogenate protein of spinal cord promotes functional recovery from spinal cord injury in rats.

Introduction: After spinal cord injury (SCI) occurs, the lesion is in a growth inhibitory microenvironment that severely hinders neural regeneration. In this microenvironment, inhibitory factors are predominant and factors that promote nerve regeneration are few. Improving neurotrophic factors in the microenvironment is the key to treating SCI. Methods: Based on cell sheet technology, we designed a bioactive material with a spinal cord-like structure -SHED sheet induced with homogenate protein of spinal cord (hp-SHED sheet). Hp-SHED sheet was implanted into the spinal cord lesion for treating SCI rats with SHED suspensions as a control to investigate the effects on nerve regeneration. Results: Hp-SHED sheet revealed a highly porous three-dimensional inner structure, which facilitates nerve cell attachment and migration. Hp-SHED sheet in vivo restored sensory and motor functions in SCI rats by promoting nerve regeneration, axonal remyelination, and inhibiting glial scarring. Discussion: Hp-SHED sheet maximally mimics the microenvironment of the natural spinal cord and facilitate cell survival and differentiation. Hp-SHED sheet could release more neurotrophins and the sustained action of neurotrophins improves the pathological microenvironment, which effectively promotes nerve regeneration, axonal extension, and inhibits glial scarring, thereby promoting the in situ centralis neuroplasticity. Hp-SHED sheet therapy is a promising strategy for effective treatment of SCI based on neurotrophins delivery.

Renal-friendly Li+-doped carbonized polymer dots activate Schwann cell autophagy for promoting peripheral nerve regeneration.

Activation of autophagy in Schwann cells (SCs) has emerged as a powerful trigger for peripheral nerve injury (PNI) repair. Lithium ion (Li+) is a classical autophagy activator that plays an important role in promoting axonal extension and remyelination. However, the therapeutic window of existing lithium drugs is extremely narrow, and the adverse side effects, especially nephrotoxicity, severely limit their therapeutic value. Herein, Li+-doped carbonized polymer dots (Li-CPDs) was synthesized for the first time to change the pharmacokinetics of Li+ from occupying epithelial sodium channels to lipid raft-mediated endocytosis. The in-vivo results confirmed that Li-CPDs could accelerate the removal of myelin debris and promote nerve regeneration via activating autophagy of SCs. Moreover, Li-CPDs exhibited almost no renal toxicity compared to that of raw lithium drugs. Thus, Li-CPDs could serve as a promising Li+-based nanomedicine for PNI regeneration with improved biosafety. STATEMENT OF SIGNIFICANCE: Regardless of the fact that lithium drugs have been used in treatment of mental illness such as manic depression, the systemic side effects and renal metabolic toxicity still seriously restrict their clinical application. Since Li+ and Na+ compete for ion channels of cell membrane, the cell entry efficiency is extremely low and easily affected by body fluctuations, which seems to be an unsolvable problem. Herein, we rationally exploited the endocytotic features of CPDs to develop Li-CPDs. The Li-CPDs improved the entry pathway, greatly reduced nephrotoxicity, and inherited the biological function of Li+ to activate autophagy for promoting peripheral nerve regeneration. Due to the BBB-crossing property of Li-CPDs, it also showed application prospects in future research on central nervous system diseases.

Intracavernous injection of platelet-rich plasma reverses erectile dysfunction of chronic cavernous nerve degeneration through reduction of prostate hyperplasia evidence from an aging-induced erectile dysfunction rat model.

Age-induced erectile dysfunction (ED) is a convoluted medical condition, and restoring erectile function (EF) under geriatric conditions is highly complicated. Platelet-rich plasma (PRP) treatment is an inexpensive cell-based therapeutic strategy. We have aimed to restore EF in aged-ED rats with PRP as a therapeutic tool. Male rats were grouped into aged and young according to age. The young rats were considered as normal control (NC) and treated with saline. Aged were further divided into 2 groups and treated with intracavernous (IC) PRP and saline. Treatment was scheduled at the 9th and 10th week for NC and 41th and 42th week for aged-ED rats, with EF analysis scheduled on the 12th week for NC and 44th week for aged-ED rats, respectively. Erectile response, immunofluorescence staining, and electron microscopic analyses were performed. IC PRP treatment effectively reduced prostate hyperplasia(PH). EF response indicated a significant increase in crucial EF parameters in PRP-treated aged-ED rats. Histological evidence denoted a rigid and restored development of tunica adventitia of the dorsal artery, decreased vacuolation of the dorsal penile nerve, and structural expansion of the epineurium. Masson's trichrome and immunostaining results affirmed an elevated expression of α-smooth muscle actin(α-SMA) in the corpus cavernosum(CC). Ultrastructure findings revealed that PRP effectively rejuvenated degenerating nerves, preserved endothelium and adherent junctions of corporal smooth muscle, and restored the axonal scaffolds by upregulating neurofilament-H (NF-H)expression. Finally, PRP enhanced neural stability by enhancing the axonal remyelination processes in aged-ED rats. Hence, PRP treatment was proven to restore EF in aged-ED rats, which was considered a safe, novel, cost-effective, and hassle-free strategy for EF restoration in geriatric patients.

Title: Immunotherapy; a ground-breaking remedy for spinal cord injury with stumbling blocks: An overview.

Spinal cord injury (SCI) is a debilitating disorder with no known standard and effective treatment. Despite its ability to exacerbate SCI sequel by accelerating auto-reactive immune cells, an immune response is also considered essential to the healing process. Therefore, immunotherapeutic strategies targeting spinal cord injuries may benefit from the dual nature of immune responses. An increasing body of research suggests that immunization against myelin inhibitors can promote axon remyelination after SCI. However, despite advancements in our understanding of neuroimmune responses, immunoregulation-based therapeutic strategies have yet to receive widespread acceptance. Therefore, it is a prerequisite to enhance the understanding of immune regulation to ensure the safety and efficacy of immunotherapeutic treatments. The objective of the present study was to provide an overview of previous studies regarding the advantages and limitations of immunotherapeutic strategies for functional recovery after spinal cord injury, especially in light of limiting factors related to DNA and cell-based vaccination strategies by providing a novel prospect to lay the foundation for future studies that will help devise a safe and effective treatment for spinal cord injury.

Prospects for the use of olfactory mucosa cells in bioprinting for the treatment of spinal cord injuries.

The review focuses on the most important areas of cell therapy for spinal cord injuries. Olfactory mucosa cells are promising for transplantation. Obtaining these cells is safe for patients. The use of olfactory mucosa cells is effective in restoring motor function due to the remyelination and regeneration of axons after spinal cord injuries. These cells express neurotrophic factors that play an important role in the functional recovery of nerve tissue after spinal cord injuries. In addition, it is possible to increase the content of neurotrophic factors, at the site of injury, exogenously by the direct injection of neurotrophic factors or their delivery using gene therapy. The advantages of olfactory mucosa cells, in combination with neurotrophic factors, open up wide possibilities for their application in three-dimensional and four-dimensional bioprinting technology treating spinal cord injuries.

Stem Cell Therapies for Functional Recovery After Spinal Cord Injury: Mechanisms, Challenges, and Applications

Context: Spinal cord injury (SCI), a debilitating and catastrophic condition, leads to sensory motor impairments, paralysis, and high mortality. It consists of initial physical insult and secondary injury. Despite much research on SCI treatment, it is still one of the incurable damages because of its complex pathophysiology and limited neuronal regeneration ability. In recent years, stem cell therapy has been a promising and exciting strategy for SCI treatment. Evidence Acquisition: In this review, the articles published in PubMed, Google Scholar, Science Direct, and Scopus from 2000 to 2022 were collected using keywords such as spinal cord injury, stem cell therapy, neuroprotection, neuroregeneration, neurotrophic factors, anti-inflammatory cytokines, and neural cell death. The articles whose full texts were available and met the inclusion criteria were examined. According to the inclusion criteria, 30 articles were analyzed. Results: Stem cell therapy can promote neuroplasticity and neuroregeneration in the damaged spinal cord. Grafted cells can reconstruct nerves and create new circuits after SCI. Stem cell transplantation can also replace lost oligodendrocytes, thus promoting axon remyelination. Many neurotrophic factors and anti-inflammatory cytokines are secreted by transplanted stem cells to decrease secondary injury and neural cell death, thus inhibiting the glial scar formation after SCI. Stem cells also have antioxidant, anti-inflammatory, immunomodulatory, and anti-apoptotic effects. Grafted stem cells can block microglial activation and astrocyte reactivity and enhance revascularization. Conclusions: Stem cells isolated from different tissues can be promising candidates and attractive options for treating the injured spinal cord. Despite remarkable progress in animal studies, cell transplantation's clinical efficacy and adequacy for SCI remain limited and dubitable. Many essential challenges must be considered in translation to the clinic. It is hoped that the invention of new methods and the anti-inflammatory, anti-apoptotic, antioxidant, and neuronal repair properties of stem cells can effectively improve the sensorimotor function of patients with SCI.

Phosphorene hydrogel conduits as "neurotrophin reservoirs" for promoting regeneration of peripheral nerves.

Treatment of large gaps in peripheral nerves is a major clinical challenge. Artificial nerve guidance conduits (NGCs) have provided new opportunities for guiding nerve regeneration. In this study, multifunctional black phosphorus (BP) hydrogel NGCs loaded with neuregulin 1 (Nrg1) were fabricated to support peripheral-nerve regeneration: they exhibited good flexibility and nerve regeneration-related cell induction, promoted Schwann-cell proliferation and accelerated neuron-branch elongation. Nrg1 induced the proliferation and migration of Schwann cells, which had beneficial roles in promoting nerve regeneration. In vivo immunofluorescence studies revealed BP hydrogel NGCs loaded with Nrg1 promoted sciatic-nerve regeneration and axon remyelination. Our method has great potential for promoting treatment of peripheral-nerve injuries.

Three-dimensional nanofibrous sponges with aligned architecture and controlled hierarchy regulate neural stem cell fate for spinal cord regeneration.

Background: Spinal cord injury (SCI) induces neuronal death and disrupts the nerve fiber bundles, which leads to severe neurological dysfunction and even permanent paralysis. A strategy combining biomimetic nanomaterial scaffolds with neural stem cell (NSC) transplantation holds promise for SCI treatment. Methods: Innovative three-dimensional (3D) nanofibrous sponges (NSs) were designed and developed by a combination of directional electrospinning and subsequent gas-foaming treatment. Immunofluorescence, mRNA sequencing, magnetic resonance imaging, electrophysiological analysis, and behavioral tests were used to investigate the in vitro and in vivo regenerative effects of the 3D NSs. Results: The generated 3D NSs exhibited uniaxially aligned nano-architecture and highly controllable hierarchical structure with super-high porosity (99%), outstanding hydrophilicity, and reasonable mechanical performance. They facilitated cell infiltration, induced cell alignment, promoted neuronal differentiation of NSCs, and enhanced their maturation mediated through cellular adhesion molecule pathways. In vivo, the NSC-seeded 3D NSs efficiently promoted axon reinnervation and remyelination in a rat SCI model, with new "neural relays" developing across the lesion gap. These histological changes were associated with regain of function, including increasing the neurological motor scores of SCI rats, from approximately 2 to 16 (out of 21), and decreasing the sensing time in the tape test from 140 s to 36 s. Additionally, the scaffolds led to restoration of ascending and descending electrophysiological signalling. Conclusion: The as-fabricated 3D NSs effectively regulate NSC fates, and an advanced combination of 3D NS design and transplanted NSCs enables their use as an ideal tissue-engineered scaffold for SCI repair.

Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration.

Novel neuron-Schwann cell co-culture models to study peripheral nerve degeneration and regeneration.

The best of both worlds: mastering nerve regeneration combining biological and nanotechnological tools.

The best of both worlds: mastering nerve regeneration combining biological and nanotechnological tools.

Kir4.1 channel activation in NG2 glia contributes to remyelination in ischemic stroke.

Stroke is one of the most common neurological diseases in the world and is clinically manifested by transient or permanent brain dysfunction. It has a high mortality and disability rate, which severely affects people's health and diminishes the quality of life. However, there is no efficient treatment that can be considered curative and there are other less well-known theories of pathogenesis. Therefore, it is imperative to gain a full understanding of the pathophysiology of ischemia and to seek new therapeutic strategies. We first examined Kir4.1 channel and myelin based protein (MBP) expression in brain tissues from acute ischemic patients by Western blotting. We then established a transient ischemic mouse model (tMCAO) to conduct molecular, cell biological, transmission electron microscopy and pharmacokinetic studies, as well as in Kir4.1 cKO mice. Finally, neuroimaging and behavioral analyses were used to examine whether activation of Kir4.1 channel by luteolin could contribute to neuronal functional recovery in ischemic stroke. In acute ischemic stroke patients, we first demonstrated that Kir4.1 ion channels were greatly impaired and a severe demyelination of axons occurred in ischemic infarction area of cerebral cortex in these patients. Further evidence showed that the deficits of Kir4.1 channels in NG2 glia led to the myelin loss of axons in a transient ischemic mouse model (tMCAO). Treating ischemic mice with a natural botanical extract, luteolin augmented Kir4.1 channel currents in NG2 glia and consequently promoted remyelination of axons, alleviated the infarction area and ultimately improved motor function in a series of behavioral tests. Targeting Kir4.1 ion channels expressed in NG2 glial cells by luteolin treatment highlights an effective therapeutic strategy for a prompt brain functional recovery in ischemic stroke. This work was supported by grants from the Ministry of Science and Technology China Brain Initiative (2022ZD0204702, to X.T.), the National Natural Science Foundation of China (82271466, 82171279, 31970904 and 31571063), the Program for Professor of Special Appointment (Eastern Scholar for Dr. X.T.) at Shanghai Institutions for Higher Learning (1510000084), Shanghai Pujiang Talent Award (15PJ1404600), Shanghai Municipal Science and Technology Major Project (2018SHZDZX05) and Shanghai Science and Technology Project (17411954000).

A Narrative Review of Advances in Neural Precursor Cell Transplantation Therapies for Spinal Cord Injury.

A spinal cord injury (SCI) is a destructive event that causes a permanent deficit in neurological function because of poor regenerative potential. Transplantation therapies have attracted attention for restoration of the injured spinal cord, and transplantation of neural precursor cells (NPCs) has been studied worldwide. Several groups have demonstrated functional recovery via this therapeutic intervention due to the multiple beneficial effects of NPC transplantation, such as reconstruction of neuronal circuits, remyelination of axons, and neuroprotection by trophic factors. Our group developed a method to induce NPCs from human induced pluripotent stem cells (hiPSCs) and established a transplantation strategy for SCI. Functional improvement in SCI animals treated with hiPSC-NPCs was observed, and the safety of transplanting these cells was evaluated from multiple perspectives. With selection of a safe cell line and pretreatment of the cells to encourage maturation and differentiation, hiPSC-NPC transplantation therapy is now in the clinical phase of testing for subacute SCI. In addition, a research challenge will be to expand the efficacy of transplantation therapy for chronic SCI. More comprehensive strategies involving combination treatments are required to treat this problematic situation.

Combining a Density Gradient of Biomacromolecular Nanoparticles with Biological Effectors in an Electrospun Fiber-Based Nerve Guidance Conduit to Promote Peripheral Nerve Repair.

Peripheral nerve injury is a serious medical problem with limited surgical and clinical treatment options. It is of great significance to integrate multiple guidance cues in one platform of nerve guidance conduits (NGCs) to promote axonal elongation and functional recovery. Here, a multi-functional NGC is constructed to promote nerve regeneration by combining ordered topological structure, density gradient of biomacromolecular nanoparticles, and controlled delivery of biological effectors to provide the topographical, haptotactic, and biological cues, respectively. On the surface of aligned polycaprolactone nanofibers, a density gradient of bioactive nanoparticles capable of delivering recombinant human acidic fibroblast growth factor is deposited. On the graded scaffold, the proliferation of Schwann cells is promoted, and the directional extension of neurites from both PC12 cells and dorsal root ganglions is improved in the direction of increasing particle density. After being implanted in vivo for 6 and 12 weeks to repair a 10-mm rat sciatic nerve defect, the NGC promotes axonal elongation and remyelination, achieving the regeneration of the nerve not only in anatomical structure but also in functional recovery. Taken together, the NGC provides a favorable microenvironment for peripheral nerve regeneration and holds great promise for realizing nerve repair with an efficacy close to autograft.

A Dual-network Nerve Adhesive with Enhanced Adhesion Strength Promotes Transected Peripheral Nerve Repair.

Peripheral nerve transection has a high prevalence and results in functional loss of affected limbs. The current clinical treatment using suture anastomosis significantly limits nerve recovery due to severe inflammation, secondary damage, and fibrosis. Fibrin glue, a commercial nerve adhesive as an alternative, avoids secondary damage but suffers from poor adhesion strength. To address their limitations, a highly efficacious nerve adhesive based on dual-crosslinking of dopamine-isothiocyanate modified hyaluronic acid and decellularized nerve matrix is reported in this paper. This dual-network nerve adhesive (DNNA) shows controllable gelation behaviors feasible for surgical applications, robust adhesion strength, and promoted axonal outgrowth in vitro. The in vivo therapeutic efficacy is tested using a rat-based sciatic nerve transection model. The DNNA decreases fibrosis and accelerates axon/myelin debris clearance at 10 days post-surgery, compared to suture and commercial fibrin glue treatments. At 10 weeks post-surgery, the strong adhesion and bioactivity allow DNNA to significantly decrease intraneural inflammation and fibrosis, enhance axon connection and remyelination, aid motor and sensory function recovery, as well as improve muscle contraction, compared to suture and fibrin treatments. Overall, this dual-network hydrogel with robust adhesion provides a rapid and highly efficacious nerve transection treatment to facilitate nerve repair and neuromuscular function recovery.

A new insight on peripheral nerve repair: the technique of internal nerve splinting.

Neuropathic pain produced by symptomatic neuromas is an important problem after peripheral nerve injury (PNI). End-to-end anastomosis of the nerve stump for PNI is well established but cannot efficiently prevent neuroma-in-continuity formation. Sciatic nerve injury was used in the experimental model. Seventy-two rats were randomly divided into four groups: rats with nerve anastomosis sites supported with silicone tubes represented the internal nerve splinting (INS) group (n = 18); rats with end-to-end nerve anastomosis represented control group 1 (CON1) (n = 18); rats with INS and the nerve anastomosis site represented control group 2 (CON2) (n = 18); and rats that underwent the same surgical procedures for skin and muscle operations but without sciatic nerve injury represented the normal group (n = 18). Gross evaluations of the nerve anastomosis sites, gastrocnemius muscle atrophy, axonal regeneration and remyelination, neuropathic pain, and scar hyperplasia of the neuromas were performed, as well as motor function evaluations. Axonal regeneration, remyelination, and gastrocnemius muscle atrophy were similar between the INS group and CON1 (p > 0.05). However, neuropathic pain and scar hyperplasia-as evaluated according to the expression of anti-sigma-1 receptor antibody and anti-α-smooth muscle actin, respectively-and the weight ratios of the neuromas were reduced in the INS group compared with those of CON1 and CON2 (p < 0.05). Application of INS in nerve repair effectively prevented traumatic neuroma-in-continuity formation and inhibited neuropathic pain without influencing nerve regeneration in rats.

Andrographolide contributes to spinal cord injury repair via inhibition of apoptosis, oxidative stress and inflammation.

Background: Spinal cord injury (SCI) is a common disorder of the central nervous system with considerable socio-economic burden. Andrographolide (Andro), the main active component of Andrographis paniculata, has exhibited neuroprotective effects in different models of neurological diseases. The aim of this study was to evaluate the neuroprotective effects of Andro against SCI and explore the related mechanisms. Methods: SCI was induced in rats by the Allen method, and the modeled animals were randomly divided into sham-operated, SCI, SCI + normal saline (NS) and SCI + Andro groups. The rats were injected intraperitoneally with Andro (1 mg/kg) or the same volume of NS starting day one after the establishment of the SCI model for 28 consecutive days. Post-SCI tissue repair and functional recovery were evaluated by measuring the spinal cord water content, footprint tests, Basso-Beattie-Bresnahan (BBB) scores, hematoxylin-eosin (HE) staining and Nissl staining. Apoptosis, oxidative stress and inflammation, as well as axonal regeneration and remyelination were analyzed using suitable markers. The in vitro model of SCI was established by treating cortical neurons with H2O2. The effects of Andro on apoptosis, oxidative stress and inflammation were evaluated as indicated. Results: Andro treatment significantly improved tissue repair and functional recovery after SCI by reducing apoptosis, oxidative stress and inflammation through the nuclear factor E2-related factor 2/heme oxygenase-1 (Nrf-2/HO-1) and nuclear factor-kappa B (NF-κB) signaling pathways. Furthermore, Andro treatment promoted M2 polarization of the microglial cells and contributed to axonal regeneration and remyelination to improve functional recovery after SCI. In addition, Andro also attenuated apoptosis, oxidative stress and inflammation in H2O2-stimulated cortical neurons in vitro. Conclusion: Andro treatment alleviated SCI by reducing apoptosis, oxidative stress and inflammation in the injured tissues and cortical neurons, and promoted axonal regeneration and remyelination for functional recovery.