Use of divalent metal lactates in the manufacture of nerve damage repair products

Abstract

This invention belongs to the field of biomedical technology and specifically relates to the use of divalent metal lactates in the manufacture of products for the prevention, improvement, repair, and treatment of nerve damage. Preferably, the divalent metal lactate includes one or more of the following: calcium lactate, magnesium lactate, zinc lactate, and ferrous lactate. This invention provides a novel treatment method for repairing damage to the central and peripheral nervous systems and has broad potential applications in the treatment and repair of central nervous system damage caused by trauma or other causes, or peripheral neuritis or peripheral nerve sensory abnormalities caused by viruses, diabetes, chemotherapy drugs, etc.

Description

Technical Field

[0001] The present invention belongs to the field of biomedical technology, and specifically relates to the use of divalent metal lactate in the manufacture of products for preventing, improving, repairing, and treating nerve injuries.

Background Art

[0002] The central nervous system and the peripheral nervous system constitute the complete nervous system of the human body, and the nervous system plays a leading role in maintaining the homeostasis of the internal environment and the integrity and unity of the body and its adjustment and balance with the external environment. As modernization of society progresses, an increase in traffic accidents, sports accidents, etc. is inevitable, and at the same time, potential violent incidents and natural disasters may also cause damage to the nervous system.

[0003] Spinal cord injury is a severe form of central nervous system injury that causes sensory and motor impairments in patients, placing a serious burden on their families and society. Spinal cord injury is a complex and intricate process, divided into primary and secondary injury based on the pathological process of neuronal damage. The severity of spinal cord injury is primarily determined at the secondary injury stage, mainly because the microenvironment of the spinal cord changes significantly during this stage. This includes increased levels of reactive oxygen species, hypoxia due to impaired oxygen transport caused by vascular damage, and increased inflammatory responses. Furthermore, spontaneous regeneration of the spinal cord after injury is impossible due to the low regenerative capacity of the nerves themselves. Clinically, the therapeutic effects of surgery or rehabilitation training on spinal cord injury patients are limited and cannot effectively promote nerve regeneration and functional recovery. Due to the complexity of the pathophysiological processes after spinal cord injury, no existing monotherapy in clinical practice has achieved satisfactory results in treating spinal cord injury. Currently, autologous nerve grafting is considered the gold standard in treating nerve defects, but its clinical application is severely limited by the limited supply of donor nerves and the resulting nerve dysfunction at the donor site. Therefore, there is a persistent and urgent need in clinical practice for a drug to treat spinal cord injury that is safe to use, has reliable therapeutic effects, is inexpensive, and is easy to administer.

[0004] Furthermore, the repair of peripheral nerve injuries, particularly long-distance defects, and the reconstruction of nerve function are global challenges in clinical treatment. Autologous or allogeneic nerve grafting is a commonly used repair method for treating peripheral nerve injuries in clinical practice today, but it presents a range of problems, including limitations on donor sources, differences in donor and recipient nerve structures, and loss of nerve function at the donor site, scarring, and immune rejection. Peripheral neuritis and peripheral neuropathy are currently the most common peripheral nerve injuries in clinical practice. Peripheral neuritis, also known as peripheral neuritis or polyneuritis, is a dysfunction of nerves at the distal end of the limbs caused by various etiologies. Peripheral neuritis can be caused by a variety of factors, including nutritional metabolism, drugs and intoxication, vasculitis, tumors, trauma, or mechanical compression, and primarily manifests as dysfunction of sensory, motor, and autonomic nerves within the innervation area of ​​the damaged nerve. Symptoms of peripheral neuritis include decreased sensation, pain, numbness or tingling, crawling, burning, and hyperesthesia. Peripheral neuritis can be multiple or solitary, symmetrical or asymmetrical, and is one of the most common diseases of the nervous system. When the etiology of peripheral neuritis is known, treating the underlying cause can alleviate symptoms and restore damaged nerves. However, treatment is not sufficiently effective for primary peripheral neuritis of unknown etiology or that is refractory. According to data, peripheral neuritis leaves sequelae in approximately 40% of patients, showing a relatively high disability rate and seriously impacting patients' physical and mental health and quality of life. Currently, there are not many treatment options for peripheral neuritis in clinical practice, and Western medicine is mainly used. For example, in clinical practice, peripheral neuritis caused by various factors can all be treated with high doses of B vitamins, such as vitamins B1, B6, and B12. If pain is severe, analgesics and sedatives are used. In cases of inflammatory demyelinating disease, corticosteroids, such as methylprednisolone, dexamethasone, or hydrocortisone, can be used. However, these drugs have strong toxicity and side effects with long-term use, are prone to causing drug dependence, and make it difficult to achieve the goal of complete cure.

[0005] In previous research, the inventors discovered that during the degradation process of poly-L-lactic acid (PLLA), the molecular structure of PLLA is gradually destroyed, slowly hydrolyzing to lactic acid. This lactic acid can induce human fibroblasts to increase collagen production, leading to an increase in collagen fibers in the dermis and resulting in filling and repair effects. Based on this, the inventors also discovered that PLLA, lactic acid, and their related lactate compounds have beneficial effects on the repair of tissues such as cartilage, connective tissue, tendons, fascia, and nerves (see CN202210028046.9). This invention is a continuation of previous research and discovers a novel use of divalent metal lactates in the manufacture of products for the prevention, improvement, repair, and treatment of nerve damage. [Overview of the Initiative]

[0006] To overcome the shortcomings and deficiencies of prior art, the present invention provides a novel use of divalent metal lactates. In the course of research, the inventors unexpectedly discovered that divalent metal lactates can effectively prevent, improve, repair, and treat central and peripheral nerve damage, and based on this discovery, they diligently continued their research to complete the present invention.

[0007] To achieve the objectives of the present invention, the present invention employs the following technical approach: This invention provides for the use of divalent metal lactates in the manufacture of products for the prevention, improvement, repair, and treatment of nerve damage, wherein the tissue in which nerve damage has occurred is selected from collagen-rich nerve tissue.

[0008] In a selectable embodiment, in the above use, the nerve injury is central nervous system injury or peripheral nervous system injury, and the prevention, improvement, repair, and treatment of the nerve injury are nerve regeneration, nerve number increase, and / or nerve repair.

[0009] In selectable embodiments, in the above use, the central nervous system injury includes spinal cord injury or cerebrospinal neuritis, and the peripheral nervous system injury includes peripheral nerve injury, peripheral neuritis, or peripheral neuropathy.

[0010] As an optional embodiment, in the above use, the peripheral neuritis is selected from one or more of the following: facial neuritis, diabetic peripheral neuritis, viral peripheral neuritis, chemotherapeutic peripheral neuritis, or Guillain-Barré syndrome.

[0011] In an optional embodiment, in the above use, the symptoms of peripheral neuritis include decreased sensation, pain, numbness or tingling, crawling sensation, burning sensation, hyperesthesia, etc.

[0012] In an optional embodiment, the divalent metal lactate in the above use includes one or more combinations of calcium lactate, magnesium lactate, zinc lactate, and ferrous lactate.

[0013] In a selectable embodiment, in the above use, the divalent metal lactate is selected from magnesium lactate or a composition of zinc lactate and magnesium lactate.

[0014] Preferably, in parts by weight, the ratio of magnesium lactate to zinc lactate in the composition is 1:10 to 10:1.

[0015] More preferably, in parts by weight, the ratio of magnesium lactate to zinc lactate in the composition is 1:10, 1:9, 1:8, 1:7, 1:6, 1:5, 1:4, 1:3, 1:2, 1:1, 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, or 10:1.

[0016] Most preferably, in parts by weight, the ratio of magnesium lactate to zinc lactate in the composition is 4:1.

[0017] As an optional embodiment, in the above use, the product is selected from one or more of the following: drugs, kits, health foods, and medical devices.

[0018] The concentration of the divalent metal lactate in the product is 10 to 80 mmol / L, and more preferably, the concentration of the divalent metal lactate in the product is 20 to 60 mmol / L.

[0019] In a selectable embodiment, the medical device in the above use includes one or more combinations of medical tape, bandage, gauze, dressing material, sponge, and medical suture.

[0020] In an optional embodiment, in the above use, the drug comprises a divalent metal lactate as an active ingredient, and the drug further comprises a pharmaceutically acceptable carrier or excipient.

[0021] Preferably, in the drug, the divalent metal lactate is the sole active ingredient.

[0022] As an optional embodiment, in the above use, the dosage form of the drug includes an injectable preparation or a topical preparation.

[0023] Preferably, the topical preparation includes one or more combinations of ointments, creams, patches, sprays, solutions, and lotions.

[0024] Preferably, the method of administering the product includes one or more of the following: intravenous injection, in situ injection, intramuscular injection, subcutaneous injection, oral administration, or topical application.

[0025] Furthermore, those skilled in the art will understand that the method of use of the product, as well as the dosage and volume of administration, may be determined by a clinician depending on the age, physical condition, and disease of the subject.

[0026] The present invention has the following beneficial effects compared to the prior art: The present invention provides a new treatment method for repairing central and peripheral nerve injuries, which is safe, has a reliable therapeutic effect, low price, and simple administration method. In particular, the present invention discovers the use of divalent metal lactate containing one or a combination of calcium lactate, magnesium lactate, zinc lactate, and ferrous lactate in the manufacture of products for preventing, improving, repairing, and treating nerve injuries. Therefore, it has broad application prospects in the treatment and repair of central nerve injuries caused by causes such as trauma, or peripheral neuritis or peripheral nerve sensory abnormalities caused by viruses, diabetes, chemotherapy drugs, etc.

Embodiment for Implementing the Invention

[0027] Hereinafter, the present invention will be further described with reference to specific examples. It should be understood that the specific examples described here are only for interpreting the present invention and do not limit the scope of the present invention.

[0028] For those where specific techniques or conditions are not specified in the examples, they are carried out according to the techniques or conditions described in the literature of the technical field or according to the product manual. The reagents or instruments used are all ordinary products that can be purchased through regular channels if the manufacturer is not specified.

[0029] The experimental methods in the following examples are all conventional methods unless otherwise specified. The test materials used in the following examples are all commercially available products unless otherwise specified.

[0030] In the following examples, all experiments were repeated 3 times, and the sample size of each group was at least 3. The data obtained from the experiments were statistically analyzed using SPSS 21.0 software. Mean ± standard deviation (Mean ± SD) was used for the statistical description of measurement data, and the index comparison between groups was performed by analysis of variance. P < 0.05 is considered to have a statistical difference. When P < 0.05, the comparison between groups can be performed by LSD-t test.

[0031] Example 1: Influence of Divalent Metal Lactate on Animals with Sciatic Nerve Injury Model 1. Establishment of a sciatic nerve injury model and grouping of experiments Forty 8-week-old SD rats (half male, half female, sex ratio 1:1) weighing 200-220g were placed in a temperature-controlled chamber (22±2℃). The animals were anesthetized by intraperitoneal injection of 3.0% (w / v) pentobarbital sodium (0.2 ml / 100g). After complete anesthesia, the hair on the left rump of the rats was shaved, and the shaved area was disinfected with alcohol and iodine swabs. Then, an oblique incision was made, and the area was bluntly dissected through the gap in the gluteal muscles to expose the left sciatic nerve. Using hemostatic forceps, the sciatic nerve was clamped three times (10s, 10s intervals each time) 0.5cm from the lower edge of the piriformis muscle, and the clamping point was marked by suturing with surgical sutures to the muscle adjacent to the clamping point. The muscle and skin were immediately sutured together, and the area was disinfected again. Postoperatively, the animals were randomly divided into four groups of 10 each. Rats were housed in separate cages, and then administered either a drug or saline solution intraperitoneally once a day for four consecutive weeks, according to the group divisions. The experimental group divisions and treatment methods are shown in Table 1. Postoperatively, the rats' overall condition, skin ulcers around the incision site, and recovery of limb function on the surgical side were carefully observed.

[0032] [Table 1]

[0033] 2. Footprint collection and sciatic nerve index scoring A rat walking record box with a passage length of 90 cm, width of 15 cm, and height of 20 cm was constructed. A 15 cm wide continuous recording paper was placed at the bottom. At 1, 2, 3, and 4 weeks post-surgery, a colored, non-toxic dye was applied to the soles of the rats' hind feet, and they were made to walk on the continuous recording paper, leaving footprints on both sides. Footprints from the experimental foot (E) and the normal foot (N) were selected, and the following variables were measured: 1) print length (PL), the distance from heel to toe; 2) toe spread (TS), the lateral distance from the 1st to the 5th toe; and 3) inter toe distance (IT), the lateral distance from the 1st to the 4th toe. The sciatic nerve function index (SFI) is calculated by substituting the three variables above into the following formula. An SFI of 0 indicates normality, while an SFI of -100 indicates complete injury. The formula is as follows: SFI=-38.3×(EPL-NPL) / NPL+109.5×(ETS-NTS) / NTS+13.3×(EIT-NIT) / NIT-8.8

[0034] Rat footprints were collected at various postoperative time points (1 week, 2 weeks, 3 weeks, and 4 weeks), and the SFI was calculated to evaluate the motor function and recovery status of rats in each group. The results are shown in Table 2. The results showed that at 2, 3, and 4 weeks postoperatively, the SFI of the low, medium, and high-dose magnesium lactate groups was significantly better than that of the control group treated with physiological saline (Table 2, medium-dose magnesium lactate group P<0.01, low and high-dose magnesium lactate groups P<0.05). Low, medium, and high-dose magnesium lactate were shown to have some therapeutic effect and to promote the functional recovery of the sciatic nerve. Furthermore, at 2, 3, and 4 weeks postoperatively, the SFI of the medium-dose magnesium lactate group was significantly better than that of the low and medium-dose magnesium lactate groups (P<0.05), indicating that medium-dose magnesium lactate has a superior therapeutic effect on nerve damage and is more advantageous for the recovery of nerve function.

[0035] [Table 2]

[0036] 3. Real-time quantitative PCR 3.1 Extraction of total RNA The sciatic nerve was removed, washed in DEPC-treated water, 0.5 mL of Trizol was added, it was thoroughly ground, and the supernatant was collected by centrifugation. 0.1 mL of chloroform was added, and the supernatant was collected by centrifugation. 0.8 mL of isopropanol was added, and the supernatant was discarded after centrifugation. 1 mL of 75% ethanol was added, and the supernatant was discarded after centrifugation. 20 μL of DEPC-treated water was added to dissolve the RNA. The concentration and purity of the total RNA solution were measured using a UV-Vis spectrophotometer.

[0037] 3.2 Real-time quantitative PCR reaction Caspase-3 and GAP-43 expression were detected in the sciatic nerve tissue of each group using the RT-qPCR method.

[0038] Primer design Caspase-3 upstream primer 5'-GAGCTTGGAACGGTACGATA-3' Downstream primer 5'-CCGTACCAGAGCGAGATGAC-3' GAP-43 upstream primer 5'-GTGTGTGAGCCTGTCCTCTC-3' Downstream primer 5'-AAAACCGGGGTACAGTGCAA-3'

[0039] Caspase-3 plays a crucial role in the apoptotic process and is also a potential drug target. Studies have shown that Caspase-3 strongly inhibits DNA replication, transcription, and damage repair, ultimately leading to irreversible apoptotic effects in cells. Therefore, reducing Caspase-3 activation can effectively suppress the progression of apoptosis. The real-time quantitative PCR results for Caspase-3 are shown in Table 3. The results show that Caspase-3 mRNA expression in the saline control group did not show any significant changes at each period. Compared to the same time points in the saline control group, Caspase-3 mRNA expression levels in the low, medium, and high-dose magnesium lactate groups were clearly downregulated on days 1, 3, and 7 after model establishment (P<0.05). In addition, within 7 days after model establishment, Caspase-3 mRNA levels in the low, medium, and high-dose magnesium lactate groups gradually decreased over time (P<0.05). Compared to the low-dose group, Caspase-3 mRNA expression levels in the medium- and high-dose magnesium lactate groups were clearly downregulated on days 1, 3, and 7 (P<0.05). Compared to the high-dose group, Caspase-3 mRNA expression levels in the medium-dose magnesium lactate group were significantly reduced at each time point (P<0.05). After sciatic nerve injury occurred, Caspase-3 expression in rat neurons was significantly enhanced, and the number of apoptotic neurons increased accordingly. Injection of magnesium lactate can reduce Caspase-3 protein and decrease the occurrence of apoptosis due to nerve injury.

[0040] [Table 3]

[0041] GAP-43 is a membrane phosphorylated protein widely present in neurons and is one of the markers of neuronal regeneration. It can play an important role in neuronal regeneration by regulating the actin cytoskeleton. The real-time quantitative PCR results for GAP-43 are shown in Table 4. The results show that the expression of GAP-43 mRNA in the saline control group did not show any significant change. Compared to the same time point in the saline control group, the expression levels of GAP-43 mRNA in the low, medium, and high-dose magnesium lactate groups were clearly elevated on days 1, 3, and 7 after model establishment (P<0.05). In addition, within 7 days after model establishment, the GAP-43 mRNA levels in the low, medium, and high-dose magnesium lactate groups gradually increased over time, reaching a peak on day 7 (P<0.05). Compared to the low-dose group, the expression levels of GAP-43 mRNA in the medium and high-dose magnesium lactate groups were clearly upregulated on days 1, 3, and 7 (P<0.05). Compared to the high-dose group, GAP-43 mRNA expression levels were significantly elevated in the medium-dose magnesium lactate group at each time point (P<0.05). Magnesium lactate can increase GAP-43 expression, reduce sciatic nerve injury in rats, and promote nerve regeneration.

[0042] [Table 4]

[0043] Example 2: Effects of divalent metal lactates on spinal cord injury model animals 1. Establishment of a rat spinal cord injury model Forty 8-week-old SD rats (half male, half female, sex ratio 1:1) weighing 200-220g were placed in a temperature-controlled chamber (22±2℃). The animals were anesthetized by intraperitoneal injection of 3.0% (w / v) pentobarbital sodium (0.2mL / 100g). After complete anesthesia, the anesthetized animals were fixed in a prone position, shaved, and disinfected as usual. A longitudinal incision (2-3cm) was made along the midline of the back, using the 12th thoracic vertebra (T12) as the reference point. Starting from this point, the incision was made from the lateral to the medial side down to the subcutaneous fascia, and the dorsal arch plates of rat T9-11 were precisely excised to expose the dura mater of the spinal cord. An aneurysm clip was used to clamp the middle portion of the exposed spinal cord for 40 seconds to create a spinal cord injury (SCI) model. During the experiment, the spinal cord injury group rats were induced to urinate by compressing their bladder once in the morning and once in the evening each day. After urination, the perineum was kept clean and dry, and any limbs wet with urine were immediately washed and dried. The animals' positions were also changed frequently. To prevent infection, gentamicin (2000 U / kg·d) was administered intramuscularly for three days postoperatively. Postoperatively, the animals were randomly divided into four groups of 10 rats each, and the rats were housed in separate cages. Subsequently, according to the group division, drugs or saline solution were administered intraperitoneally once a day for four consecutive weeks. The experimental group divisions and treatment methods are shown in Table 5.

[0044] [Table 5]

[0045] 2. Motor System Score (BBB Score) We evaluated the limb function of rats after spinal cord injury using the BBB score method, a neurological function assessment method proposed by American researchers Basso et al. The method was as follows: the animals were placed in an open container, and the walls of the container were lightly tapped to encourage them to crawl. We then observed the gait, propulsion, and coordination of the hip, knee, and ankle joints of the animals. The results are shown in Table 6.

[0046] As can be seen from Table 6, after treatment with magnesium lactate, the rats in each group showed varying degrees of functional recovery, with the medium-dose magnesium lactate group showing the fastest recovery. At 1 day post-surgery, the BBB scores of the rats in each group did not show a statistically significant difference (P>0.05). Over time, the BBB scores in each group gradually increased, and the differences between the groups also gradually widened. At 4 weeks post-surgery, the medium-dose magnesium lactate group had the highest score, followed by the high-dose magnesium lactate group and the low-dose magnesium lactate group, while the saline-treated control group had the lowest score. Here, the difference between the low-dose and high-dose magnesium lactate groups was not statistically significant (P=0.213), but the differences between all other groups were statistically significant (P<0.05).

[0047] [Table 6]

[0048] 3. Real-time quantitative PCR A 0.5 cm section of injured spinal cord was excised, centered on the injured area, and RT-PCR was performed to measure the gene expression of brain-derived neurotrophic factor (BDNF), glial fibrillary acidic protein (GFAP), and neuron-specific enolase (NSE).

[0049] 3.1 Extraction of total RNA The tissue was placed in a 1 mL homogenization tube. 100 mg of tissue was placed in a homogenization tube, RNA extract was added, the mixture was thoroughly pulverized, centrifuged, and the supernatant was collected for use. 250 μL of chloroform was added, and the supernatant was collected after centrifugation. 0.8 mL of isopropanol was added, and the supernatant was discarded after centrifugation. 1 mL of 75% ethanol was added, and the supernatant was discarded after centrifugation. 15 μL of RNase-free water was added to dissolve the RNA. The concentration and purity of the total RNA solution were measured using a UV-Vis spectrophotometer.

[0050] 3.2 Reverse Transcription Reaction 3.3 Real-time quantitative PCR reaction Primer design BDNF upstream primer 5'-GTCAAGTGCCTTTGGAGCCT-3' Downstream primer 5'-CATGGGATTGCACTTGGTCTC-3' GFAP upstream primer 5'-AGTCGGCGAGTTACCAGGAG-3' Downstream primer 5'-TTAATGACCTCGCCATCCCG-3' NSE Upstream Primer 5'-TATCCTGGAGAACAGCGAAGC-3' Downstream primer 5'-GACAAAGTCCTGGTAGAGTGCCC-3'

[0051] BDNF is one of the most widely distributed and abundantly expressed neurotrophic factors in the mammalian brain, playing a crucial role in the normal growth, development, and plasticity of synapses, and can suppress cell apoptosis by activating downstream pathways. As can be seen from Table 7, at one week post-surgery, the difference in BDNF expression between the low, medium, and high-dose magnesium lactate groups in the control group treated with physiological saline was statistically significant (P<0.05). The difference in BDNF expression between the low-dose magnesium lactate group and the high-dose magnesium lactate group was not statistically significant (P=0.628). At four weeks post-surgery, the difference in BDNF expression between the physiological saline-treated control group and the low-dose magnesium lactate group was not statistically significant (P=0.820), but the differences between each of the other groups were all statistically significant (P<0.05). At four weeks post-surgery, the differences in GFAP and NSE expression among the four groups were statistically significant (P<0.05). As an important neurotrophic factor, BDNF plays a crucial role in regulating neuronal growth, differentiation, and synaptic plasticity by binding to specific receptors and activating downstream pathways. As shown in Table 7, divalent metal lactates can increase BDNF expression and, consequently, activate downstream anti-apoptotic pathways, thereby reducing apoptosis in neurons after spinal cord injury and participating in the process of neuronal remodeling.

[0052] [Table 7]

[0053] GFAP expression is an important indicator of spinal nerve cell growth, proliferation, and differentiation, and is considered a therapeutic target for acute spinal cord injury. As can be seen from Table 8, at one week post-surgery, the difference in GFAP expression between the low, medium, and high-dose magnesium lactate groups in the control group treated with physiological saline was statistically significant (P<0.05). At one week post-surgery, the difference in GFAP expression among the four groups was statistically significant (P<0.05). At four weeks post-surgery, the difference in GFAP expression among the four groups was statistically significant (P<0.05). GFAP is an astrocyte-specific marker protein, and since astrocytes are the most numerous cells in the central nervous system, they show high expression levels post-surgery. Compared to the other groups, GFAP expression was clearly reduced in the medium-dose divalent lactate group, suggesting that it inhibits astrocyte proliferation and, consequently, suppresses glial scar formation, a process that can promote axonal regeneration and neural remodeling.

[0054] [Table 8]

[0055] NSE is an enzyme that plays a crucial role in respiration within nerve cells and is widely present in brain tissue and other peripheral nerve cells. NSE is involved in glycolysis in the body, and when damage such as hypoxia, ischemia, and poisoning occurs, NSE is released and enters the circulating blood along with the breakdown of the blood-brain barrier. As can be seen from Table 9, at one week post-surgery, the difference in NSE expression between the low, medium, and high-dose magnesium lactate groups in the control group treated with physiological saline was statistically significant (P<0.05). At one week post-surgery, the difference in NSE expression between the low, medium, and high-dose magnesium lactate groups was not statistically significant (P>0.05). At four weeks post-surgery, the difference in NSE expression between the four groups was statistically significant (P<0.05). The medium and high-dose divalent lactate groups were able to improve NSE expression levels, with the effect of improving NSE being more pronounced in the medium-dose group. Because NSE is involved in catalytic reactions in cellular glucose metabolism, increased NSE expression can improve cellular energy metabolism and promote the recovery of damaged cells.

[0056] [Table 9]

[0057] Example 3: Effects of divalent metal lactates on an animal model of autoimmune neuritis 1. Establishment of an autoimmune neuritis model and grouping of experiments Forty 8-week-old SD rats (half male, half female, sex ratio 1:1) weighing 200-220g were placed in a temperature-controlled chamber (22±2℃). 200μg of P0 180-199 A mixture of 1 mg of H37Ra, 100 μL of physiological saline, and 100 μL of IFA was thoroughly emulsified and administered as a single dose to each rat, subcutaneously into the soles of both hind limbs (100 μL in each sole). After successfully establishing the model, the rats in each group were orally administered the corresponding drug or physiological saline once a day for four consecutive weeks.

[0058] [Table 10]

[0059] 2. Behavioral scores During the administration period, rats were observed daily and behavioral scoring was performed. 0 minutes: no clinical symptoms; 5 minutes: quadriplegia or death.

[0060] In the autoimmune neuritis group, on day 1 after forced oral administration of saline, some rats began to show symptoms of varying degrees of neurological impairment, including lethargy, soiling of the coat, and erythema and swelling of both hind limbs. On day 5, all rats showed varying degrees of autoimmune neuritis symptoms, with successive appearances of decreased muscle tone and tail dragging, accompanied by paralysis. On day 8, the symptoms of autoimmune neuritis in the rats peaked, with the neurological impairment score being the highest at 4.0 ± 0.5. In the low-dose magnesium lactate group, on day 6 after administration, some rats showed varying degrees of neurological impairment symptoms. On day 11, all rats showed varying degrees of autoimmune neuritis symptoms. On day 15, the symptoms of autoimmune neuritis in the rats peaked, with the neurological impairment score being the highest at 3.0 ± 0.5. Thereafter, the symptoms of autoimmune neuritis in the rats gradually subsided, and on day 28, the neurological impairment score was 0-1. In the medium-dose magnesium lactate group, some rats showed varying degrees of neurological impairment on day 10 after administration, and all rats showed varying degrees of autoimmune neuritis on day 16. On day 21, the symptoms of autoimmune neuritis in the rats peaked, and the neurological deficit score was highest at 2.0 ± 0.5. Subsequently, the symptoms of autoimmune neuritis in the rats gradually subsided, and on day 25, the neurological deficit score became 0. In the high-dose magnesium lactate group, some rats showed varying degrees of neurological impairment on day 8 after administration, and all rats showed varying degrees of autoimmune neuritis on day 12. On day 16, the symptoms of autoimmune neuritis in the rats peaked, and the neurological deficit score was highest at 2.5 ± 0.5. Subsequently, the symptoms of autoimmune neuritis in the rats gradually subsided, and on day 33, the neurological deficit score became 0 to 1. These results indicate that magnesium lactate has a certain therapeutic effect on neurological dysfunction caused by autoimmune neuritis, and that the effect of moderate-dose magnesium lactate is most pronounced.

[0061] 3. Detection of inflammatory factor levels According to existing theories, inflammatory factors are one of the factors that exacerbate the pathogenesis of autoimmune neuritis. IL-17, a characteristic cytokine secreted by Th17 cells, is involved in the development of autoimmune diseases by inducing an inflammatory cascade response in target organs. Blood was collected from the retroorbital venous plexus of rats, centrifuged, and the supernatant was collected. The concentrations of IL-17 and IFN-γ in the serum were measured using a microplate reader, and the results are shown in Table 11. Compared to the autoimmune neuritis group administered physiological saline orally, the levels of IL-17 and IFN-γ in the serum of rats administered magnesium lactate orally were significantly reduced (P<0.05). Compared to the low-dose and high-dose magnesium lactate groups, the levels of IL-17 and IFN-γ in the medium-dose magnesium lactate group were significantly reduced (P<0.05). This suggests that magnesium lactate can reduce the secretion of inflammatory cytokines due to autoimmune neuritis, and that the effect of medium-dose magnesium lactate is most pronounced.

[0062] [Table 11]

[0063] In the above use, the results for calcium lactate, zinc lactate, ferrous lactate, and other divalent metal lactates, including combinations thereof, are similar to those for magnesium lactate, and therefore will not be explained here.

[0064] Example 4: Effects of divalent metal lactates on an animal model of autoimmune encephalomyelitis 1. Establishment of an autoimmune encephalomyelitis model and grouping of experiments Forty 8-week-old SD rats (half male, half female, 1:1 sex ratio) weighing 200-220g were placed in a temperature-controlled chamber (22±2℃). MOG 35-55 Dilute PBS to 6 mg / mL with polypeptide and mix with CFA in equivolume. Connect a 5 mL syringe using a dual-channel connector and mix by repeatedly pushing and pulling, then MOG 35-55A water-in-oil antigen emulsion was prepared. Antigen immunization was performed using experimental rats, and the antigen emulsion was subcutaneously injected at multiple locations on the back, with a total of 0.2 mL of the antigen emulsion (MOG) injected at four locations per rat. 35-55 The rats were injected with a polypeptide (containing 600 μg / rat), and at 0 and 48 hours after the completion of immunization with the antigen emulsion, PTX was administered intraperitoneally as a sensitizer to improve the model's incidence. After successfully establishing the model, the rats in each group were forcibly administered the corresponding drug or saline solution once a day for four consecutive weeks.

[0065] [Table 12]

[0066] 2. Scores for neurological function deficits During the administration period, rats were observed daily and scored for neurological function defects. 0 minutes: no clinical symptoms; 5 minutes: near death or death.

[0067] In the autoimmune encephalomyelitis group, on day 5 after forced oral administration of saline, some rats began to show symptoms of varying degrees of neurological dysfunction. On day 9, all rats showed symptoms of varying degrees of autoimmune encephalomyelitis, with decreased muscle tone, tail dragging, and paralysis occurring in succession. On day 12, the symptoms of autoimmune encephalomyelitis in the rats peaked, with the neurological dysfunction score being the highest at 3.5 ± 0.5. In the low-dose magnesium lactate group, on day 7 after administration, some rats began to show symptoms of varying degrees of neurological dysfunction. On day 12, all rats showed symptoms of varying degrees of autoimmune encephalomyelitis. On day 16, the symptoms of autoimmune encephalomyelitis in the rats peaked, with the neurological dysfunction score being the highest at 2.5 ± 0.5. Thereafter, the symptoms of autoimmune encephalomyelitis in the rats gradually subsided, and on day 28, the neurological dysfunction score was between 0 and 1. In the medium-dose magnesium lactate group, on day 12 after administration, some rats showed symptoms of varying degrees of neurological impairment. On day 18, all rats showed symptoms of varying degrees of autoimmune encephalomyelitis. On day 23, the symptoms of autoimmune encephalomyelitis in rats peaked, and the neurological deficit score was highest at 1.5 ± 0.5. Subsequently, the symptoms of autoimmune encephalomyelitis in rats gradually subsided, and on day 26, the neurological deficit score became 0. In the high-dose magnesium lactate group, on day 10 after administration, some rats showed symptoms of varying degrees of neurological impairment. On day 15, all rats showed symptoms of varying degrees of autoimmune encephalomyelitis. On day 19, the symptoms of autoimmune encephalomyelitis in rats peaked, and the neurological deficit score was highest at 2.5 ± 0.5. Subsequently, the symptoms of autoimmune encephalomyelitis in rats gradually subsided, and on day 31, the neurological deficit score became 0-1. Magnesium lactate has a certain therapeutic effect on neurological dysfunction caused by autoimmune encephalomyelitis, and the effect of medium-dose divalent lactate is most pronounced in this regard.

[0068] 3. Detection of inflammatory factor levels After killing the rats, spinal cord tissue was extracted, homogenized with tissue lysate, and the supernatant was collected after centrifugation. The concentrations of TNF-α, IL-6, and IL-β were measured, and the results are shown in Table 13. Compared to the autoimmune encephalomyelitis group administered physiological saline orally, the levels of TNF-α, IL-6, and IL-β in the spinal cord of rats administered magnesium lactate orally were significantly reduced (P<0.05). Compared to the low-dose and high-dose magnesium lactate groups, the levels of TNF-α, IL-6, and IL-β were significantly reduced in the medium-dose magnesium lactate group (P<0.05). Magnesium lactate was shown to reduce the secretion of inflammatory cytokines due to autoimmune encephalomyelitis, thereby mitigating the destruction of myelin sheath tissue, with the effect of medium-dose magnesium lactate being the most pronounced.

[0069] [Table 13]

[0070] Clearly, those skilled in the art can make various modifications and variations to the present invention without departing from the spirit and scope of the invention. Thus, the present invention is also intended to include such modifications and variations, provided that these modifications and variations fall within the scope of the claims of the present invention and the equivalent art.

Claims

1. The use of divalent metal lactates in the manufacture of products for the prevention, improvement, repair, and treatment of nerve damage, characterized in that the tissue in which nerve damage occurs is selected from collagen-rich nerve tissue.

2. The use according to claim 1, characterized in that the nerve injury is central nervous system injury or peripheral nervous system injury, and the prevention, improvement, repair, and treatment of the nerve injury are nerve regeneration, increase in nerve number, and / or nerve repair.

3. The use according to claim 2, characterized in that the central nervous system injury includes spinal cord injury or cerebrospinal neuritis, and the peripheral nervous system injury includes peripheral nerve injury, peripheral neuritis, or peripheral neuropathy.

4. The use according to claim 3, characterized in that the peripheral neuritis is selected from one or more of facial neuritis, diabetic peripheral neuritis, viral peripheral neuritis, chemotherapeutic peripheral neuritis, or Guillain-Barré syndrome, and the symptoms of the peripheral neuritis include decreased sensation, pain, numbness or tingling, crawling sensation, burning sensation, and hyperesthesia.

5. The use according to any one of claims 1 to 4, characterized in that the divalent metal lactate comprises one or more of calcium lactate, magnesium lactate, zinc lactate, and ferrous lactate.

6. The use according to claim 5, characterized in that the divalent metal lactate is selected from magnesium lactate or a composition of zinc lactate and magnesium lactate, preferably, in parts by weight, the ratio of zinc lactate to magnesium lactate in the composition is 1:10 to 10:

1.

7. The use according to claim 1, characterized in that the product is selected from one or more of drugs, kits, health foods, and medical devices, preferably the concentration of the divalent metal lactate in the product is 5 to 250 mmol / L, and more preferably the concentration of the divalent metal lactate in the product is 30 to 150 mmol / L.

8. The use according to claim 7, characterized in that the medical device includes one or more combinations of medical tape, bandages, gauze, dressings, sponges, and medical sutures.

9. The use according to claim 7, characterized in that, in the drug, the divalent metal lactate is an active ingredient, and the drug further comprises a pharmaceutically acceptable carrier or excipient.

10. The use according to claim 7, characterized in that the dosage form of the drug includes an injection or a topical preparation, preferably the topical preparation includes one or more combinations of ointments, creams, patches, sprays, solutions, and lotions, and preferably the method of administering the product includes one or more of intravenous injection, in situ injection, intramuscular injection, subcutaneous injection, oral administration, or topical application.

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