Table 1.
Summary of plants, mushrooms, and decoctions their natural products relating to peripheral nerve regeneration.
| Source | Molecule(s)/Ingredients | Experimental Model | Effective Concentration | Application Method | Biological Effect | Mechanism | Reference |
|---|---|---|---|---|---|---|---|
| PLANT | |||||||
| Achyranthes bidentata | Polypeptides |
In vitro (SCs isolated from the sciatic nerves of 1-day old SD rats) |
0.1 µg/mL | Incubation | Promoted migration of SCs | Upregulation of NOX4/DUOX2-derived ROS production | [44] |
| Polypeptides |
In vitro
(DRG explants harvested from spinal and peripheral roots of postnatal day 1 SD rats) |
0.01, 0.1, 1 µg/mL (dose-dependent manner) | Incubation | Promoted neurite outgrowth from cultured DRG explants/neurons | Activation of ERK1/2 | [45] | |
|
In vivo (Adult New Zealand rabbits) |
6.0 mg/kg | Intravenous injection | Enhanced nerve regeneration and functional restoration after crush injury to rabbit common peroneal nerve (increased CMAP, density, diameter and thickness of myelinated fibers, and number of motor neurons in anterior horn) | N/A | |||
| Polypeptides (Fraction K) |
In vitro (DRG explants harvested from spinal and peripheral roots of postnatal day 1 SD rats) |
50, 250 ng/mL (dose-dependent manner) | Incubation | Promoted neurite outgrowth in DRG explant and neurons | Activation of ERK1/2 | [46] | |
|
In vivo (ICR mice) |
10 mg/kg | Intravenous injection | Promoted peripheral nerve regeneration in mice after SNI (increased diameter and thickness of myelinated fibers, CSA of gastrocnemius muscle fibers, SFI, and CMAP) | N/A | |||
| Polypeptides |
In vivo (SD rats) |
2 mg in 0.2 mL saline | Intraperitoneal injection | Promoted functional and histological recovery after rat sciatic nerve crush (increased SFI, CMAP, MNCV, myelin thickness, lamellae number, CSA of gastrocnemius muscle fibers) | Modulation of mRNA expression of GAP-43, neurotrophic factors (NGF, BDNF, CNTF), and neurotrophic factor receptors (TrkA, TrkB) | [47] | |
| Polypeptides |
In vivo (ICR mice) |
1, 4, 16 mg/kg (dose-independent manner) | Tail vein injection | Promoted functional and histological recovery after rat sciatic nerve crush (increased SFI, CMAP, MNCV, number, and diameter of myelinated fibers, axon diameter, myelin thickness, lamellae number, CSA of gastrocnemius muscle fibers) | N/A | [48] | |
| Aqueous extract |
In vivo (Adult New Zealand rabbits) |
10, 20 mg/kg (dose-dependent manner) | Intravenous injection | Promoted peripheral nerve regeneration in the crushed common peroneal nerve in rabbits (increased CMAP, CSA of tibialis posterior muscle, number of regenerated myelinated nerve fibers, and motoneurons in anterior horn of the spinal cord) | N/A | [49] | |
| Alpinate Oxyphyllae Fructus (Alpinia oxyphylla Miq) | Protocatechuic acid |
In vitro (RSC96 SCs) |
1 mM | Incubation | Promoted proliferation and survival of RSC96 SCs | Upregulation of IGF-1 and activation of PI3K/Akt signaling | [50] |
| Aqueous extract |
In vitro (RSC96 SCs) |
Proliferation: 20, 60, 200 µg/mL (dose-independent manner Migration: 20–200 µg/mL (dose-dependent manner |
Incubation | Promoted proliferation and migration of RSC96 SCs | Upregulation of PAs (uPA, tPA) and MMP2/9 mediated through the activation of MAPK pathway (ERK1/2, JNK, p38) | [51] | |
|
In vivo (SD rats) |
30, 60, 100, 150, 200 µg/mL (dose-independent manner) | Injection into a silicone rubber tube bridging a 15mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI | ||||
| Astragalus membranaceus | Astragaloside IV |
In vivo (BALB/c mice) |
2.5, 5, 10 mg/kg (dose-dependent manner) | Intraperitoneal injection | Promoted sciatic nerve regeneration and functional recovery in mice (increased number and diameter of myelinated nerve fibers, MNCV, CMAP) | Upregulation of GAP-43 expression | [52] |
| Astragaloside IV |
In vivo (SD rats) |
50 µM | Injection into a silicone rubber tube bridging a 15mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased number of myelinated axons and CMAP) | N/A | [53] | |
| Extract |
In vivo (SD rats) |
3 g/kg in 0.01 M of PBS | Intragastric gavage | Promoted peripheral nerve regeneration in rats with SNI (increased MNCV and latency, fluorogold labeling in the DRG, mean axonal density, percentage of CGRP area ratio, and macrophage density) | Modulation of local growth factors (FGF, NGF, PDGF, TGF-β) and immunoregulatory factors (IL-1, IFN-γ) | [54] | |
| Aqueous extract |
In vitro (RSC96 SCs) |
Proliferation: 12.5, 125, 250, 500 µg/mL (optimal at 12.5 µg/mL) Migration: 1.25, 12.5, 125, 250, 500 µg/mL (optimal at 1.25 µg/mL) |
Incubation | Promoted proliferation and migration of RSC96 SCs | Proliferation: Increased cyclin protein A, D1, and E via ERK and p38 signaling pathways Migration: Activation of FGF-2 signaling, leading to upregulation of uPA and downregulation of PAI-1 |
[55] | |
| Centella asiatica | Hydro-ethanolic extract |
In vivo (SD rats) |
400 µg/mL | Nerve conduit developed using decellularized artery seeded with C. asiatca-neurodifferentiated mesenchymal stem cells bridging a 15mm sciatic nerve defect | Promoted nerve regeneration and functional restoration in rats with SNI (increased CMAP, latency, MNCV, confirmation of angiogenesis, increased MBP expression, and number of myelinated axons) | N/A | [56] |
| Citrus medica var. sarcodactylis | Aqueous extract |
In vitro (RSC96 SCs) |
0.85, 1.7, 2.55, 3.4, 4.25 µg/mL (dose-dependent manner) | Incubation | Promoted proliferation and migration of RSC96 SCs | Proliferation: Upregulation of cyclin A and B1 Migration: Activation of FGF-2 signaling, leading to the upregulation of uPA and MMP-9 |
[57] |
| Codonopsis pilosula | Aqueous extract |
In vitro (RSC96 SCs) |
20, 40, 60, 80, 100 µg/mL (dose-independent manner) | Incubation | Promoted proliferation and migration of RSC96 SCs | Proliferation: Enhanced IGF-I signaling pathway, cell cycle controlling protein expressions (cyclin A, D1, E) and MAPK pathway (ERK, p38) Migration: Stimulated FGF-2-uPA-MMP9 migration pathway |
[58] |
| Crocus sativus | Crocin |
In vivo (Wistar rats) |
20, 80 mg/kg | Intraperitoneal injection | Promoted functional recovery in rats with SNI (Increased SFI, reduced plasma MDA levels, alleviated histological changes due to a crushing injury) | N/A | [59] |
| Curcuma longa | Alcoholic extract |
In vivo (Wistar rats) |
100 mg/kg (3, 6, or 9 times across 28 days) | Intraperitoneal injection | Protected against peripheral nerve degeneration in rats with SNI (Increased number of intact neurons in the right ventral horn of spinal cord region) | N/A | [60] |
| Curcumin |
In vivo (SD rats) |
100 mg/kg (dissolved in olive oil) | Oral gavage | Promoted peripheral nerve regeneration in rats with SNI (increased mean cell volume, total volume and surface of DRG cells, total number, diameter, and area of myelinated nerve fibers) | N/A | [61] | |
| Curcumin |
In vivo (SD rats) |
100 mg/kg (dissolved in olive oil) | Oral gavage | Promoted functional recovery (improved SFI) and protective effect on DRG (increased volume and number of A- and B- cells, number of satellite cells) in rats with SNI | N/A | [62] | |
| Curcumin |
In vivo (SD rats) |
50, 100, 300 mg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased number of motoneurons, number and diameter of myelinated axons, SFI, MNCV, amplitude of CMAP, muscle fiber area and reduced latency of CMAP, mechanical withdrawal threshold, thermal withdrawal latency) | N/A | [63] | |
| Curcumin |
In vitro (SCs isolated from S100β-DsRed transgenic mice) |
0.04-1 µM (0.1 µM having the highest proliferative effect) | Incubation | Promoted proliferation and migration of SCs | Proliferation: Modulated by ERK and p38 kinase pathways | [64] | |
| Curcuma longa (curcumin); from honeybees (propolis) | Curcumin, propolis |
In vivo (Wistar rats) |
Curcumin (100 mg/kg) Propolis (200 mg/kg) |
Administration through a nasogastric tube | Promoted functional recovery in rats with SNI (Increased SFI and amplitude of CMAP, reduced latency time) | N/A | [65] |
| Dioscoreae rhizoma | Aqueous extract |
In vivo (SD rats) |
10 mg/mL | Applied directly into the crush site | Promoted peripheral nerve regeneration in rats with SNI (increased number of DRG sensory neurons and motor neurons in the spinal cord) | Increasing protein levels of GAP-43 and Cdc2 | [66] |
| Epimedium | Icariin |
In vivo (SD rats) |
20 mg in 5 mL | Injection into a poly(lactic-co-glycolic acid) biological conduit sleeve bridging a 5mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased sciatic nerve conduction velocity and number of myelinated fibers) | N/A | [67] |
| Epimedium extract, icariin |
In vivo (SD rats) |
4.873 mg/mL | Intragastric administration | Promoted peripheral nerve regeneration in rats with SNI (Increased SFI, nerve regeneration based on nerve pinch test, MNCV, muscle wet weight) | N/A | [68] | |
| Gardenia jasminoides Ellis | Genipin |
In vivo (SD rats) |
3% aqueous gelatin solution fixed with 3% genipin | Injection into a silicone rubber tube bridging a 10mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI | N/A | [69] |
| Gastrodia elata Blume | Gastrodin |
In vitro (RSC96 SCs) |
50, 100, 200 µM (dose-dependent manner) | Incubation | Promoted proliferation of RSC96 SCs in a dose- and time-dependent manner | Inhibition of ERK1/2 phosphorylation and activation of Akt phosphorylation | [70] |
| Ginkgo biloba | Ginkgo biloba extract (EGb 761) |
In vivo (SD rats) |
50 mg/kg | Intraperitoneal injection paired with an 18mm acellular nerve allograft bridging a 15mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased density of regenerated axons, muscle mass, axon number and diameter, expression of CD34 and NF200) | Increasing expression of angiogenesis-related genes (Vegf, Sox18, Prom1, IL-6) | [71] |
| Ginkgo biloba extract (EGb 761) |
In vitro (SCs isolated from spinal nerves of 1-day old SD rats) |
1, 10, 20, 50, 100 µg/mL (dose-dependent manner) | Incubation | Promoted cell attachment and survival of SCs | N/A | [72] | |
|
In vivo (SD rats) |
10, 50 µg/mL | Injection into poly(DL-lactic acid-co-glycolic acid) conduit seeded with Schwann cells bridging a 12mm sciatic nerve defect |
Promoted histological and functional recovery in rats with SNI (increased number and area of myelinated axons, increased CMAP) |
||||
| Ginseng | Ginsenoside Rg1 |
In vitro (RSC96 SCs) |
Ginseng: 100, 200, 300, 400, 500 µg/mL Ginsenoside: 5, 10, 15, 20, 25 µg/mL) (Dose-dependent manner for both) |
Incubation | Promoted proliferation and migration of RSC96 SCs | Proliferation: Enhancing protein expression of IGF-I pathway regulators (IGF-IR, PI3K, p-Akt, p-Bad, Bcl-2), cell cycle controlling proteins (cyclin D1, E, A), and MAPK signaling pathway (ERK, JNK, p38) Migration: Stimulating the FGF-2-uPA-MMP9 migrating pathway |
[73] |
| Ginsenoside Rg1 | In vivo(SD rats) | 1.5 mg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased number of motoneurons, number, and diameter of myelinated axons, SFI, MNCV, improved CMAP latency and amplitude, the increased average percentage of muscle fiber) | N/A | [74] | |
| Ginsenoside Re |
In vitro (SCs isolated from sciatic nerves of 3-day old SD rats) |
0.5 mg/mL | Incubation | Promoted proliferation and migration of SCs | Phosphorylation of ERK1/2 and JNK 1/2 | [75] | |
|
In vivo (SD rats) |
2.0 mg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased SFI, TSI, PCNA expression level, improved pathological changes due to crushing injury, GAP43, and S-100 expression) | ||||
| Green tea | (-)-Epigallocatechin-3-gallate (EGCG) |
In vivo (Wistar rats) |
50 mg/kg | Intraperitoneal injection | Promoted functional recovery (improved outcomes of foot position, toe spreading, extensor postural thrust, hopping reflex, von Frey hair, Randall–Sellito, hotplate, and tail-flick tests), improved morphological recovery in skeletal muscle tissues muscles, and protection towards muscle fibers in rats with SNI | Protection of muscle fibers from cellular death through activation of an anti-apoptotic signaling pathway (modulation of Bax, Bcl-2, and p53 expression) | [76] |
| (-)-Epigallocatechin-3-gallate (EGCG) |
In vivo (Wistar rats) |
50 mg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (improved nerve morphology and functional recovery assessed by foot position, extensor postural thrust test, and withdrawal reflex threshold) | Reversal of Bax, Bcl-2, and survivin mRNA expression induced by sciatic nerve injury | [77] | |
| Can be found in a wide variety of plants | Syringic acid |
In vitro (RSC96 SCs) |
600 µM | Incubation | Promoted proliferation and migration of RSC96 SCs | Downregulation of miR-451-5p | [78] |
| Can be found in a wide variety of plants | Ursolic acid |
In vivo (BALB/c mice) |
2.5, 5, 10 mg/kg (dose-dependent manner) | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased number and diameter of myelinated nerve fibers and soleus muscle mass) | Increasing S100 protein expression levels | [79] |
| Lycium barbarum | Polysaccharide |
In vitro (1) PC12 cells (2) Rat SCs (3) DRG neurons isolated from the embryo of 14-day pregnant rat |
10, 30, 50 mg/mL (optimal at 30 mg/mL) | Incorporated into core-shell structured nanofibrous scaffolds by coaxial electrospinning | (1) Promoted proliferation and neuronal differentiation of PC12 cells (2) Promoted proliferation and myelination of SCs (3) Promoted neurite outgrowth of DRG neurons |
N/A | [80] |
| Can be found in a wide variety of plants | Quercetin |
In vitro (RSC96 SCs) |
0.1, 1, 10 µg/mL | Incubation | Promoted proliferation of RSC96 SCs | N/A | [81] |
|
In vivo (SD rats) |
0.1, 1, 10 µg/mL | Injection into a silicone rubber tube bridging a 15mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased count and density of myelinated axons, and resulted in larger area and amplitude of CMAP) | ||||
| Morus sp. | Cortex Mori Radicis (aqueous extract) |
In vivo (SD rats) |
100 mg/kg | Gastrointestinal administration | Reduced blood glucose levels, improved nerve functions (thermal latency and mechanical threshold), reversed the loss of Nissl bodies and induced neurite outgrowth in DRG neurons, and restored the response of growth cones to NGF in diabetic rats | Neurite outgrowth: Increased expression of TRPC1, reduced Ca2+ influx, and activation of PI3K/Akt signaling | [82] |
| Pueraria lobata | Puerarin |
In vitro (RSC96 SCs) |
1, 10, 100 µM (dose-independent manner) | Incubation | Promoted growth of SCs | N/A | [83] |
|
In vivo (SD rats) |
1, 10, 100 µM (dose-independent manner) | Injection into a silicone rubber tube bridging a 15mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased density of myelinated axons, CMAP, and MNCV) | ||||
| Serum metabolites (obtained from rats fed with Pueraria lobata extract) |
In vitro (PC12 cells) |
0.01, 0.1, 1 unit | Incubation | Enhanced NGF-mediated neurite outgrowth and expression of synapsin I in PC12 cells | N/A | [84] | |
|
In vivo (SD rats) |
0.01, 0.1, 1 unit | Injection into silicone rubber chamber bridging a 10mm sciatic nerve defect |
Promoted peripheral nerve regeneration in rats with SNI (increased mean values of myelinated axon number, endoneurial area, and total nerve area) | ||||
| Radix Hedysari | Aqueous extract |
In vivo (SD rats) |
1 g/mL | Oral gavage paired with biodegradable chitin conduit bridging a 2mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with SNI (increased MNCV, fiber and axon diameter, g-ratio) | N/A | [85] |
| Polysaccharides |
In vivo (SD rats) |
0.25 g/mL | Oral gavage | Promoted peripheral nerve regeneration in rats with sciatic nerve defect (increased SFI, TFI, PFI values, MNCV, and number of regenerated myelinated nerve fibers) | N/A | [86] | |
| Rhodiola rosea L. | Salidroside |
In vivo (SD rats) |
5, 10 mg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased number and diameter of myelinated axons, number of motoneurons, SFI, amplitude of CMAP, MNCV) | N/A | [87] |
| Scutellaria baicalensis Georgi | Baicalin |
In vitro (RSC96 SCs) |
5, 10, 20 µM (dose-dependent manner) | Incubation | Promoted proliferation of RSC96 SCs | Modulation of neurotrophic factors (GDNF, BDNF, CNTF) and S100β | [88] |
| Trigonella foenum-graecum (fenugreek) | IND01 (Fenugreek seed extract) |
In vivo (Wistar rats) |
50, 100, 200 mg/kg | Oral administration | Promoted peripheral nerve regeneration in rats with: (1) partial sciatic nerve ligation (ameliorated thermal hyperalgesia, improved motor function test scores) (2) SNI (ameliorated thermal hyperalgesia, improved motor function test scores, increased MNCV) |
N/A | [89] |
| Tripterygium wilfordii Hook. F. | Triptolide |
In vivo (SD rats) |
100 µg/kg | Intraperitoneal injection | Promoted peripheral nerve regeneration in rats with SNI (increased number of motoneurons, number of myelinated axons, diameter of nerve fibers, SFI, CMAP amplitude, MNCV, muscle fiber area) | Reduction of TNF-α, IL-β, and IL-6 expression | [90] |
| MUSHROOM | |||||||
| Amanita muscaria | Muscimol |
In vivo (SD rats) |
400 μg/mL | Applied directly to the right L5 DRG | Promoted peripheral nerve regeneration in rats with SNI (prevented the development of thermal and mechanical hypersensitivity and mechanical allodynia, improved basal membrane integrity, and increased nerve fibers) | Normalization of PMP22 protein expression level by GABAergic modulation in the ipsilateral DRG | [91] |
| Hericium erinaceus | Aqueous extract |
In vivo (SD rats) |
10 mL/kg | Oral administration | Promoted peripheral nerve regeneration in rats following peroneal nerve crush | Activation of signaling pathways (Akt, MAPK, c-Jun, c-Fos) and protein synthesis | [92] |
| Polysaccharide |
In vivo (SD rats) |
30 mg/mL/kg | Oral administration | Promoted sensory functional recovery following peroneal nerve crush in rats (reduced withdrawal reflex latency) | Activation of Akt and p38 MAPK signaling and increased expression of RECA-1 | [93] | |
| Aqueous extract |
In vivo (SD rats) |
10, 20 mL/kg | Oral administration | Promoted peripheral nerve regeneration in rats following peroneal nerve crush (increased PFI, improved axon morphology, and development of neuromuscular junction) | N/A | [94] | |
| Lignosus rhinocerotis | Aqueous extract |
In vivo (SD rats) |
500, 1000 mg/kg | Oral administration | Promoted motor and sensory functional recovery in rats with SNI (improved WRL and toe-spreading reflex) | N/A | [95] |
| DECOCTION | |||||||
| Bogijetong | (1) Bogijietong decoction (18 ingredients) (2) A reconstituted formulation of BGJTD (BeD) with 4 ingredients (3) Angelica gigas (an ingredient in BeD) |
In vitro (Primary neurons isolated from DRG at lumbar levels 4 and 5 in adult rats) |
400 mg/kg | Incubation | Promoted neurite outgrowth of DRG neurons | (1) BGJTD and BeD: Downregulation of TNF-α and p38, upregulation of p-ERK1/2; (2) Angelica gigas: Regulation of ERK1/2 activity and TNF-α production | [96] |
|
In vivo (SD rats and BALB/c mice) |
400 mg/kg | Oral administration | Reduced latency time in rats | ||||
| Buyang Huanwu | Buyang Huanwu decoction (16 ingredients: Modified formulation) |
In vivo (SD rats) |
1800 mg/kg | Oral administration paired with silicone rubber tube bridging a 10mm sciatic nerve defect | Promoted peripheral nerve regeneration in rats with sciatic nerve defect (increased nerve formation, myelinated axons, and endoneurial area) | N/A | [97] |
| Jiaweibugan | Jiaweibugan decoction (9 ingredients) |
In vivo (Wistar rats) |
28.6 g/kg | Intragastric administration | Protective effect on peripheral nerve injury by playing an anti-oxidative role in a diabetic rat model (increased MNCV and serum levels of glutathione, decreased serum levels of MDA) | Downregulation of NF-kB p65 and p38 MAPK mRNA expression | [98] |
| Qian-Zheng-San | Qian-Zheng-San (3 ingredients: Typhonii rhizoma, Bombyx batryticatus, Scorpio) |
In vivo (SD rats) |
1.75 g/mL | Oral gavage | Promoted peripheral nerve regeneration in rats with sciatic nerve defect (Increased SFI, MNCV, muscle wet weight, number of regenerated axons, axon diameter, nerve fiber diameter, myelin thickness, number of motor neurons in the lumbar spinal cord anterior horn) | N/A | [99] |
Akt—protein kinase B; Bad—Bcl-2 associated agonist of cell death; Bax—Bcl-2-associated X protein; Bcl-2—B-cell lymphoma 2; BDNF—brain-derived neurotrophic factor; BGJTD—Bogijetong decoction; Cdc2—cell division cycle protein 2 homolog; CGRP—calcitonin gene-related peptide; CMAP—compound muscle action potential; CNTF—ciliary neurotrophic factor; CSA—cross-sectional area; DRG—dorsal root ganglion; DUOX2—dual oxidase 2; ERK—extracellular signal-regulated kinase; FGF—fibroblast growth factor; GABA—γ-aminobutyric acid; GAP-43—growth associated protein 43; GDNF—glial cell-derived neurotrophic factor; ICR mice—Institute of Cancer Research mice; IFN—interferon; IGF-1—insulin-like growth factor 1; IGF-IR—insulin-like growth factor 1 receptor; IL—interleukin; JNK—c-Jun N-terminal kinase; MAPK—mitogen-activated protein kinase; MBP—myelin basic protein; MDA—malondialdehyde; MMP—matrix metallopeptidase; MNCV—motor nerve conduction velocity; NF-κB—nuclear factor kappa B; NGF—nerve growth factor; NOX4—nicotinamide adenine dinucleotide phosphate oxidase 4; PAI-1—plasminogen activator inhibitor-1; PBS—phosphate buffered saline; PC12—pheochromocytoma cells; PCNA—proliferating cell nuclear antigen; PDGF—platelet-derived growth factor; PFI—peroneal nerve function index; PI3K—phosphoinositide 3-kinase; PMP22—peripheral myelin protein 22; Prom1—prominin 1; RECA-1—mouse monoclonal endothelial cell antibody; ROS—reactive oxygen species; RSC96 SC—RSC96 Schwann cell; SCs—Schwann cells; SD rats—Sprague-Dawley rats; SFI—sciatic function index; SNI—sciatic nerve injury; Sox18—sex-determining region Y-box transcription factor 18; TGF-β—transforming growth factor beta; TNF-α—tumor necrosis factor alpha; tPA—tissue plasminogen activator; Trk—tropomyosin receptor kinase; TRPC1—classical transient receptor potential 1; TSI—toe spread index; uPA—urokinase plasminogen activator; Vegf—vascular endothelial growth factor; WRL—withdrawal reflex latency.