CN104173348B - Application of the left-handed Mefloquine in prevention neurogenic pain medicine is prepared - Google Patents

Abstract

The invention discloses the application of levo-mefloquine in the preparation of medicines for treating or preventing neuropathic pain, wherein the levo-mefloquine is used as an effective active ingredient. The present invention also proposes a pharmaceutical composition comprising a therapeutically effective dose of levomefloquine and a pharmaceutically acceptable carrier. In the application of the present invention, the levo-mefloquine can significantly and effectively prevent and treat the occurrence of neuropathic pain symptoms, has no toxic and side effects, and has good application prospects.

Description

Application of L-mefloquine in the preparation of drugs for preventing neuropathic pain

technical field

The invention relates to the field of medicine, in particular to the application of levo-mefloquine in the preparation of medicines for treating or preventing neuropathic pain.

Background technique

Neuropathic pain (Neuropathic Pain, NPP) is a class of diseases caused by damage to nerve machinery (such as sports, car accidents, surgery). It is a type of chronic pain characterized by clinical features such as spontaneous pain, hyperalgesia, allodynia, and paresthesia (Neuron, 2012, 73, 638-652). According to the report of the Institute of Medicine (IOM) of the National Academy of Sciences in 2009, at least 116 million adults in the United States suffer from chronic pain diseases, and the proportion of patients with neuropathic pain is as high as 17.9%, accounting for about 3.5% of the total population of the United States; among European adults About 1 in 5 people have chronic pain, and about 25% of people with diabetes have neuropathic pain. The pathogenesis of neuropathic pain is complex, involving the peripheral nervous system, spinal cord and brain. Recent studies have found that NPP is similar to the memory mechanism of the brain (Science, 2011, 331, 87-91): a key mechanism of the disease lies in the enhancement of neural connections in the anterior cingulate cortex (ACC) of the brain , and long-term potentiation (LTP). Basic research has shown (Lancet, 2010, 9, 807-819): in the first few days of nerve damage, some NMDA receptor blockers, cAMP inhibitors, etc. can block the occurrence of LTP in ACC, which can effectively prevent neurogenic damage. The occurrence of sexual pain.

Mefloquine, chemical name: (+/-)-α-2-piperidinyl-2,8-bistrifluoromethyl-4-quinolinemethanol, trade name Lariam. The clinical application is its hydrochloride, its molecular formula: C ₁₇ H ₁₇ ClF ₆ N ₂ O.HCl, molecular weight: 414.77, white crystal, easily soluble in water, melting point mp 259-260°C (decomposition). Clinical application of mefloquine (hydrochloride) is mainly used for the prevention and treatment of cerebral malaria (Plasmodium falciparum) and Plasmodium vivax or the control of chloroquine-resistant cerebral malaria (Plasma falciparum), by Roche, the US Military Medical Research Institute and Co-developed by WHO, it was first marketed in Thailand in 1984, and then marketed in Switzerland, France, Australia, West Germany, the United Kingdom and other countries, and was approved by FDA in May 1989. Mefloquine is commonly used as an antimalarial drug for the treatment of falciparum malaria and vivax malaria. It has a strong killing effect on protozoan erythrocytic asexuals resistant to chloroquine and pyrimethamine-resistant strains. Its mechanism of action is still unclear , may be similar to quinine and the role of iron in iron protoporphyrin Ⅸ, iron protoporphyrin Ⅸ is the main component of malaria pigment, thus causing malaria pigment agglutination, but the development is slow and seldom forms clumps. Unlike quinine, however, it does not intercalate into the DNA of the malaria parasite. The plasma concentration reaches the peak within 18 hours, and its plasma half-life is longer, but individual differences are large, with an average of 14 days, and the effective level can be maintained for more than 30 days. It is metabolized into carboxylic acid metabolites in the body, and the metabolites have no effect on malaria parasites, and are mainly excreted from the body by feces and bile. The mefloquine that has been listed is a racemic drug (that is, an optical mixture), containing two enantiomers, left-handed and right-handed. It has been reported that dextro-mefloquine has a significant inhibitory effect on malaria, while levo-mefloquine Quinoquine has no inhibitory effect on malaria (J.Am.Chem.Soc.2012, 134, 3080; WO2004050625A1). Pharmacological studies have shown that when mefloquine treats malaria, it targets the Cx36 protein and can pass through the blood-brain barrier. Cx36 protein is not only detailed in the periphery, but also constitutes the electric synapse connection between neurons in the brain. It has been reported that intraperitoneal injection of mefloquine can destroy the memory ability of animals (rats/mouses) in a short period of time (Science, 2011, 331, 87-91). Mefloquine is widely used in the prevention and treatment of malaria. So far, no report has disclosed that L-mefloquine has the effect of preventing or treating neuropathic pain.

Contents of the invention

The present invention innovatively proposes for the first time the application of levo-mefloquine in the preparation of drugs for preventing or treating neuropathic pain, and the single-configuration molecule of levo-mefloquine can effectively prevent or treat neuropathic pain disorders.

In the present invention, the neuropathic pain refers to a type of pain caused by nerve damage caused by mechanical and chemical stimulation due to diseases, sports, car accidents, surgical operations, etc. It belongs to a kind of chronic pain, and the pain is manifested as spontaneous pain , hyperalgesia, allodynia, and paresthesias.

In each embodiment of the present invention, the chemical name of dexmefloquine is (+)-α-2-piperidinyl-2,8-bistrifluoromethyl-4-quinolinemethanol, and its molecular formula is: C ₁₇ H ₁₇ ClF ₆ N ₂ O, molecular weight: 378.31, its structural formula is as follows:

Among them, R and S represent the relative structure of chiral carbon atoms.

The research of the present invention found that in the application of preventing or treating neuropathic pain, the target of levoquine, connexin36 (Cx36), is closely related to neurons in the brain, based on the relationship between neuropathic pain and brain memory consolidation. In a similar mechanism, chiral mefloquine is used as a Cx36 blocker to achieve the effect of preventing and treating neuropathic pain disorders.

The research results of the present invention show that racemic mefloquine has the obvious effect of preventing and treating neuropathic pain, and levomefloquine has the remarkable effect of preventing and treating neuropathic pain, while dexmefloquine has no similar effect . In addition, in the application of the present invention for preventing or treating neuropathic pain, when the dosage of levo-mefloquine is half of the dosage of racemic-mefloquine, levo-mefloquine can achieve the same drug effect as racemic-mefloquine.

In the present invention, levocefloquine, as an active ingredient, can be made into a solution or a solid dosage form, such as injection, powder, powder, tablet, sugar-coated agent, capsule, granule, suspension, solution, syrup , drops, etc., or administered orally or by injection.

The present invention also proposes a pharmaceutical composition, which is used as a medicine for preventing or treating neuropathic pain, which includes a therapeutically effective amount of levomethofoquine and a pharmaceutically acceptable carrier or pharmaceutically acceptable adjuvant or additive.

The pharmaceutical composition of the present invention may contain conventional pharmaceutically acceptable auxiliary substances, stabilizers, wetting agents or other commonly used additives, for example, lactose, citric acid, tartaric acid, stearic acid, magnesium stearate, gypsum powder, sucrose , corn starch, talc, gelatin, agar, pectin, peanut oil, olive oil, cocoa butter, ethylene glycol, ascorbic acid, mannitol, etc. The carrier for administering the pharmaceutical composition of the present invention may be one or more solid, semi-solid or liquid diluents, fillers and other prescription auxiliary materials. The present invention can be administered through oral administration, injection, local tissue administration, etc., and can be administered in dosage forms and dosages suitable for each administration method. The pharmaceutical composition of the present invention can be any pharmaceutical solution or solid dosage form, including drops, ointment, gel, tablet, water, granule, solution and the like. The pharmaceutical composition can be in solid form such as tablet, capsule, powder, pill, granule, ointment, gel, liposome, suppository, or in liquid form such as water, injection, eye drop, emulsion, etc. For example, levocefloquine is mixed with organic or inorganic solid or liquid excipients.

The research of the present invention shows that the occurrence of pathological pain-like symptoms in CCI model rats can be effectively prevented and treated by injection of levomefloquine; the effective administration time window for levo-mefloquine to affect the pathological pain-like symptoms of CCI model rats; Micro-introduction of levo-mefloquine into the cingulate cortex can effectively prevent the occurrence of neuropathic pain-like symptoms by blocking the expression of Cx36 in the anterior cingulate cortex; injection of levo-mefloquine can effectively prevent the occurrence of pathological pain-like symptoms in SNI model rats ; It shows that the active ingredient L-mefloquine can be widely and effectively used in the preparation of medicines for preventing or treating neuropathic pain. Simultaneously, the research of the present invention shows that levo-mefloquine has no obvious effect on the exercise ability, balance ability and anxiety state of rats, has no toxic and side effects, and has a good application prospect.

Description of drawings

Fig. 1 (A), (B), (C) are the mechanical pain threshold of levo-mefloquine, dex-mefloquine, and racemic mefloquine of intraperitoneal injection of different dosages in embodiment 1 to CCI model rats Effect.

Fig. 2 (A), (B), (C) are the thermal pain threshold of levomefloquine, dexmefloquine, and racemic mefloquine of intraperitoneal injection of different dosages in embodiment 1 to CCI model rats Effect.

Figure 3 is the performance of the opening experiment of intraperitoneal injection of levo-mefloquine and racemic-mefloquine

Figure 4 is the performance of intraperitoneal injection of L-mefloquine and racemic mefloquine rotary rod experiment

The influence of intraperitoneal injection of levocefloquine at different times of Fig. 5 embodiment 3 on the mechanical pain of CCI model rats

Fig. 6 is the effect of different time intraperitoneal injection of levoquine of embodiment 3 on the thermal pain of CCI model rat

Fig. 7 is the effect of the anterior cingulate cortex implanted tube microinjection of levoquine of embodiment 4 on the mechanical pain of rats after CCI operation

Fig. 8 is the effect of the anterior cingulate cortex implanted catheter microinjection of levoquine of embodiment 4 on the thermal pain of rats after CCI operation

Figure 9 is the gene sequence of the lentivirus interference effect of Example 5

Figure 10 is an immunoblotting diagram of the down-regulation of Cx36 protein expression in this brain region by injection of lentivirus in the anterior cingulate cortex of Example 5

Figure 11 is an immunohistochemical picture of the down-regulation of Cx36 protein expression in this brain region by injection of lentivirus in the anterior cingulate cortex of Example 5

Figure 12 is the effect of microinjection of the anterior cingulate cortex of Example 5 on the mechanical pain of rats after CCI surgery after Cx36 expression down-regulated virus

Figure 13 is the effect of microinjection of Cx36 expression down-regulation virus in the anterior cingulate cortex of Example 5 on thermal pain in rats after CCI surgery

Fig. 14 is the effect of the intraperitoneal injection of levoquine of embodiment 6 on the mechanical pain of SNI model rats

detailed description

The present invention will be described in further detail in conjunction with the following specific examples and accompanying drawings, and the protection content of the present invention is not limited to the following examples. Without departing from the spirit and scope of the inventive concept, changes and advantages conceivable by those skilled in the art are all included in the present utility model, and the appended claims are the protection scope. The process, conditions, reagents, experimental methods, etc. for implementing the present invention are general knowledge and common knowledge in the art except for the content specifically mentioned below, and the present invention has no special limitation content.

In each embodiment of the present invention, all animal experiments were completed in the SPF (high clean level) animal room of the Institute of Brain Functional Genomics, East China Normal University, and all animal operations were in compliance with the rules and regulations of the animal management committee of the institute. CCI operation was carried out on adult SD rats weighing 300-350g. The operation was carried out according to the experimental procedures established by Bennett and Xie in 1988 and widely used at present: the rats were injected intraperitoneally with pentobarbital sodium for general anesthesia, the skin of the hindlimb on the operated side was cut off and disinfected; the sciatic nerve was exposed and separated from other tissues , use chrome catgut (gauge, 5-0) to make 3 light ligatures around the nerve trunk (the interval is about 1mm); suture the muscle and skin. After the animals woke up, they were put back into the cages and allowed to eat freely. From the day after CCI operation (including the day), intraperitoneal injection of 15 mg/kg levo-mefloquine, 15 mg/kg dex-mefloquine, and racemic mefloquine 30 mg/kg (containing the same Dosage of L- and D-mefloquine), and the same volume of solvent (blank control group, vehicle). At 7, 14, and 21 days after operation, the pain threshold of the rats was identified.

In each embodiment of the present invention, the preparation of levo-mefloquine injection: 100 mg of levo-mefloquine was successively prepared and dissolved in 0.05 ml of DMSO, 1.5 ml of Tween, 3 ml of PBS or normal saline.

In each embodiment of the present invention, racemic mefloquine is an optical mixture of equal amounts of enantiomers of levo-mefloquine and dex-mefloquine.

Embodiment 1 Intraperitoneal injection of mefloquine prevents and treats pathological pain-like symptoms in CCI model rats

1. Determination of mechanical pain domain indicators.

Refer to the Up-down method (Pain 85 (2000) 493-502) reported by Dixon, which is commonly used at present. Three days before the test, the animals were put into a test cage with a plexiglass box with a metal mesh bottom to adapt to the environment, once a day for 30 minutes each time. On the day of the test, half an hour after the animals entered the test cage, vonFray fibers of different bending strengths (1, 1.4, 2, 4, 6, 8, 10, 15 g) were used to stimulate the soles of the hind limbs on the side receiving the operation, and the rats’ response to the operation was determined. The paw withdrawal response to the mechanical stimulus. When a rat has a paw withdrawal response to a von Fray fiber stimulation of a certain bending intensity (until it bends), it is considered that the rat has a pain-like behavior, and the von Fray bending intensity is defined as the threshold of mechanical pain.

Within 5 consecutive days from the day of CCI operation, inject once a day, inject 5, 10, 15mg/kg levo-mefloquine, 5, 10, 15 mg/kg dex-mefloquine, 10, 20 , 30 mg/kg racemic mefloquine. Then, within the long-term time range (21 days) of the experimental observation, the pain thresholds of each rat were identified on the 7th, 14th, and 21st days after the operation, respectively, and the detection results are shown in FIG. 1 . Figure 1(A) shows the test results at 7 days after surgery, Figure 1(B) shows the test results at 14 days after surgery, and Figure 1(C) shows the test results at 21 days after surgery. Wherein, 1 represents the blank control group, 2 represents the injection of 5 mg/kg levoquine, 3 represents the injection of 10 mg/kg levoquine, 4 represents the injection of 15 mg/kg levoquine, and 5 represents the injection of 5 mg/kg dextromethorphan Fluoroquine, 6 means injection of 10 mg/kg dextromefloquine, 7 means injection of 15 mg/kg dextromefloquine, 8 means injection of 10 mg/kg racemic mefloquine, 9 means injection of 20 mg/kg racemic mefloquine , 10 represents the injection of 30 mg/kg racemic mefloquine.

As shown in Figure 1, the intraperitoneal injection of 5, 10, and 15 mg/kg levocefloquine to rats can keep the mechanical pain threshold of the model mice at a relatively high level, that is, the mechanical pain threshold rises. Among them, intraperitoneal injection of 15 mg/kg L-mefloquine has a better effect on the recovery of mechanical pain threshold. Experiments have shown that intraperitoneal injection of levo-mefloquine after CCI surgery can increase the threshold of mechanical pain. It can be seen that le-mefloquine can significantly and effectively prevent the occurrence of neuropathic pain-like symptoms.

However, intraperitoneal injection of the same dose of dexmefloquine has no effect on the recovery of mechanical pain threshold. For example, rats with intraperitoneal injection of 15 mg/kg dexmefloquine have the same mechanical pain threshold recovery as that of the blank control group. of. It can be seen that dexmefloquine does not have the effect of preventing and treating neuropathic pain.

The experiment also showed that when the dose of racemic mefloquine was double that of levo-mefloquine, the two reached the same degree of mechanical pain threshold recovery and achieved the same effect. It can be seen that racemic mefloquine has the same effect as Levomefloquine has a similar mechanical pain threshold recovery effect, which can significantly and effectively prevent and treat neuropathic pain.

2. Identification of Heat Pain Threshold Indicators

Rats were placed on a glass plate in a plexiglass box. After 30 minutes, use a thermal radiation stimulator to irradiate the surface of the rat's hindlimb foot on the side of the operation, and record the time for the rat to show a paw withdrawal response to the thermal stimulus, which is defined as the tolerance time of the rat to the thermal stimulus. A measure of pain sensitivity to thermal stimuli.

For 5 consecutive days from the day of the CCI operation, inject once a day, intraperitoneally inject 5, 10, 15 mg/kg levo-mefloquine, 5, 10, 15 mg/kg dex-mefloquine, 10, 20, 30 mg/kg kg racemic mefloquine. In the observed long-term time frame (21 days), the pain thresholds of the rats were identified at 7, 14, and 21 days after the operation, and the test results are shown in Figure 2, and Figure 2 (A) shows the detection at 7 days after the operation As a result, FIG. 2(B) shows the test results at 14 days after surgery, and FIG. 2(C) shows the test results at 21 days after surgery. Among them, 1 represents the blank control group, 2 represents the injection of 5 mg/kg levoquine, 3 represents the injection of 10 mg/kg levoquine, 4 represents the injection of 15 mg/kg levoquine, and 5 represents the injection of 5 mg/kg dextromethorphan Fluoroquine, 6 means injection of 10 mg/kg dextromefloquine, 7 means injection of 15 mg/kg dextromefloquine, 8 means injection of 10 mg/kg racemic mefloquine, 9 means injection of 20 mg/kg racemic mefloquine , 10 represents the injection of 30 mg/kg racemic mefloquine.

As shown in Figure 2, the intraperitoneal injection of 5, 10, and 15 mg/kg levocefloquine to rats can keep the heat pain threshold of the model mice at a relatively high level, that is, the heat pain threshold rises. Among them, intraperitoneal injection of 15 mg/kg L-mefloquine has a better effect on the recovery of heat pain threshold. Experiments have shown that after CCI surgery, intraperitoneal injection of levo-mefloquine increases the thermal pain sensitivity threshold. It can be seen that levo-mefloquine can significantly and effectively prevent the occurrence of neuropathic pain-like symptoms.

However, the same dose of dexmefloquine injected intraperitoneally did not have the effect of raising the thermal pain sensitivity threshold. Are the same. It can be seen that dexmefloquine does not have the effect of preventing and treating neuropathic pain.

Experiments also show that when the dose of racemic mefloquine is twice that of levo-mefloquine, both of them will reach the same degree of recovery of thermal pain threshold and achieve the same effect. It can be seen that racemic mefloquine has The thermal pain sensitivity threshold recovery similar to levoquine can significantly and effectively prevent and treat neuropathic pain.

Example 2: Toxicological testing of related drugs

Give normal mice intraperitoneal injections of levoquine (15 mg/kg) and racemic mefloquine (30 mg/kg) respectively, and identify the drug toxicity on the same day.

The open-field experiment was used to determine whether the animal's basic exercise amount and anxiety level changed. A single rat was placed in the center of a square open observation box with transparent walls and a gray bottom. The tracking analysis system was used to record and analyze the rat's level through an infrared device. Number of grids. Animal behavior was recorded for a total of 15 minutes, and the movement distance was analyzed. The experimental results are shown in Fig. 3, wherein, 1 represents the control group, 2 represents intraperitoneal injection of 15 mg/kg L-mefloquine, and 3 represents intraperitoneal injection of 30 mg/kg racemic mefloquine.

Using the rotating rod test to measure the animal's movement and balance ability, the rats were trained for three days: on the first day, the rats were placed on the rotating rod, and the rotating rod began to rotate at a constant speed of 5 revolutions per minute, and the training was performed for 5 minutes/minute. times, 2 times in total; on the second day, the speed gradually increased from 5 rpm to 15 rpm within 5 minutes, and the training was 5 minutes/time, 2 times in total; on the third day (combined with drug administration), the speed was increased at 5 Gradually increase from 8 rpm to 15 rpm within 1 minute, and each rat was trained 2 times for 5 minutes/time, 2 times in total. The fourth day (test, drug administration on this day): the rotating speed was increased from 8 rev/min to 25 rev/min within 3 minutes, and the time for the rat to stay on the rotating rod without falling was recorded; the measurement was repeated 3 times. The experimental results are shown in Figure 4, wherein, 1 represents the control group, 2 represents the intraperitoneal injection of 15 mg/kg levo-mefloquine, and 3 represents the intraperitoneal injection of 30 mg/kg racemic mefloquine.

The experimental results show that: compared with the rats (blank control) that did not receive the injection of levoquine, the rats that received the injection of levoquine had no abnormalities in the behavioral indicators in the open field experiment and the rotarod test. No abnormalities were found in the behavioral indexes of the rats injected with quinine in the open field test and the rotarod test. Similarly, compared with rats that received racemic mefloquine injections, the behavioral indicators of rats that received levo-mefloquine injections were not abnormal. It can be seen that levo-mefloquine and racemic-mefloquine have no obvious effect on rats' exercise ability, balance ability, anxiety state, etc., and have no toxic and side effects.

Example 3: Effective administration time window of L-mefloquine on the prevention and treatment of pathological pain-like symptoms in CCI model rats

The initial administration time is placed on the third day or the fourth day of the CCI operation, and the rest of the steps are similar to Example 1, that is, administration once a day for five consecutive days; a better dosage of 15 mg/kg L-methyl Fluoroquine; the mechanical pain threshold and thermal pain threshold of the rats were detected on the day, 14th day and 21st day after CCI operation.

The experimental results are shown in Figure 5 and Figure 6, the mechanical pain threshold and thermal pain threshold of the rats were significantly increased after the administration of the drug was started on the third day after the CCI operation. On the fourth day after the operation, the mechanical pain threshold and thermal pain threshold of the rats did not rise significantly. The experimental results show that after CCI surgery, the later the administration time, the weaker the drug effect; the effect of administration on the day after the operation is better.

Example 4: Prevention and treatment of pathological pain-like symptoms in CCI model rats by micro-introduction of L-mefloquine into the anterior cingulate cortex

In order to identify whether the disease prevention and treatment effect of intraperitoneal injection of L-mefloquine occurs in the anterior cingulate cortex of the brain, this experiment uses local drug delivery technology to inject L-mefloquine into the anterior cingulate cortex at fixed points, and measure the threshold of mechanical pain and thermal pain. Firstly, the rats were anesthetized with pentobarbital sodium, the head was fixed in a stereotaxic instrument, the skull was exposed, and a craniotomy was performed above the anterior cingulate cortex. According to the coordinates of the anterior cingulate cortex of the rat brain atlas, a stainless steel casing with a movable inner core was embedded in the anterior cingulate cortex and fixed with dental cement. On the postoperative day and the following 4 days, a small amount of L-mefloquine (administration group) or the same volume of solvent (control group) was introduced every day. At 3, 7, and 21 days after operation, the mechanical and thermal pain thresholds were measured. In this embodiment, the amount of introduced trace amount of L-mefloquine is 0.09 mg/kg.

The experimental results are shown in Figures 7 and 8: the anterior cingulate cortex was microintroduced with levocefloquine, and the mechanical pain threshold and thermal pain threshold were significantly increased at 3, 7, and 21 days after the operation. The experimental results are shown separately. In addition, the threshold recovery effect in this example is equivalent to the threshold recovery effect produced by intraperitoneal injection in Example 1, as shown in Fig. 1 and Fig. 2 . Experiments have shown that the drug effect of intraperitoneal injection of L-mefloquine works by blocking the Cx36 protein in the anterior cingulate cortex, and a small amount of L-mefloquine in the anterior cingulate cortex can effectively prevent the occurrence of neuropathic pain-like symptoms.

Example 5: Identification of drug off-target potential by local interference of Cx36 expression in the anterior cingulate cortex

In order to further confirm that the drug effect of L-mefloquine is caused by blocking the activity of Cx36 protein in the anterior cingulate cortex, rather than drug off-target. In this experiment, RNA interference technology was used to down-regulate Cx36 protein, according to the gene sequence of Cx36 (5'-ATACAGGTGTGAATGAGGGAGGATG-3'(sense);

5′-TGGAGGGTGTTACAGATGAAAGAGG-3′(antisense)

Three interference sequences were designed, all packaged into plasmids, and a lentiviral transfer system ShRNA-Cx36-GFP was constructed (refer to PlosOne, 2013, 8(1), e55198 for specific steps), as shown in FIG. 9 .

The virus carrying the interfering sequence was injected into the anterior cingulate cortex. One week later, the rats were sacrificed and the relevant brain regions were extracted for Western blot identification and fluorescence immunohistochemical identification respectively. The results are shown in Figure 10 and Figure 11 respectively. A significant downregulation of Cx36 expression was detected in both. The experiments showed that the anterior cingulate cortex The expression of Cx36 protein was effectively down-regulated.

The mechanical pain and thermal pain thresholds of the rats that received the virus transfer were measured at 3, 7, and 21 days after the operation. The experimental results are shown in Figure 12 and Figure 13 respectively. , 21 days showed a significant rise in mechanical pain threshold and thermal pain threshold. Moreover, the threshold recovery effect in this example is equivalent to the threshold recovery effect produced by intraperitoneal injection in Example 1. Experiments have shown that the drug effect of levomefloquine acts on Cx36 in the anterior cingulate cortex, and down-regulates the expression of Cx36 in the anterior cingulate cortex, which can effectively prevent the occurrence of neuropathic pain-like symptoms.

Example 6: Prevention and treatment of pathological pain-like symptoms in SNI model rats by intraperitoneal injection of L-mefloquine

The experiment aimed at another commonly used neuropathic pain model mouse—SNI model, to further test the prevention and treatment effect of L-mefloquine on the occurrence of neuropathic pain. Refer to the method reported by Decosterd and woolf (Pain, 2000, 87, 149-158.): cut the skin of one hindlimb and separate the muscle, expose the main trunk of the sciatic nerve and its lower branches, namely tibial nerve, common peroneal nerve and sural nerve; The tibial nerve and common peroneal nerve were cut, and the small sural nerve was reserved; the muscles and skin were sutured. With a dose of 30mg/kg, L-mefloquine was intraperitoneally injected once a day on the day of SNI operation and 4 days afterward; the same volume of solvent injection was used as the control group. At 3, 7, and 21 days after operation, the mechanical pain threshold was measured.

The experimental results are shown in Figure 14: intraperitoneal injection of 10 mg/kg L-mefloquine in the short-term (4 days) after the SNI operation can reduce the mechanical pain threshold of the model mice within the observed long-term time range (21 days). Maintain a high level, that is, the mechanical pain threshold rises. The experimental results showed that: L-mefloquine can effectively prevent and treat the occurrence of neuropathic pain-like symptoms in SNI model mice.

The above-mentioned embodiments are just examples to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those skilled in the art to understand and implement the present invention, and not to limit the protection scope of the present invention. All equivalent changes or modifications made according to the essence of the present invention shall fall within the protection scope of the present invention.

Claims (2)

1. application of the left-handed Mefloquine in the medicine for preparing prevention neurogenic pain, wherein, the left-handed Mefloquine Molecular formula is C₁₇H₁₆F₆N₂O, shown in its structure such as formula (I),

Wherein, the neurogenic pain refers to the class pain for being caused nerve damage by mechanical stimulus and being triggered.

2. application of the left-handed Mefloquine as active component in the medicine for preventing neurogenic pain is prepared；Wherein, it is described Neurogenic pain refers to the class pain for being caused nerve damage by mechanical stimulus and being triggered.