The Role of Saponins in the Neuropathic Pain: Comparison
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神经性疼痛是由体感神经系统受累的组织损伤或疾病引起的慢性疼痛，严重影响患者的身体机能和生活质量。皂苷是一类结构多样的化合物，由皂苷元和糖基组成。构成皂苷的糖类常见的有Neuropathic pain is a chronic pain caused by tissue injury or disease involving the somatosensory nervous system, which seriously affects the patient’s body function and quality of life. Saponins are a class of compounds with diverse structures, consisting of sapogenin and glycosyl groups. The common ones of the saccharides that make up saponins are D-葡萄糖、D-半乳糖、D-木糖、L-阿拉伯糖、L-鼠李糖等。 glucose, D-galactose, D-xylose, L-arabinose, and L-rhamnose, etc.

  • neuropathic pain
  • saponins
  • mechanism

1.人参皂甙

人参皂甙是人参的主要生物活性成分

1. Ginsenosides

Ginsenosides are the major biologically active components of ，具有广泛的药理活性。根据其苷元的骨架，人参皂苷可分为两类，四环三萜达玛烷型皂苷（原人参二醇（Ginseng, which have a wide range of pharmacological activities. According to the skeleton of their aglycones, ginsenosides can be classified into two groups, tetracyclic triterpene dammarane-type saponins (protopanaxadiol (PPD）型，原人参三醇（)-, protopanaxatriol (PPT）型）（图1)-type) (Figure 1A）和四环三萜齐墩果烷型皂苷[) and tetracyclic triterpene oleanane-type 48saponins ,[1][2][3]. 49So far, 50more than ]。迄今为止，已分离出100多种不同的人参皂苷单体，如人参皂苷Rb1、Rb2、Rc、Rd、Re、Rg1和Rf，它们的药理和药代动力学特性各不相同[ different ginsenoside monomers have been isolated, such as ginsenosides Rb1, Rb2, Rc, Rd, Re, Rg1, and Rf, the pharmacological and pharmacokinetic properties of which are 51、52different ]。
[4][5].
Molecules 27 03956 g002 550
图Figure 1. 人参皂苷（Chemical structures of ginsenosides (A）、柴胡皂苷（), saikosaponins (B）、黄芪甲苷（), astragaloside IV (C）、薯蓣皂苷元和薯蓣皂苷（), and diosgenin and dioscin (D）的化学结构（注：) (Note: PPD，原人参二醇；PPT，原人参三醇；Glc，葡萄糖苷；Rha，鼠李糖苷；Fuc，果糖苷）。, protopanaxadiol; PPT, protopanaxatriol; Glc, glucoside; Rha, rhamnoside; Fuc, fructoside).
基于动物模型的数据表明，人参皂苷在神经性疼痛中发挥有益作用。在 Data based on animal models have shown that ginsenosides play a beneficial role in neuropathic pain. In a study conducted by Jee Youn Lee 等人进行的一项研究中。[et al. [6], peripheral and central neuropathic pain was induced by tail nerve injury or contusive 21]，外周和中枢神经性疼痛分别由雄性spinal SDcord 大鼠的尾神经损伤或挫伤性脊髓损伤injury (SCI) 引起。口服总皂苷（TSE）人参皂甙Rb1后显示出显着的镇痛作用。研究发现，TSE和人参皂甙Rb1抑制小胶质细胞/星形胶质细胞的活化，降低炎症因子水平，如白细胞介素1β（IL-1β）、白细胞介素6（IL-6）、诱导型一氧化氮合酶（iNOS）、和环氧合酶in male SD rats, respectively. Remarkable analgesic effects were shown after the application of oral total saponin extract (TSE), ginsenoside Rb1. The research found that TSE and ginsenoside Rb1 inhibited the activation of microglia/astrocytes, and attenuated inflammatory factors levels, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2)。进一步的结果表明，TSE、人参皂甙 Rb1 和 Rb1-代谢物-化合物 K 也发挥可能通过雌激素受体介导的镇痛作用。高超等人进行的其他研究。据报道，鞘内注射人参皂苷 Rg1 以剂量依赖性方式显着抑制慢性缩窄性损伤（CCI）诱导的热痛觉过敏。它可能通过抑制磷酸化 p38 丝裂原活化蛋白激酶. Further results demonstrated that TSE, ginsenoside Rb1, and Rb1-metabolite-compound, K, also exerted analgesic effects that might be mediated through the estrogen receptor. Other research conducted by Gao Chao et al. reported that intrathecal injection of ginsenoside Rg1 significantly inhibited chronic constrictive injury (CCI)-induced thermal hyperalgesia in a dose-dependent manner. It might be mediated by inhibiting the expression of phosphorylated p38 mitogenactivated protein kinase (p-p38MAPK) 和核因子and nuclear factor kappa-B (NF-κB) 亚基磷酸化 p65 的表达，以及离子化钙结合接头分子subunit phosphorylated p65, and the activation of ionized calcium binding adaptor molecule-1 (IBA-1) 的激活来介导在脊髓小胶质细胞中，导致中枢敏化的下调[22in the spinal microglia, resulting in downregulation of the central sensitization ]。此外，其他研究表明，在[7]. CCI 大鼠的脊髓和 DRG 中，人参皂甙 Rf 显着降低了n addition, other studies showed that ginsenoside Rf robustly decreased IL-1β 和 IL-6，但增加了背根神经节and IL-6, but increased the expression of IL-10 in the dorsal root ganglion (DRG) 中 IL, in both the spinal cord and DRG of CCI rats [8]. Thus, ginsenoside Rf may adjust the balance between proinflammatory and anti-10inflammatory factors to promote its antinociceptive effect in neuropathic pain. Many studies have revealed the key role of proinflammatory cytokines in the pathophysiology of neuropathic pain [9][10][11][12]. The above studies all explained that related 的表达ginsenosides [inhibited 23inflammation ]。因此，人参皂甙through Rf 可以调节促炎因子和抗炎因子之间的平衡，从而促进其在神经性疼痛中的镇痛作用。
许多研究揭示了促炎细胞因子在神经性疼痛的病理生理学中的关键作用different pathways to relieve [neuropathic 53pain. Furthermore, 54other studies ,have 55shown ,that 56ginsenoside ]。上述研究均说明相关人参皂苷通过不同途径抑制炎症以缓解神经性疼痛。此外，其他研究表明，人参皂甙Rb1抑制神经元凋亡[ inhibits neuronal apoptosis [13] and promotes the neurogenesis and regulates the expressions of brain-derived neurotrophic 24factor ]，促进神经发生，调节脑源性神经营养因子（(BDNF）和) and caspase-3的表达，发挥神经保护作用[ to play a neuroprotective effect [14]. On the other hand, clinically chronic pain patients are often accompanied by depression, and some depressive patients also have chronic somatic pain symptoms [15]. Therefore, the relationship between pain and the occurrence of depression has become the focus of recent studies. It has shown that intraperitoneal 57injection ]。另一方面，临床上慢性疼痛患者常伴有抑郁症，部分抑郁症患者还伴有慢性躯体疼痛症状[of 58 ]]。因此，疼痛与抑郁症发生的关系成为近期研究的重点。研究表明，腹腔注射人参皂甙ginsenoside Rg2 not only alleviates the mechanical allodynia and 不仅可以缓解 CCIthermal hyperalgesia, but also relieves anxiety and depression in CCI rats [16], though its underlying mechanism needs to be further explored. So far, most of the analgesic mechanisms of ginsenosides in the 大鼠的机械性异常性疼痛和热痛觉过敏，还可以缓解焦虑和抑郁neuropathic pain are limited to the exploration of inflammatory factors, lacking in-depth analysis of its targeted molecular targets. In addition, whether the regulatory effects of ginsenosides are related with different neuropathic pain-related brain regions is still largely unknown. Further studies focusing on these points may provide a research basis for the precise regulation of drugs.

2. Saikosaponins

Saikosaponins are [derived 59 ]]，尽管其潜在机制需要进一步探索。迄今为止，人参皂苷在神经性疼痛中的镇痛机制大多局限于对炎症因子的探索，缺乏对其靶向分子靶点的深入分析。此外，人参皂甙的调节作用是否与不同的神经性疼痛相关脑区有关，在很大程度上仍是未知数。围绕这些点开展进一步的研究可为药品的精准调控提供研究依据。

2.柴胡皂苷

柴胡皂甙是从from 传统中药材之一Bupleurum 的伞形科中的柴胡or （  Bupleurum  scorzonerifolium）中 in the Umbelliferae, one of the traditional Chinese herbal medicines, and are the main active ingredients of 提取的，是柴胡的主要活性成分Bupleurum [[17]. So far, more 60than ]。迄今为止，已从柴胡中分离出100多种柴胡 kinds of saikosaponins have been isolated from 皂甙，其中主要有齐墩果烷和熊果五环三萜皂甙[Bupleurum, the main ones of which are oleanane and ursolic pentacyclic triterpene saponins [18][19][20][21][22]. According to their chemical structure, saikosaponins are divided into 61,62,63,64,65]。柴胡皂苷按其化学结构分为-A、, -B、-C、-D、-M、-N、-P、-T类，其中柴胡皂苷D（SSD）被认为是活性最高的一类，其次是柴胡皂苷, -C, -D, -M, -N, -P, and -T categories, and Saikosaponin D (SSD) is considered to be the most active one, followed by Saikosaponin A (SSA) [23][24]. [Their chemical 66structures ,are 67shown ]。它们的化学结构in 如图Figure 1B. Both B所示。
体内外实验研究均表明，柴胡皂苷能抑制瞬时受体电位锚蛋白in vivo and in vitro experimental studies have shown that saikosaponins can inhibit the activation of transient receptor potential ankyrin 1（ (TRPA1）的激活，显着降低异硫氰酸烯丙酯（AITC）诱导的动物伤害性反应[) and significantly reduce the nociceptive response of animals induced by allyl isothiocyanate (AITC) [25]. Molecular docking and site-directed mutagenesis analyses 25demonstrated ]。分子对接和定点诱变分析表明，柴胡皂苷与that Asn855 残基附近的saikosaponins bind to the TRPA1 疏水袋结合，后者一旦突变为 Ser，并且以前与增强的人类疼痛感知结合在一起 [hydrophobic pocket near the Asn855 residue, which once mutated to Ser and was previously united with enhanced pain perception 25in ,humans 68[25][26]. ]。Gyeongbeen 还报道，SSD 的多次给药可以显着缓解长春新碱诱导的机械超敏反应，这部分是通过抑制also reported that multiple administrations of SSD could significantly relieve mechanical hypersensitivity induced by vincristine, which was carried out partially by suppressing the activity of TRPA1 的活性来实现的[25]. Therefore, it can be further speculated [that 25]。因此，可以进一步推测SSD可能在化疗药物、糖尿病或 might play a certain therapeutic role in the neuropathic pain that is induced by chemotherapeutics, diabetes, or CCI诱发的神经性疼痛中发挥一定的治疗作用，其中TRPA1的表达和敏感性也发生了改变，导致疼痛反应和知觉异常。 [, in which the expression and sensitivity of TRPA1 were changed as well, resulting in abnormal pain response and 69、70、71、72、73 ]。_perception _[27][28][29][30][31]. _However, _the _analgesic _effect _of 然而，SSD 的镇痛作用在链脲佐菌素SSD is different between streptozotocin (STZ) 和紫杉​​醇诱导的疼痛模型之间是不同的。前者短期口服有效，后者需要多次给药才能缓解疼痛[- and paclitaxel-induced pain models. Short-term oral administration was effective in the former, while multiple administrations were required for the pain relief of the latter [32]. This indicates that the analgesic effect 26]。这表明of SSD may 的镇痛作用不仅可以作为not only act as an antagonist of TRPA1 的拮抗剂，还可以发挥抗炎活性，减少神经损伤引起的氧化应激。相关研究报道，SSD可以抑制糖皮质激素受体向线粒体的易位，减少, but also exert anti-inflammatory activity to reduce the oxidative stress caused by nerve damage. Related research reported that SSD could restrain the translocation of the glucocorticoid receptor to the mitochondria, and decrease the H2O2-induced 2phosphorylation of extracellular-regulated Okinase 2诱导的细胞外调节激酶（(ERK）、), c-Jun N-末端激酶（c-JNK）和terminal kinase (c-JNK), and p38MAPK 下调神经元to downregulate the activity of neuronal PC12 细胞的活性cells [[33][34][35]. It 27is ,well 74known ,that 75activation ]。
众所周知，DRGof 和脊髓神经元中 NF-κB 的激活与伤害感受信息的转导和处理有关。因此，抑制in both DRG and spinal cord neurons is associated with the transduction and processing of nociceptive messages. Therefore, inhibition of NF-κB 可以缓解慢性疼痛状态can alleviate chronic painful states [36]. Studies have [shown 76that ]。研究表明，SSA 通过抑制 CCI 诱导的脊髓alleviates neuropathic pain by inhibiting CCI-induced elevation of p-p38 MAPK 和and NF-κB 水平升高来减轻神经性疼痛levels in the spinal cord [37]. In addition, cytokine dysregulation is one of the characteristic manifestations of neuropathic pain symptoms [38]. It could [also 28be ]。此外，细胞因子失调是神经性疼痛症状的特征性表现之一found [that 77]。还可以发现，SSA 显着抑制某些免疫相关细胞毒因子的表达，包括significantly inhibited the expression of certain immune-related cytotoxic factors, including COX-2 和 iNOS，以及类似的促炎细胞因子，如and iNOS, and, likewise, the pro-inflammatory cytokines, such as TNF-α、IL-1β 和 IL-6 . 同时，重要的抗炎细胞因子, IL-1β, and IL-6. Meanwhile, the expression of the important anti-inflammatory cytokine IL-10 的表达显着上调，表明它在脂多糖 was significantly upregulated, suggesting that it had anti-inflammatory activity in lipopolysaccharide (LPS) 刺激的巨噬细胞中具有抗炎活性-stimulated macrophages [39][40]. Further [research 29showed ,that 30]。进一步的研究表明，SSA 通过阻止blocked the NF-κB signaling pathway by preventing phosphorylation of the NF-κB 抑制剂inhibitor α (IκBα) 的磷酸化来阻断 NF-κB 信号通路，从而使 , thereby allowing p65 NF-κB 保留在细胞质中，防止其转移到细胞核。此外，SSA 通过下调to remain in the cytoplasm, preventing it from translocating to the nucleus. In addition, SSA inhibited the MAPK signaling pathway by downregulating the phosphorylation of p38 MAPK、c-JNK 和 ERK 的磷酸化来抑制, c-JNK, and ERK to exert the anti-inflammatory activity MAPK[40]. 信号通路，从而发挥抗炎活性On [the 30basis, ]。在此基础上，SSA 似乎通过抑制水通道蛋白 appeared to counteract the neurological function deficits after traumatic brain injury via inbiting aquaporin-4 (AQP-4) 和基质金属蛋白 and matrix metalloprotein-9 (MMP-9) 来抵消创伤性脑损伤后的神经功能缺陷，以解释其神经保护作用 to account for its neuroprotective effects [41]. On the other hand, a study [of 31]。另一方面，Seong Shoon Yoon 等人的研究。表示et al. expressed that SSA 主要通过介导 exhibited a significant inhibitory effect on morphine-reinforced behavior and drug addiction predominantly via mediating GABAB 受体对吗啡强化行为和药物成瘾表现出显着的抑制作用receptors [[42][43]. 78 , 79 ]。Davoud Ahmadimoghaddam 等人。据报道，et al. reported that Bupleurum falcatum 以L. roots essential oil, of which SSA was one of the main constituents [44], exerted its antinociceptive and antiallodynic effects through the regulation 为主要成分之一的柴胡 精油，通过调节of L-精氨酸-NO arginine-NO-cGMP-KATP 通道通路，以及与阿片类药物、过氧化物酶体增殖物激活的和大麻素受体channel pathways, as well as interaction with opioid, peroxisome proliferator-activated, and cannabinoid receptors [44]. The voltage-gated [sodium 32]。电压门控钠通道channel Nav1.7 是一种对河豚毒素敏感的钠通道亚型，由is a tetrodotoxin-sensitive sodium channel subtype and is encoded by SCN9A 编码。众所周知，. It is well known that the dysfunction of Nav1.7 的功能障碍与疼痛障碍有关 has the correlation with pain disorders [45]. Relevant research [showed 80that ]。相关研究表明，SSA通过对 displayed the analgesic effects on the thermal pain and formalin-induced pain in mice via strong inhibitory effect on the peak currents of Nav1.7峰值电流的强抑制作用，对小鼠热痛和福尔马林引起的疼痛具有镇痛作用[ [46]. The above studies have shown 33that ]。
上述研究表明，SSD和 and SSA可通过多种途径在不同的神经性疼痛模型中发挥镇痛作用，其作用机制有异同。后续可以结合它们的结构特点和作用机制进行深入分析，为靶点的精准调控提供研究依据。

3. 黄芪甲苷

黄芪，黄芪 can exert analgesic effects in different neuropathic pain models through multiple pathways, and their mechanisms of action have similarities and differences. In the follow-up, we can combine their structural characteristics with the mechanisms of action for deep analysis to provide a research basis for the precise regulation of the targets.

3. Astragalosides

Astragali Radix, the dried roots of Astragalus membranaceus （(Fisch.）Bge) Bge.  的干燥根 。变种。var. mongholicus  (Bge.) Hsiao，或, or 黄芪Astragalus membranaceus (Fisch.) Bge.，被称为高档中药, is known as a high-grade traditional Chinese medicine [47]. There are three main types of compounds in astragalus: saponins, flavonoids, and polysaccharides, and triterpene saponins are the major constituents [48][49][50]. It is reported that more than 40 kinds of saponins have been isolated and identified from the dried [astragalus 81roots ]。黄芪中的化合物主要有三类：皂甙、黄酮和多糖，其中三萜皂甙是主要成分[via 82、83、84]。据报道，通过HPLC和 and GC-MS从干燥的黄芪根中分离鉴定了40多种皂苷，如黄芪甲苷I-VIII、乙酰黄芪甲苷、异黄芪甲苷I、III、黄芪甲素II、环黄芪甲苷、环黄芪苷B、短叶黄芪苷等。, such as astragalosides I–VIII, acetylastragaloside, isoastragaloside I, III, astramembrannin II, cycloastragenol, cycloascauloside B, brachyoside B, astrasieversianin X, 等etc. [[51][52][53][54]. 85Among these, 86astragaloside ,IV 87 , 88 ]。其中，黄芪甲苷（(AS-IV）被称为主要活性成分和定性控制生物标志物。) is known as the major active ingredient and qualitative control biomarker. AS-IV是3 -O-β- is 3-O-beta-d-xylopyranosyl-6-O-β--xylopyranosyl-6-O-beta-d-吡喃葡萄糖基-glucopyranosyl-环黄芪醇（图1cycloastragenol (Figure 1C), the molecular formula ），分子式为is C 41 H 68O 14 [55]. It  [is generally accepted that the transient receptor 89potential ]。
人们普遍认为，瞬时受体电位香草素vanilloid 1 (TRPV1) channel is a polymodal receptor for various 通道是一种对热毒和辣椒素等各种刺激的多模式受体，也是一种重要的疼痛传感器 [stimuli such as noxious heat 90and capsaicin, 91and is also an important pain sensor [56][57]. ]。在炎症或神经损伤的情况下，TRPV1 在 Aδ 纤维和 C 纤维中过度表达is overexpressed in Aδ fibers and C fibers in the situation of inflammation or nerve injury [58]. [In 92addition, ]。此外，嘌呤能purinergic P2×3 受体是配体门控的非选择性阳离子通道，在与伤害感受信息相关的小直径和中等直径感觉神经元中高度选择性表达，在病理性疼痛的产生和维持中起关键作用[ × 3 receptors are ligand-gated nonselective cation channels, highly selectively expressed in small-diameter and medium-diameter sensory neurons related to nociceptive information, and play a key role in the generation and maintenance of pathological pain [59][60]. In the research 93，94]。在by Guo-Bing Shi 等人的研究中，et al., AS-IV 不仅显着下调 Aδ 纤维中not only dramatically downregulated the expression of TRPV1 的表达，显着上调伤害性阈值，而且抑制 DRG 神经元中 P2×3 的表达，从而减轻机械性异常性疼痛 in Aδ fibers to remarkably upregulate the nociceptive threshold, but also inhibited P2 × 3 expression in DRG neurons to attenuate the mechanical allodynia [[61]. 34Meanwhile, ]。同时，AS-IV 通过在雪旺细胞和神经细胞之间的髓鞘碎片中积累胶质细胞源性神经营养因子家族受体α1（GFRα1），即胶质细胞源性神经营养因子（GDNF）选择性受体，恢复了受损坐骨神经的组织学结构。受损的轴突 restored the histological structure of the damaged sciatic nerve by accumulating glial cell-derived neurotrophic factor family receptorα1 (GFRα1), the glial cell derived neurotrophic factor (GDNF) selective receptor, in the debris of myelin between the Schwann cells and the damaged axon [61]. It [also 34reduced ]。它还降低了the DRG 中levels of GFRα1 和and GDNF 的水平，这些水平由 CCI 高度表达和诱导，有助于恢复受损的神经纤维in DRG, which were highly expressed and induced by CCI, contributing to the restoration of injured nerve fibers [62][63]. In the [peripheral 95nervous system, 96]。
在周围神经系统中，适当剂量的the appropriate dose of AS-IV也能大大促进周围神经的再生[ could also greatly promote the regeneration of peripheral nerves [64]. 35Growth-associated ]。生长相关蛋白protein 43 在脊髓 L4-6 段中较低，但在正常 is lower in spinal cord segments L4–6 but active in growing neuronal axons in normal Balb/c 小鼠的生长神经元轴突中活跃。作为神经损伤中的一种特殊生物标志物，它在神经生长中起着至关重要的作用，并与神经元轴突生长密切相关 [mice. As a particular biomarker in 36nerve injury, it 89plays a vital role in nerve growth, and 97strongly associates with neuronal axon growth [55][65][66][67]. Previous research showed ,that 98]。既往研究表明，AS-IV 显着上调再生神经组织中生长相关蛋白significantly upregulated the expression of growth-related protein 43 的表达，从而增加小鼠坐骨神经中有髓神经纤维的数量和直径，同时提高运动神经传导速度和动作电位幅度。36in regenerated nerve tissue, thereby increasing the number and diameter of myelinated nerve fibers in the sciatic nerve of mice, while elevating motor nerve conduction velocity and action potential amplitude [65]. Moreover, ]。此外，AS-IV 还对 STZ 诱导的糖尿病大鼠的周围神经病变产生镇痛作用。首先，它降低了糖尿病大鼠的血糖和糖化血红蛋白also conducted analgesic effects on peripheral neuropathy in STZ-induced diabetic rats. Firstly, it reduced blood glucose and glycosylated hemoglobin (HbA1C) levels, and increased plasma insulin levels in diabetic rats [68]. It is crucial 1 C) 水平，并增加了血浆胰岛素水平 [ 37to control the levels of ]。控制 HbA HbA1水平至关重要C，因为它的浓度与糖尿病相关并发症的发生率密切相关，这已被临床试验证明 because its concentration is closely related to the incidence of diabetes-related complications, which has been proven by clinical trials [[69]. 99Secondly, ]。其次，AS-IV 增强了神经中谷胱甘肽过氧化物酶的活性，抑制了红细胞中醛糖还原酶的活化，减少了神经和红细胞中晚期糖基化终产物的积累，这不仅可能激活细胞抗氧化防御系统，而且还增强了抗氧化应激损伤对周围神经的能力。第三，AS-IV作为AR抑制剂，然后增强 enhanced the activity of glutathione peroxidase in nerves, suppressed the activation of aldose reductase in erythrocytes, and decreased the accumulation of advanced glycation end products in both nerves and erythrocytes, which might not only activate the cellular antioxidant defense system, but also aggrandize the ability of antioxidative stress injury on peripheral nerves. Thirdly, AS-IV acted as the AR inhibitor, and then enhanced Na+, +，K +-ATP酶活性，改善延迟的运动神经传导速度，增加神经血流量，并防止结构性神经纤维损伤以纠正周围神经缺损[ase activity, improved the delayed motor nerve conduction velocity, increased nerve blood flow, and prevented structural nerve fiber damage to correct peripheral nerve 37defects ]。[68].

4.薯蓣皂苷元

薯蓣皂苷元是一种天然存在的甾体皂苷元，在自然界中含量丰富。薯蓣皂苷元的主要来源包括三

4. Diosgenin

Diosgenin is a naturally occurring steroidal sapogenin and is abundant in nature. Primary sources of diosgenin include the three 种薯蓣Dioscorea 属物种和一种species and one 异菝葜Heterosmilax 物种，即species, namely, D. zingiberensis、,  D. septemloba、,  D. collettii和, and H. yunnanensis [70].  [Diosgenin can also be obtained 100from ]。薯蓣皂苷元也可以从胡芦巴fenugreek ( T. foenum graecum Linn ) 和and Costus speciosus [71][72][73].  [It 101is ,a 102C27 ,spiroketal 103steroid ]sapogenin, 中获得。它是一种C27螺缩酮类固醇皂苷元，3β-羟基-5-螺甾烯（图13β-hydroxy-5-spirostene (Figure 1D），其分子式为), and its molecular formula is C 27 H42O3 [74]. OAs a representational phytosteroid, diosgenin is an important basic raw material for the production of steroid hormone drugs and has received increasing attention in the pharmaceutical industry for decades [75]. In addition, diosgenin itself has a wide range of biological effects. The following studies mainly describe its role in neuropathic pain. Neuropathic pain, one of the common complications of diabetes mellitus, manifests as increased sensitivity to noxious stimuli [76]. To evaluate the effects of diosgenin in the treatment of diabetes-induced neuropathic pain, an in 3vivo  [study 104was ]。作为具有代表性的植物甾体，薯蓣皂苷元是生产甾体激素类药物的重要基础原料，几十年来越来越受到制药行业的关注[performed 105on ]。此外，薯蓣皂苷元本身具有广泛的生物学作用。以下研究主要描述了其在神经性疼痛中的作用。
神经性疼痛是糖尿病的常见并发症之一，表现为对有害刺激的敏感性增加a [rat 106model ]。为了评估薯蓣皂苷元在治疗糖尿病引起的神经性疼痛中的作用，对of STZ 引起的糖尿病大鼠模型进行了体内研究。研究表明，薯蓣皂苷元可提高糖尿病大鼠福尔马林试验后期的机械和热伤害感受阈值并降低疼痛评分-induced diabetes. It was demonstrated that diosgenin upturned mechanical and thermal nociceptive thresholds and lowered pain scores at the late phase of the formalin test in diabetic rats [77]. Since elevated oxidative stress is one of the key factors in diabetes-related neurological dysfunction, it can lead to vascular dysfunction, resulting in intraneural hypoxia, which can lead to impaired motor and sensory nerve function [78][79]. Studies showed that diosgenin could reduce the content [of 38malondialdehyde ]。由于氧化应激升高是糖尿病相关神经功能障碍的关键因素之一，可导致血管功能障碍，导致神经内缺氧，进而导致运动和感觉神经功能受损[(MDA) 107in serum, 108 ]]。研究表明，薯蓣皂苷元可降低糖尿病大鼠血清、DRG和坐骨神经中丙二醛（MDA）的含量，恢复超氧化物歧化酶（, and sciatic nerve of diabetic rats and restored the activities of superoxide dismutase (SOD）和过氧化氢酶的活性，从而抑制氧化应激，增强抗氧化防御系统的功能。) and catalase, thereby inhibiting oxidative stress and enhancing the function of the antioxidant defense system [[77]. 38Furthermore, ]。此外，NF-κB 是一种重要的核转录因子，负责控制编码炎症和伤害感受相关介质的基因, an important nuclear transcription factor, is responsible for the control of genes encoding inflammation and nociception-related mediators [[80]. 109Upregulation ]。已证实糖尿病大鼠背根神经节神经元中of NF-κB 的上调，其抑制显着降低伤害性反应 [in the DRG neurons of diabetic rats has 110been proven, and 111its inhibition significantly reduces nociceptive responses [81][82][83]. It reported ,that 112]。据报道，薯蓣皂苷元在diosgenin LPSdownregulated 诱导的肺损伤模型中下调the NF-κB p65/p50 信号通路signaling pathway in the LPS-induced lung injury model [84]. However, based on the available reports, there is no specific experimental research regarding whether diosgenin exerts its analgesic effect in diabetes-induced neuropathic pain [by 113regulating ]。但从现有报道来看，薯蓣皂苷元是否通过调节NF-κB发挥其在糖尿病性神经性疼痛中的镇痛作用尚无具体的实验研究，相关研究有待进一步开展。神经生长因子（NGF）作为一种神经营养因子，是一种蛋白质因子，在维持交感神经和感觉神经元的生长、发育和功能方面起着至关重要的作用。它刺激轴突生长，保持轴突大小，防止成熟神经元受伤后死亡，并调节神经系统的各种功能，包括突触可塑性和神经传递, and related research needs to be further developed. Nerve growth factor (NGF), as a neurotrophic factor, is a protein factor that plays a vital role in the maintenance of the growth, development, and function of sympathetic and sensory neurons. It stimulates the axon growth, maintains the axon size, prevents the postinjury death of mature neurons, and regulates various functions of the nervous system, including synaptic plasticity and neurotransmission [85][86]. [In 114diabetic neuropathy,115 the function of ]。在糖尿病神经病变中，NGF功能受损，NGF相关基因表达发生改变，是糖尿病神经病理性疼痛进展的重要因素。 is impaired and the expression of NGF-related genes is modified, which are important factors in the progress of diabetic neuropathic pain. A study conducted by Tong Ho KANG 等人进行的一项研究。揭示薯蓣皂苷元上调糖尿病大鼠坐骨神经中NGF的水平。类似的效果还报道了薯蓣皂苷元增加 et al. revealed that diosgenin upregulated the level of NGF in the sciatic nerve of diabetic rats. The comparable effects also reported that diosgenin increased the neurite outgrowth of PC12 细胞的神经突生长，通过诱导 NGF 提高糖尿病小鼠的坐骨神经传导速度，减少髓鞘干扰，增加有髓轴突的面积，改善受损轴突的信号传递，从而减轻糖尿病性神经性疼痛cells, enhanced the sciatic nerve conduction velocity of diabetic mice by inducing NGF, reduced myelin disturbance, increased the area of myelinated axons, and improved the signal transmission of damaged axons, thereby alleviating diabetic neuropathic pain [87]. In addition to the diabetic neuropathy model, the role of diosgenin in the treatment of neuropathic pain has also been [reported 39in ]。
除了糖尿病神经病变模型外，薯蓣皂苷元在治疗神经性疼痛中的作用也已在the CCI 大鼠模型中得到报道。rat model. In 2017年，赵伟新等。进行了一项体内研究，结果表明薯蓣皂苷元可以上调 CCI 降低的机械戒断阈值和热戒断潜伏期。这是因为薯蓣皂苷元不仅抑制了 CCI 诱导的促炎细胞因子, Wei-Xin Zhao et al. performed an in vivo study, and the results demonstrated that diosgenin could upregulate CCI-reduced mechanical withdrawal threshold and thermal withdrawal latency. This was due to the fact that diosgenin not only inhibited CCI-induced elevation of proinflammatory cytokines TNF-α、, IL-1β 和 IL-2 的升高，而且还抑制了脊髓中的氧化应激。此外，薯蓣皂苷元通过抑制 pand IL-2, but also suppressed oxidative stress in the spinal cord. Moreover, diosgenin remarkably restrained the expression of p-p38 MAPK 和and NF-κB 信号通路的激活，显着抑制 p-in the spinal cord and eased neuropathic pain in CCI rats by inhibiting the activation of p38 MAPK 和and NF-κB 的表达，减轻signaling pathways [88]. CCI 大鼠的神经性疼痛[n other research [89], sciatic-crushed-nerve injury in rats decreased the sciatic function index, which was widely used 40to ]。在其他研究中evaluate [functional 41]，大鼠坐骨神经损伤降低了坐骨神经功能指数，该指数被广泛用于评估功能性步态gait [[90], 116increased ]，增加腹外侧导水管周围灰质和室旁核中the c-Fos 的表达，抑制了由以下因素引起的运动功能的恢复。 BDNF 的过度表达，以及对炎症有反应的expression in the ventrolateral periaqueductal gray and paraventricular nucleus, restrained recovery of locomotor function caused by the overexpression of BDNF, and aggrandized expressions of COX-2 和 iNOS 的过度表达。幸运的是，薯蓣皂苷元能够显着改善上述病理状态，并在周围神经损伤后发挥控制疼痛和功能恢复的潜在能力。
and iNOS that responded to inflammation. Fortunately, diosgenin was able to significantly improve the above pathological states, and exploited potential abilities in pain control and functional recovery after peripheral nerve injury.

3.5. O. sanctum 富含皂苷的提取物

5. Saponin-Rich Extracts of O. sanctum

除了上述四种已鉴定出结构清晰的植物皂苷的镇痛作用外，还发现了富含皂苷的O. sanctum提取物具有相似的作用。O. sanctum是唇形科植物罗勒的地上部分。现代药理研究表明，O. sanctum化学成分复杂，种类多样，包括挥发油、黄酮类及其苷类、香豆素类、苯丙素类和脂肪酸类，主要是挥发油和黄酮类及其苷类[111]。此外，已从O. sanctum的酒精提取物中分离出多种皂苷。[112]，其中最重要的是以熊果酸和齐墩果酸为主的五环三萜皂苷[113-115]，具有广泛的药理作用。

In addition to the analgesic effects of the above four plant saponins that have been identified with clear structures, saponin-rich extracts of O. sanctum have also been found with similar effects. O. sanctum is the aerial part of Ocimum basilicum, a plant of the Labiatae family. Modern pharmacological studies have illustrated that the chemical composition of O. sanctum is complex and the types are diverse, including volatile oils, flavonoids and their glycosides, coumarins, phenylpropanoids, and fatty acids, mainly volatile oils and flavonoids and their glycosides [91]. In addition, a variety of saponins have been isolated from the alcoholic extract of O. sanctum [92], the most important of which are pentacyclic triterpenoid saponins that are dominated by ursolic and oleanolic acids [93][94][95], and have a wide range of pharmacological effects.

氧化应激 [116] 和钙稳态的改变 [117] 被认为与神经性疼痛密切相关。在神经系统疾病期间，细胞内钙调节系统的功能障碍会产生氧化应激 [118]，而自由基的增加会导致神经元变性和细胞凋亡。另一方面，由氧化应激引起的代谢异常[119]、蛋白质聚集体的形成[120]和膜通透性的变化[121]都会增加钙水平，它们共同作用促进神经性疼痛的恶化。O. sanctum具有良好的抗氧化作用 [122,123]，可防止自由基损伤 [124]，并且能够降低钙水平 [125]。O. sanctum在印度部分地区用作神经补品，用于缓解头痛、关节痛和肌肉痛。在 Muthuraman 等人进行的实验中，O. sanctum的给药减轻了坐骨神经横断引起的周围神经病变和运动协调，减弱了截肢引起的硫代巴比妥酸活性物质、总钙和谷胱甘肽水平的降低以剂量依赖的方式[125]。提示O. sanctum的镇痛作用可能与其抗氧化和降低钙水平有关。此外，在其他研究中，用O. sanctum治疗其富含皂苷的部分可减轻由慢性缩窄性损伤和化学治疗剂长春新碱引起的神经性疼痛，这与其对氧化应激和钙水平的影响有关[125,126]。基于上述发现，可以观察到，O. sanctum给药对钙水平的下调可能是由于直接影响或继发于氧化应激的降低。然后，它对神经元产生镇痛或抗凋亡作用。据报道，皂苷具有抗氧化作用 [127] 和降钙作用 [128]。因此，O. sanctum皂苷的镇痛作用可以通过直接或间接降低钙水平来构建。

Oxidative stress [96] and alterations in calcium homeostasis [97] are thought to be closely associated with neuropathic pain. During neurological disorders, dysfunction of the intracellular calcium regulatory system produces oxidative stress [98], and increases in free radicals lead to neuronal degeneration and apoptosis. On the other hand, metabolic abnormalities [99], formation of protein aggregates [100], and changes in membrane permeability [101] caused by oxidative stress all increase calcium levels, and they act together to promote the deterioration of neuropathic pain. O. sanctum has a good antioxidant effect [102][103], protects against free radical damage [104], and is able to reduce calcium levels [105]. O. sanctum is used as a neurotonic in parts of India for the relief of headache, joint pain, and muscle pain. In the experiments conducted by Muthuraman et al., the administration of O. sanctum attenuated sciatic nerve transection-induced peripheral neuropathy and motor in-co-ordination, attenuated the amputation-induced reduction in thiobarbituric acid reactive species, total calcium, and glutathione levels in a dose-dependent manner [105]. It suggested that the analgesic effect of O. sanctum might be related to its antioxidation and reduction of calcium levels. Additionally, in other studies, treatment with O. sanctum and its saponin-rich fraction reduced neuropathic pain caused by chronic constrictive injury and chemotherapeutic agent vincristine, associated with its effects on the oxidative stress and calcium levels [105][106]. Based on the above findings, it can be observed that the downregulation of calcium levels by O. sanctum administration may be due to a direct effect on or secondary to a decrease in oxidative stress. Then, it produces an antinociceptive or antiapoptotic effect on neurons. It has been reported that Saponins have antioxidant [107] and calcium lowering effects [108]. Thus, the antinociceptive effect of O. sanctum saponins may be constructed through direct or indirect reduction of calcium levels.

还有证据表明，O. sanctum叶子和种子可降低兔子的尿酸水平 [129]，而尿酸水平升高与痛风性关节炎和其他关节炎症有关 [130]。O. sanctum的乙醇提取物具有镇痛作用，并涉及神经递质系统（如阿片受体和去甲肾上腺素）的相互作用 [131]。这些研究支持传统使用O. sanctum治疗炎症和疼痛，但不排除其他活性成分如黄酮类和酚类的作用。

There is also evidence that O. sanctum leaves and seeds reduce uric acid levels in rabbits [109], and elevated uric acid levels are associated with gouty arthritis and other joint inflammation [110]. The ethanolic extract of O. sanctum can be antinociceptive, and involves the interaction of neurotransmitter systems such as opioid receptors and norepinephrine [111]. These studies support the traditional use of O. sanctum for the treatment of inflammation and pain, without excluding the effects of other active ingredients such as flavonoids and phenols.

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