Application of NAT10 antagonists in the preparation of drugs for the prevention and / or treatment of epilepsy

Abstract

This invention relates to the field of pharmaceutical science, and more particularly to the application of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of epilepsy. This invention provides the application of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of neurological diseases characterized by epileptic seizures. This invention is the first to demonstrate through pharmacological experiments that a NAT10 antagonist, remodelin, has anti-epileptic effects, thus possessing high clinical application value and development prospects.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical science, and more particularly to the use of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of epilepsy. Background Technology

[0002] Epilepsy, the second most common disease after cerebrovascular disease, is a chronic, recurrent brain dysfunction caused by various factors. The main characteristic of epilepsy is abnormal neuronal discharge, and frequent seizures lead to progressive neuronal damage. Studies have shown that the mechanisms of epilepsy involve ion channel alterations, synaptic remodeling, inflammation, glial proliferation, and neuronal death. However, existing antiepileptic drugs only control seizures in about two-thirds of patients and cannot fundamentally improve their pathophysiological state. Therefore, there is an urgent need to further understand the molecular mechanisms of epilepsy in order to develop safer and more effective antiepileptic drugs.

[0003] NAT10 belongs to the GCN5-related N-acetyltransferase (GANT) family and is the only mRNA ac4C modifying enzyme discovered to date.

[0004] The NAT10 antagonist remodelin has the following chemical structure and molecular formula: C10 15 H 14 N4S4; molecular weight 282.37; CAS number 949912-58-7; is a light yellow powder. Its chemical formula is:

[0005]

[0006] There are currently no reports in the literature regarding the use of the NAT10 antagonist remodelin in antiepileptic drugs. Summary of the Invention

[0007] In view of this, the present invention provides the application of NAT10 antagonists in the preparation of drugs for the prevention and / or treatment of epilepsy. This invention is the first to demonstrate through pharmacological experiments that a NAT10 antagonist, remodelin, has anti-epileptic effects, thus possessing high clinical application value and development prospects.

[0008] To achieve the above-mentioned objectives, the present invention provides the following technical solution:

[0009] This invention provides the use of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of neurological disorders characterized by epileptic seizures.

[0010] In some embodiments of the present invention, the NAT10 antagonist prolongs the seizure latency period in the above-described applications.

[0011] In some embodiments of the present invention, the NAT10 antagonist reduces the severity of epileptic seizures in the above-described applications.

[0012] In some embodiments of the present invention, in the above applications, the NAT10 antagonist includes remodelin.

[0013] In some embodiments of the present invention, in the above-described applications, the drug uses the NAT10 antagonist as the active ingredient.

[0014] In some embodiments of the present invention, the above-described applications include: a NAT10 antagonist and pharmaceutically acceptable adjuvants and / or excipients.

[0015] In some embodiments of the present invention, in the above applications, the dosage of the drug is 10-40 mg / kg.

[0016] In some embodiments of the present invention, in the above applications, the dosage of the drug is 40 mg / kg.

[0017] In some embodiments of the present invention, in the above applications, the administration method of the drug includes: systemic administration.

[0018] This invention provides the use of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of epilepsy.

[0019] In some embodiments of the present invention, the NAT10 antagonist prolongs the seizure latency period in the above-described applications.

[0020] In some embodiments of the present invention, the NAT10 antagonist reduces the severity of epileptic seizures in the above-described applications.

[0021] In some embodiments of the present invention, in the above applications, the NAT10 antagonist includes remodelin.

[0022] In some embodiments of the present invention, in the above-described applications, the drug uses the NAT10 antagonist as the active ingredient.

[0023] In some embodiments of the present invention, the above-described applications include: a NAT10 antagonist and pharmaceutically acceptable adjuvants and / or excipients.

[0024] In some embodiments of the present invention, in the above applications, the dosage of the drug is 10-40 mg / kg.

[0025] In some embodiments of the present invention, in the above applications, the dosage of the drug is 40 mg / kg.

[0026] In some embodiments of the present invention, in the above applications, the administration method of the drug includes: systemic administration.

[0027] This invention provides the use of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of neurological disorders characterized by epileptic seizures.

[0028] The beneficial effects of this invention include:

[0029] (1) This invention is the first to demonstrate through pharmacological experiments that a NAT10 antagonist, remodelin, has an anti-epileptic effect, and therefore has high clinical application value and development prospects.

[0030] (2) This invention discloses the use of the NAT10 antagonist remodelin in the prevention and treatment of epilepsy and neurological diseases characterized by epileptic seizures. Extensive experiments have demonstrated that intraperitoneal injection of the NAT10 antagonist remodelin in mice significantly improves their epileptic seizure symptoms. Attached Figure Description

[0031] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the accompanying drawings used in the description of the embodiments or the prior art will be briefly introduced below.

[0032] Figure 1 This demonstrates the effect of remodelin on the seizure severity in mice in the pentylenetetrazol epilepsy model group;

[0033] Figure 2 This study demonstrates the effect of remodelin on the latency of epileptic seizures in mice in the pentylenetetrazol epilepsy model group. Detailed Implementation

[0034] This invention discloses the use of NAT10 antagonists in the preparation of medicaments for the prevention and / or treatment of epilepsy.

[0035] It should be understood that the expression “one or more of…” individually includes each of the objects described after the expression, as well as various different combinations of two or more of the described objects, unless otherwise understood from the context and usage. The expression “and / or” combined with three or more described objects should be understood to have the same meaning, unless otherwise understood from the context.

[0036] The terms “including,” “having,” or “containing,” including the use of their grammatical synonyms, should generally be understood as open-ended and non-restrictive, for example, not excluding other unstated elements or steps, unless otherwise specifically stated or understood from the context.

[0037] It should be understood that as long as the present invention remains operable, the order of steps or the order of performing certain actions is not important. In addition, two or more steps or actions can be carried out simultaneously.

[0038] The use of any and all examples or exemplary language such as "for example" or "including" in this document is merely intended to better illustrate the present invention and does not limit the scope of the present invention unless a claim is made. No language in this specification should be construed as indicating that any unclaimed element is essential for the practice of the present invention.

[0039] In addition, the numerical ranges and parameters used to define the present invention are approximate values. The relevant values in the specific embodiments have been presented as precisely as possible herein. However, any numerical value inherently inevitably contains standard deviations caused by individual testing methods. Therefore, unless otherwise clearly stated, it should be understood that all ranges, quantities, numerical values, and percentages used in this disclosure are modified by "about". Here, "about" generally means that the actual value is within plus or minus 10%, 5%, 1%, or 0.5% of a specific numerical value or range.

[0040] For the first time, the present invention proves through pharmacological experiments that a NAT10 antagonist, remodelin (Taizhou Core Chemical Co., Ltd., 1622921-15-6), has an anti-epileptic effect, so it has high clinical application value and development prospects.

[0041] The present invention discloses the use of the NAT10 antagonist remodelin in the prevention and treatment of epilepsy and neurological diseases characterized by epileptic seizures. Through a large number of experiments, it is confirmed that intraperitoneal injection of the NAT10 antagonist remodelin in mice can significantly improve their epileptic seizure symptoms.

[0042] Therefore, remodelin can be used to prepare anti-epileptic drugs.

[0043] In the present invention, the experimental animals selected are all 8-week-old healthy male C57BL / 6 mice, weighing 22-24 grams, and all are purchased from Hunan Slack Jingda, license number: SCXK(Hunan)2016-0002. The C57BL / 6 mice in different groups are all placed in an artificial 12-hour day-night cycle lighting environment (7:00 AM - 7:00 PM) for feeding. The mice in each group are divided into cages with 4-6 mice in each cage, and the mice in the cages can freely eat and drink; the daily food and water of the mice are replaced regularly.

[0044] In Example 1 of the present invention, the raw materials and reagents used can be purchased from the market.

[0045] The following further elaborates the present invention in conjunction with examples:

[0046] Example 1

[0047] Male C57BL / 6 mice were randomly assigned to three groups: a pentylenetetrazol model group (solvent control group, DMSO), a low-dose remodelin group (10 mg / kg), a medium-dose group (20 mg / kg), a high-dose remodelin group (40 mg / kg), and the same doses of the antiepileptic drug sodium valproate (VPA) (40 mg / kg) and sodium valproate (VPA) (200 mg / kg). Each group received an intraperitoneal injection of the corresponding dose of the drug or solvent control for 7 consecutive days. One hour after the drug or solvent injection on day 7, 45 mg / kg of pentylenetetrazol was injected intraperitoneally, and behavioral changes in the mice were closely observed for 1 hour. Seizure intensity was assessed according to the Racine grading system, and the seizure latency (starting from the end of pentylenetetrazol administration until the first myoclonic jerk event) and seizure grade (highest grade) were recorded.

[0048] Seizure severity in mice was determined according to the modified Racine criteria: Grade 0: no response; Grade I: rhythmic tics of the muscles of the corner of the mouth, ear, or face; Grade II: head nodding accompanied by more severe facial tics; Grade III: forelimb clonic seizures without standing; Grade IV: forelimb clonic seizures with standing; Grade V: generalized tonic-clonic seizures with falling.

[0049] Experimental results: Compared with the epilepsy model group, remodelin intervention significantly reduced the severity of epileptic seizures (e.g., Figure 1 As shown), prolonging the latency period of epileptic seizures (such as...) Figure 2 As shown in the figure, this indicates that remodelin has an ameliorative effect on pentylenetetrazol-induced epilepsy; at the same time, compared with the same dose of the antiepileptic drug VPA, 40 mg / kg remodelin has a better antiepileptic effect, manifested as a lower seizure grade (e.g., ...). Figure 1 (as shown) and longer seizure latency (e.g. Figure 2 (As shown).

[0050] The above description is only a preferred embodiment of the present invention. It should be noted that for those skilled in the art, several improvements and modifications can be made without departing from the principle of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.

Claims

1. Application of NAT10 antagonists in the preparation of anticonvulsant drugs; The NAT10 antagonist is remodelin.

2. Use according to claim 1, wherein The NAT10 antagonist prolongs the seizure latency period.

3. The application as described in claim 2, characterized in that, The NAT10 antagonist reduces the severity of epileptic seizures.

4. The application as described in claim 3, characterized in that, The drug uses the NAT10 antagonist as its active ingredient.

5. The application as described in claim 4, characterized in that, The drug includes: a NAT10 antagonist and pharmaceutically acceptable adjuvants and / or excipients.

6. The application as described in claim 5, characterized in that, The dosage of the drug is 10~40 mg / kg.

7. The application as described in claim 6, characterized in that, The drug is administered via systemic administration.

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