Methylprednisolone (MP), a synthetic corticosteroid, has been extensively studied for its therapeutic mechanisms in spinal cord injury. Research indicates that MP can upregulate anti-inflammatory factors, reduce inflammatory cell infiltration, alleviate neural edema, prevent intracellular potassium depletion, stabilize membrane structures, inhibit lipid peroxidation and the generation of oxygen free radicals [2] , and suppress neuronal apoptosis [3] . The National Acute Spinal Cord Injury Study (NASCIS) [4] once recommended high-dose methylprednisolone pulse therapy for spinal cord injury: administration within 8 hours post-injury, with an initial dose of 30 mg/kg in the first hour, followed by 5.4 mg/kg/h over the subsequent 23 hours. This protocol was widely adopted in clinical practice, and some patients exhibited improved or restored neurological function after treatment. Subsequent animal studies by numerous researchers globally confirmed that high-dose MP could enhance motor and sensory function and promote neurological recovery in rats with spinal cord injury [5] [6] .

However, in recent years, the severe side effects associated with high-dose MP have drawn significant attention and sparked debate. Some scholars, based on multiple randomized controlled trials and observational studies, have concluded that high-dose MP therapy offers no long-term benefits and may instead increase the risk of complications—such as prolonged immunosuppression, sepsis, pulmonary infections, gastrointestinal ulcers and bleeding, and adrenal insufficiency [7] [8] —thereby causing additional suffering, delaying recovery, and in severe cases, endangering patients’ lives. Consequently, the 2013 edition of the “Guidelines for the Management of Acute Cervical Spine and Spinal Cord Injuries” no longer recommends high-dose MP pulse therapy as a standard treatment for acute spinal cord injury [9] . Instead, it is regarded merely as a therapeutic option rather than a routine protocol. Current clinical practice often employs medium-to-low dose methylprednisolone (e.g., a loading dose of 10 - 30 mg/kg, followed by appropriately tapered doses) in combination with other therapeutic modalities to better balance potential efficacy with safety concerns.

In light of this, recent approaches often combine MP with other treatments. For example, MP combined with mouse nerve growth factor [10] not only reduces inflammatory responses but also promotes nerve regeneration, more effectively improving neurological function and daily living activities. Similarly, MP combined with mild hypothermia therapy [11] synergistically mitigates inflammation and oxidative stress while reducing cellular metabolic demand, thereby better protecting neurons, lowering the risk of postoperative complications, and enhancing patients’ quality of life. After years of research and discussion, the use of MP for spinal cord injury has been relatively well-established. However, due to its significant side effects and limited benefits at high doses, it has gradually fallen out of clinical use in recent years, with its research prospects now being considerably constrained.

Gangliosides are a class of acidic glycolipid complexes that naturally occur as components of cell membranes, particularly abundant in the nerve cells of mammals. Exogenous monosialotetrahexosylganglioside (GM1) is the most commonly used ganglioside in clinical practice for treating spinal cord injury. Its pharmacological action is primarily achieved through binding to the neuronal cell membranes in the human body.

As GM1 is a natural constituent of mammalian neuronal membranes, it offers several advantages for spinal cord injury treatment, including the ability to cross the blood-brain barrier, a favorable safety profile, minimal adverse effects, and multiple routes of administration. These characteristics have made it a focus of recent research. Studies indicate that GM1 exerts neuroprotective effects through various mechanisms, such as reducing tissue edema, inhibiting neuronal apoptosis, suppressing lipid peroxidation, enhancing neuronal tolerance to hostile microenvironments, promoting synaptic remodeling, and facilitating nerve regeneration [12] - [15] .

Given the limited pharmacological options currently available for promoting neural repair, GM1 has increasingly been used in recent years as an adjunct therapy for spinal cord injury. It is often combined with methylprednisolone [16] , erythropoietin [17] , and other agents to achieve synergistic effects. Such combinations allow for reduced dosages of individual drugs, improve therapeutic outcomes, enhance safety, and mitigate side effects associated with drugs like methylprednisolone.

However, as gangliosides cannot yet be synthetically produced, their cost remains high. The need for long-term and high-dose GM1 treatment in most spinal cord injury patients imposes a substantial financial burden on families, which to some extent limits its widespread clinical application.

Following spinal cord injury, disruption of the blood-spinal cord barrier (BSCB) and local tissue acidosis occur. The massive generation of oxygen free radicals within the tissue induces lipid peroxidation, leading to local microvascular occlusion and spasm, which subsequently causes spinal cord ischemia, parenchymal edema, and neuronal death [18] . Therefore, it has been proposed that the use of oxygen free radical scavengers in the early stages of spinal cord injury may reduce neuronal cell death. In recent years, natural products such as curcumin and resveratrol have been widely investigated as agents to counteract oxygen free radicals after spinal cord injury.

Zhou Gongshe et al. [19] demonstrated through experiments on rats with spinal cord injury that curcumin significantly downregulates oxidative stress and inflammation levels and improves neurological function, primarily by inhibiting nuclear factor-kappa B (NF-κB) and Caspase-3. The regulatory effect of curcumin on oxidative stress after spinal cord injury is mainly reflected in the expression levels of antioxidant enzymes [20] . Although curcumin has been extensively studied in other central nervous system diseases, such as traumatic brain injury and Alzheimer’s disease [21] [22] , its antioxidant effects specifically in the context of spinal cord injury remain relatively underexplored. This indicates that the antioxidant mechanisms of curcumin in spinal cord injury require further investigation.

Resveratrol, a non-flavonoid polyphenolic organic compound, is a natural antioxidant. However, due to its poor solubility and limited ability to cross the blood-brain barrier, Li et al. [23] developed chitosan-modified hollow manganese dioxide nanoparticles (CM), while Zhang Yinyin et al. [24] designed functional selenium-doped silica nanoparticles for the delivery of resveratrol. Experimental studies have shown that carrier-mediated delivery of resveratrol enables rapid release at the injury site, directly decomposing reactive oxygen species into water and oxygen. This rapidly alleviates tissue hypoxia, suppresses oxidative stress and inflammatory responses at the lesion site, and promotes the recovery of motor function.

Currently, research on natural products for spinal cord injury is more prevalent in China than abroad. Further clinical trials are needed to confirm their efficacy and potential for clinical application.

After spinal cord injury, Ca²⁺ ions from surrounding areas flow into the injured tissue, leading to an overload of both total and intracellular Ca²⁺ levels. This results in reduced local spinal blood flow, increased oxygen free radical production, and further exacerbation of the injury. This process is recognized as a major pathway leading to neuronal death [25] . Consequently, some researchers have employed calcium channel antagonists to inhibit calcium influx and prevent the progression of secondary damage.

Nimodipine (NMD), a dihydropyridine calcium channel blocker commonly used in cerebrovascular diseases, binds to specific receptors in the central nervous system to prevent Ca²⁺ entry into cells. This reduces intracellular Ca²⁺ concentration, effectively decreasing free radical generation, attenuating neuronal death, improving spinal cord blood flow, and alleviating edema in spinal and surrounding cells, thereby exerting a neuroprotective effect.

Guo et al. [26] observed in experimental studies that after six weeks of NMD treatment, spinal cord-injured rats exhibited a reduction in lesion size and increased preservation of neurons around the injury site. These findings suggest that NMD treatment can mitigate the extent of damage in spinal cord injury, offering a potential therapeutic strategy.

However, the use of nimodipine may cause a decrease in mean arterial pressure and increase the risk of hypotension. Therefore, careful evaluation of the patient’s condition is essential before administration. Maintaining systemic blood pressure stability and ensuring adequate local perfusion are critical to avoid adverse events.

Currently, research on nimodipine for spinal cord injury remains largely confined to animal studies, and no clinical consensus has been reached regarding its use in treating human spinal cord injury.

Beyond the drugs discussed above, several other candidates are currently under investigation in preclinical or early clinical development stages. These include Minocycline (recognized for its anti-inflammatory and anti-apoptotic properties), Erythropoietin (implicated in both neuroprotection and angiogenesis), and small-molecule inhibitors targeting specific signaling pathways (such as Rho kinase inhibitors, ROCK inhibitors). These agents have demonstrated therapeutic potential in animal models but await validation in large-scale clinical trials, representing significant future directions for pharmacotherapeutic development in SCI.

Chuanxiong (Ligusticum chuanxiong) is known in traditional Chinese medicine as a “blood-activating and qi-moving herb,” primarily valued for its effects in promoting blood circulation, removing blood stasis, moving qi, and alleviating pain. Ligustrazine, also known as tetramethylpyrazine, is a bioactive monomer extracted from Chuanxiong and belongs to the class of amide alkaloids [27] .

Using network pharmacology analysis, Qi et al. [28] suggested that ligustrazine exhibits significant neuroprotective effects after spinal cord injury. Through experimental studies, Liu et al. [29] found that ligustrazine alleviates neuronal ferroptosis by modulating the GPX4/ACSL4 axis, thereby protecting surviving neurons around the lesion, reducing glial scar formation, decreasing lesion size, improving neuronal survival, and promoting functional recovery after spinal cord injury.

To further evaluate the clinical efficacy of different dosages, Du Fangtao et al. [30] conducted a study involving 90 non-surgical spinal cord injury patients, who were divided into control and observation groups. Both groups received conventional treatment, with the control group receiving 120 mg and the observation group 240 mg of ligustrazine via intravenous drip. After treatment, both groups showed increased Botsford and FIM scores compared to pre-treatment levels, with the observation group demonstrating significantly greater improvement. The study concluded that ligustrazine promotes functional recovery in spinal cord injury patients, with higher doses yielding more pronounced effects.

Although current studies have achieved certain progress in elucidating the mechanisms and clinical efficacy of ligustrazine in treating spinal cord injury, several limitations remain. For instance, most reported research—both domestic and international—is still based on animal experiments. There is no unified consensus regarding its clinical dosage and administration in spinal cord injury treatment, and further validation of its therapeutic effectiveness in clinical settings is still needed.

Curcumin, a compound isolated from the traditional Chinese herb turmeric (Curcuma longa), has attracted considerable research interest in recent years. Su Xiaochen et al. [31] demonstrated that curcumin can inhibit the inflammatory response following spinal cord injury by regulating the NLRP3 inflammasome, thereby promoting functional recovery in the limbs of rats. Feng Jianhao et al. [32] confirmed that curcumin suppresses the formation of glial scars by inhibiting the JAK/STAT3 signaling pathway, contributing to the repair of spinal cord injury. Weichao Li et al. [33] suggested that the therapeutic effect of curcumin on spinal cord injury may be achieved through enhanced autophagy, likely mediated by suppression of the Akt/mTOR signaling pathway.

In summary, curcumin modulates multiple signaling pathways in vivo, exerting effects such as inhibiting neuroinflammation, alleviating spinal cord edema, reducing oxidative stress, suppressing neuronal apoptosis, diminishing glial scar formation, and promoting neuronal repair and regeneration [34] [35] , thereby mitigating spinal cord injury.

With its low toxicity and ability to cross the blood-brain barrier, curcumin holds promising potential for the treatment of spinal cord injury. However, its clinical application is limited by rapid hepatic metabolism and a short half-life [36] , which necessitate further pharmaceutical improvements. Current research on curcumin for spinal cord injury remains constrained by certain limitations, including a lack of large-scale, multi-center clinical studies and insufficient evidence-based medical support.

Panax notoginseng is a commonly used herb in traditional Chinese medicine for promoting blood circulation and removing blood stasis, primarily cultivated in Yunnan and Guangxi provinces of China. The primary bioactive components responsible for its medicinal effects are Panax notoginseng saponins (PNS). PNS is known for its multiple pharmacological properties, including dissipating stasis, stopping bleeding, reducing swelling, relieving pain, tonifying qi and blood, inhibiting platelet aggregation, exerting anti-inflammatory effects, and providing antioxidant benefits [37] . Its potential in neuroprotection has increasingly become a focus of research.

Studies have demonstrated that PNS protects nerve cells through several mechanisms: inhibiting oxidative stress, promoting the release of nerve growth factors to nourish neurons, facilitating glial cell generation to reduce scar formation, and directly dilating blood vessels to improve blood flow in the injured spinal cord area [38] [39] .

Current research reports indicate that PNS has certain therapeutic effects on the recovery of neurological and motor functions following spinal cord injury, showing promising potential for further investigation. However, most studies on PNS remain at the animal experiment stage in China, with limited international attention and publications on its application. Therefore, extensive clinical research is still needed to further clarify its efficacy and support its future translation into clinical practice.

Salvia miltiorrhiza, known as Danshen in Chinese, is traditionally used to promote blood circulation, remove blood stasis, clear heart fire, calm the mind, cool the blood, and reduce swelling [40] . Clinically, Salvia miltiorrhiza injection is commonly employed in the treatment of acute spinal cord injury (SCI). Compared to international research, domestic studies in China on its application for SCI are more extensive and in-depth.

Although Salvia miltiorrhiza cannot reverse already damaged neurons, it can protect unaffected or injured but viable nerve cells from further secondary damage, providing broad neuroprotective effects. It acts through multiple dimensions and pathways to improve neurological function in central nervous system (CNS) disorders, and is used in the prevention and treatment of various prevalent CNS conditions such as stroke, spinal cord injury, Alzheimer’s disease, Parkinson’s disease, and epilepsy [41] .

Current research suggests that Salvia miltiorrhiza exerts its neuroprotective effects in spinal cord injury by inhibiting neuroinflammation, dilating local microcirculation, suppressing apoptosis, reducing oxidative stress, and promoting the expression of neurotrophic factors [42] [43] . However, Jiang Yiyuan et al. [44] found through experiments that ligustrazine outperforms tanshinone IIA (a primary active component of Danshen) in suppressing inflammatory responses and protecting neurons. As research progresses, some scholars propose that Salvia miltiorrhiza may be more effective when used in combination with other agents, producing synergistic effects for enhanced recovery after SCI. A commonly studied combination is Salvia miltiorrhiza with Chuanxiong (Ligusticum chuanxiong), both herbs known for activating blood and moving qi. Liu Gang et al. [45] used network pharmacology to identify 484 potential targets for the Chuanxiong-Danshen pair in SCI treatment. Protein-protein interaction (PPI) network analysis revealed extensive interactions among these targets, with APP, PI3K, MAPK1/3, and AKT1 being the most critical proteins. Enrichment analysis indicated that the combination primarily alleviates secondary spinal cord injury by activating the PI3K/AKT signaling pathway.

Nevertheless, research on Salvia miltiorrhiza for SCI still has limitations. For instance, Salvia miltiorrhiza contains numerous active components, yet most studies focus only on tanshinone IIA. Other constituents contributing to neuroprotection remain incompletely identified and require further experimental validation, representing a promising direction for future research. Additionally, the relatively mild efficacy of Salvia miltiorrhiza and the lack of long-term clinical studies on its therapeutic outcomes have led to considerable controversy regarding its effectiveness.

Buyang Huanwu Decoction is composed of seven herbs: Radix Astragali (raw Huangqi), Rhizoma Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Dangguiwei), Pheretima (Dilong), Semen Persicae (Taoren), Flos Carthami (Honghua), and Radix Paeoniae Rubra (Chishao). Together, these components work to tonify qi, activate blood circulation, and unblock collaterals. It is widely used for treating hemiplegia, facial deviation, and speech difficulties resulting from stroke with qi deficiency and blood stasis syndrome [46] .

In traditional Chinese medicine, spinal cord injury is viewed as an impairment of the Governor Vessel (Du Mai) with stasis obstructing the collaterals, compounded by severe depletion of primordial qi and prolonged lying, leading to further qi injury. This condition often corresponds to the pattern of qi deficiency and blood stasis. Consequently, some researchers propose the use of Buyang Huanwu Decoction for spinal cord injury, although its precise mechanisms remain incompletely elucidated.

Experimental studies by Guo Dehua et al. suggest that Buyang Huanwu Decoction promotes the proliferation of spinal astrocytes in rats with spinal cord injury and inhibits the formation of glial scars, thereby facilitating the recovery of motor function. Domestic research has reported multiple potential mechanisms, including activation of the PI3K/Akt/mTOR pathway [47] , inhibition of the JAK2/STAT3 signaling pathway [48] , promotion of neuronal regeneration through key pathways such as BDNF/TrkB [49] , reduction in platelet-activating factor (PAF) content in spinal tissue [50] , downregulation of malondialdehyde (MDA) levels, and upregulation of superoxide dismutase (SOD) activity to protect vascular endothelial cells from oxygen free radical damage [51] . These effects collectively contribute to inhibiting neuronal apoptosis, reducing spinal inflammation, and mitigating secondary injury.

However, the exact therapeutic mechanisms are still not fully understood. Further research is encouraged to provide more robust theoretical foundations for the application of Buyang Huanwu Decoction in treating spinal cord injury.

Jisuikang is an empirical formula developed by Professor Wang Jianwei, a renowned traditional Chinese medicine practitioner in Jiangsu Province. It is composed of the following herbs: raw Astragalus root (Sheng Huangqi), Chinese angelica (Danggui), Sichuan lovage (Chuanxiong), salvia root (Danshen), red peony root (Chishao), leech (Shuizhi), centipede (Wugong), prepared rhubarb (Zhi Dahuang), alismatis rhizome (Zexie), poria (Fuling), immature bitter orange (Zhishi), magnolia bark (Houpo), cistanche (Roucongrong), epimedium (Yinyanghuo), ground beetle (Dibiechong), plantain seed (Cheqianzi), and bitter cardamom (Yizhiren). The formula collectively acts to remove stasis, unblock the Governor Vessel (Du Mai), and harmonize qi and blood [52] .

Jisuikang has been demonstrated to improve local microcirculation at the site of spinal cord injury, prevent secondary damage, effectively reduce the occurrence of complications, and facilitate repair and neural functional reconstruction in the injured area [53] . Recent experimental studies suggest that its mechanisms include inhibiting the activation of astrocytes [53] , significantly suppressing glial scar formation and the expression of CSPG in the injured region [54] , downregulating GFAP expression to control glial scar formation [55] , promoting the activation of both M1 and M2 microglia [56] , and inhibiting the NLRP3 inflammasome [57] . These actions collectively contribute to improving local microcirculation, controlling glial scar formation, alleviating secondary injury, and promoting the recovery of neurological function, offering a new direction for comprehensive pharmacological treatment of spinal cord injury.

A current research limitation is that studies on the mechanism of Jisuikang are largely confined to its inhibitory effects on glial scar formation, indicating a need for broader investigation into other potential pathways and systemic effects.

Nerve growth factor (NGF), a member of the neurotrophin protein family, was the first neurotrophic factor to be discovered. Although present in relatively low concentrations in the central nervous system (CNS) under physiological conditions, it plays an essential role in the growth, development, and maturation of nerve cells [58] [59] .

When the CNS is injured, the body upregulates the secretion of NGF to promote neuronal growth, development, and repair. However, in cases of moderate to severe injury, endogenous NGF production is insufficient to provide adequate protection and repair, and its effects are short-lived. Therefore, exogenous administration of NGF is necessary to compensate for this deficiency [60] .

Extensive research has confirmed that exogenous NGF supplementation can inhibit apoptosis of spinal neurons, prevent or mitigate secondary damage, preserve residual spinal function, promote axonal regeneration, and facilitate neurological recovery following spinal cord injury, thereby improving patients’ quality of life. Moreover, NGF therapy is associated with minimal toxic side effects and a high safety profile, making it a promising candidate for clinical application and a focus of recent investigation [61] .

However, conventional methods of NGF administration are limited by the blood-brain barrier, which restricts its therapeutic efficacy in promoting neurological recovery. Advances in stem cell therapy have led researchers to explore the induction of neural stem cells (NSCs) to stimulate neuronal differentiation in SCI models. Consequently, transplantation of genetically modified NSCs to regulate NGF delivery has garnered significant attention. For instance, Chen Mengji et al. [62] used adeno-associated virus (AAV) as a vector to engineer genetically modified NSCs and transplanted them into rats with spinal cord injury. They found that these NSCs not only differentiated effectively into neurons and astrocytes, promoting repair, but also enhanced NGF secretion, thereby protecting adjacent damaged neurons and reducing neuronal death.

This approach represents a promising strategy for treating SCI and offers novel therapeutic insights. Nevertheless, challenges such as technical complexity, high costs, and a lack of clinical efficacy data currently hinder its widespread clinical adoption.

Vascular endothelial growth factor (VEGF) not only demonstrates potent angiogenic capabilities but also exhibits significant potential in neuroprotection and neural repair [63] . As a pro-angiogenic factor, VEGF promotes blood vessel formation by activating endothelial cells, thereby enhancing blood supply to neurons, improving the microenvironment of neural tissues, and facilitating neural recovery following spinal cord injury [64] . Additionally, studies have shown that VEGF can promote axonal regeneration, further contributing to functional restoration after SCI [65] . However, achieving optimal therapeutic outcomes requires precise regulation of VEGF expression levels, a challenge that necessitates further in-depth investigation.

Following spinal cord injury (SCI), endogenous recovery attempts are hindered by several factors: inactivation of regenerative pathways in neurons and their stem cells; myelin debris and associated inhibitory molecules such as Nogo, myelin-associated glycoprotein (MAG), and oligodendrocyte-myelin glycoprotein (OMgp); and inhibitory extracellular matrix components [66] . In light of these barriers, cell and gene therapies have emerged as promising strategies for traumatic SCI in recent years.

Gene therapy involves modifying gene expression—for instance, through transfection of genes encoding neurotrophic factors or axonal guidance molecules—to promote neural regeneration [67] . It offers high selectivity and specificity while potentially reducing the side effects associated with conventional pharmacological treatments. Although this approach has attracted significant research interest, it remains largely experimental and has not yet entered clinical use. Widespread clinical application will require resolving challenges such as immune rejection, economic feasibility, and long-term safety, all of which warrant further investigation.