WO2023104019A1 - Use of dihydronicotinamide riboside and nicotinamide mononucleotide in treatment of adolescent self-injury and severe environmental factor-induced depression - Google Patents

Abstract

Use of β-nicotinamide mononucleotide in the preparation of a drug for reducing anxiety accompanied by self-injurious thoughts and/or feelings in a subject, or in the preparation of a drug for reducing self-injurious thoughts and/or feelings caused by anxiety in a subject. Use of β-dihydronicotinamide riboside in the preparation of a drug for treating or preventing adolescent depression. β-Nicotinamide mononucleotide or β-dihydronicotinamide riboside as a single active ingredient has an inhibitory effect on adolescent depression and self-injurious behaviors.

Description

Application of dihydronicotinamide riboside and nicotinamide mononucleotide in the treatment of adolescent self-injury and adverse environmental factors-induced depression technical field

The invention belongs to the field of medicine, and in particular relates to the application of dihydronicotinamide ribose and nicotinamide mononucleotide in treating adolescent self-injury and depression induced by adverse environmental factors.

Background technique

Depression is an affective mental disorder. The clinical manifestation is "three lows"-depressed mood, loss of interest, lack of motivation, and lasts for at least 2 weeks. 80% of adolescents with depression have non-suicidal self-injury behaviors. Non-suicidal self-injury behaviors refer to individuals taking a series of repeated, deliberate, and direct injuries to their bodies without suicidal thoughts, and are not socialized. permitted behavior. Self-injury is divided into 5 categories: cuts or burns, self-poisoning, intentional non-recreational risk taking, self-beating, and other self-injurious behaviors. Among them, bleeding from cuts is the most common. At present, non-suicidal self-injury behavior is regarded clinically as one of the symptoms caused by depression, and adolescents with depression report that they can relieve negative emotions in this way.

Antidepressant drugs commonly used in clinical practice include SSRIs, SNRIs, and NaSSAs. It mainly acts on neurotransmitters such as dopamine, norepinephrine and 5-hydroxytryptamine. Mood stabilizers are also used to treat treatment-resistant depression. The disadvantages of antidepressants such as SSRIs, SNRIs, and NaSSAs are slow drug effects and poor therapeutic effects, and antidepressants have a series of side effects. These side effects involve the functions of various systems throughout the body, including sleep disturbances, appetite changes, headaches, nausea, digestive disorders, liver toxicity, and decreased sexual function.

Commonly used mood stabilizers are usually accompanied by significant adverse reactions. Some mood stabilizers, such as lithium salts, divalproex sodium, etc., have a relatively strict blood concentration window, and serious effects will occur after exceeding the ideal blood concentration window, so the use of such drugs in clinical practice usually requires Accompanied by blood concentration monitoring to ensure drug efficacy and control side effects.

The coenzyme nicotinamide adenine dinucleotide (NAD+) is involved in important life processes such as cell DNA repair, mitochondrial respiration and inflammatory response. In the field of neuroscience, increasing the concentration of NAD+ in cells through NAD+ precursors and NAD+ metabolic regulation drugs can significantly improve cognitive ability, repair neurodegeneration caused by trauma, and improve neurodegenerative diseases. Supplementation of NAD+ precursors such as nicotinamide riboside (NR ⁾ and nicotinamide mononucleotide (NMN) can improve symptoms of muscle ^atrophy1 and neurodegenerative diseases2 in mouse models. The use of drug molecules (such as P7C3 molecules) can activate the rate-limiting enzyme NAMPT in NAD+ biosynthesis, which has a significant neuroprotective effect ³ . Its derivative P7C3-A20 can repair the blood-brain barrier damage caused by brain injury in the traumatic brain injury mouse model, curb chronic neurodegeneration, and restore mouse cognition ⁴ . However, there is no background technology reporting the application of NAD+ precursor NMN and dihydronicotinamide riboside (NRH) in improving depression and depression-related self-injury.

NAD+ supplementation programs based on NAD+ precursors have positive effects on the nervous system, including significantly improving cognitive performance, repairing neurodegeneration caused by trauma, and improving neurodegenerative diseases. However, there is no report that NMN and NRH can improve the symptoms of adolescent depression caused by behavioral modeling and self-injury caused by drug modeling.

1. Zhang, H.; Ryu, D.; Wu, Y.; Gariani, K.; Wang, X.; Luan, P.; .; Schoonjans, K.; Menzies, KJ; Auwerx, J., NAD(+) repletion improves mitochondria and stem cell function and enhances life span in mice. Science 2016, 352 (6292), 1436-43.

2. McElroy, GS; Reczek, CR; Reyfman, PA; Mithal, DS; Horbinski, CM; Chandel, NS, NAD+ Regeneration Rescues Lifespan, but Not Ataxia, in a Mouse Model of Brain Mitochondrial Complex I Dysfunction. Cell Metab 2020, 32 (2), 301-308 e6.

3. Wang, G.; Han, T.; Nijhawan, D.; Theodoropoulos, P.; Naidoo, J.; Yadavalli, S.; Mirzaei, H.; neuroprotective chemicals function by activating the rate-limiting enzyme in NAD salt. Cell 2014, 158 (6), 1324-1334.

4. Vazquez-Rosa, E.; Shin, MK; Dhar, M.; Chaubey, K.; Cintron-Perez, CJ; Tang, X.; , S.; Franke, K.; Crosby, DR; Schroeder, R.; Emery, J.; Yin, TC; Fujioka, H.; Reynolds, JD; Harper, MM; Jain, MK; A20 treatment one year after TBI in mice repairs the blood-brain barrier, arrests chronic neurodegeneration, and restores cognition. Proc Natl Acad Sci USA 2020, 117 (44), 27667-27675.

technical problem

The antidepressant active ingredient provided by the present invention is β-nicotinamide mononucleotide (NMN) or β-dihydronicotinamide riboside (NRH), which is used in the treatment or prevention of self-injury in adolescence and depression induced by adverse environmental factors in developmental stages.

technical solution

One aspect of the present invention provides that β-nicotinamide mononucleotide can reduce the anxiety associated with self-injury thoughts and/or feelings of subjects in the preparation, or reduce the self-injury thoughts and/or feelings of subjects due to anxiety. Uses in Drugs of Feeling.

Further, the subject is an adolescent subject.

Further, the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.

Further, the subject has self-harm thoughts and/or feelings due to drug-induced anxiety.

Another aspect of the invention provides a method for reducing self-harming thoughts and/or feelings comprising administering β-nicotinamide mononucleotide to a subject in need thereof.

Further, the subject is an adolescent subject.

Further, the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.

Further, the subject has self-harm thoughts and/or feelings due to drug-induced anxiety.

Another aspect of the present invention provides a drug for reducing thoughts and/or feelings of self-harm, wherein the drug uses β-nicotinamide mononucleotide as an active ingredient.

Further, the medicine is an oral medicine or an injection medicine.

Another aspect of the present invention provides a use of β-dihydronicotinamide riboside in the preparation of a drug for treating or preventing adolescent depression.

Further, the pubertal depression patients are human beings aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development.

Further, the adolescent depression is induced by the stress of long-term stressful events.

Further, the adolescent depression is induced by stressful events in early life.

Another aspect of the present invention provides the use of β-dihydronicotinamide riboside in the preparation of drugs for the desire to survive in normal subjects;

Another aspect of the present invention provides a method for preventing or treating adolescent depression with β-dihydronicotinamide riboside, the method comprising administering β-dihydronicotinamide riboside to a subject in need.

Another aspect of the present invention provides a drug for preventing or treating adolescent depression, which uses β-dihydronicotinamide riboside as an active ingredient.

Further, the medicine is an oral medicine or an injection medicine.

Beneficial effect

The present invention provides the first discovery that NMN or NRH as a single active ingredient has an inhibitory effect on adolescent depression and self-injury behavior.

The antidepressant active ingredients provided by the invention can significantly reduce the self-injury bleeding behavior and anxiety behavior related to adolescent depression, and its effectiveness reaches the level similar to mood stabilizers. The active ingredient NMN provided by the invention has no toxic and side effects as confirmed in various animal experiments and clinical experiments.

Description of drawings

Figure 1 shows the performance statistics of tail suspension time and forced swimming test: NRH administration group significantly improved the tail suspension time of depression model mice.

Figure 2. The statistics of self-injury (SIB) in mice in the adolescent anxiety model: the score of self-injury is 1, and the score of no self-injury is 0. NMN administration significantly reduced the incidence of SIB.

Embodiments of the present invention

In order to make the above objects, features and advantages of the present invention more obvious and understandable, the specific implementation modes of the present invention will be described in detail below, but they should not be construed as limiting the scope of implementation of the present invention.

Purification and preparation of embodiment 1NMN and NRH

NMN : Using chemically pure NMN as raw material, it is further purified by preparative HPLC, using methanol/water as the mobile phase, collecting the purified peaks, and freeze-drying the collected liquid to obtain purified NMN for experiments.

NRH :Under Ar atmosphere, nicotinamide riboside ( NR) (2.90 g, 10.0 mmol, 1.0 eq.), K ₂HPO ₄ (3.48 g, 20.0 mmol, 2.0 eq.) and 50 mL deionized water, and at 0 ^oStirred under the condition of C for 5 minutes, then slowly added Na to the mixture in batches. ₂S ₂o ₆ (1.74 g, 10.0 mmol, 1.0 eq.), continue to react at this temperature for 1 hour after the addition is complete. HPLC monitors the reaction, and after the raw materials are basically converted, the reaction solution is separated and purified with a C18 reverse preparative column (H ₂O : MeOH = 95:5), the collected solution was freeze-dried to obtain the pure target product NRH, yellow solid (1.45g, 57% yield).

Embodiment 2 adolescent depression model

The adolescent depression model was prepared by mother-infant separation, which is one of the commonly used models for constructing stressful events in early life. In mice, mother-infant separation results in changes in corticosterone secretion, but the dynamics of corticosterone induced by mother-infant separation are significantly different from those in a mouse model of depression after repeated injections of corticosterone (Iijima, M. ; Ito, A.; Kurosu, S.; Chaki, S., Pharmacological characterization of repeated corticosterone injection-induced depression model in rats. Brain Res 2010, 1359 , 75-80.). Studies have shown that in addition to inducing anxiety, early life stressful events represented by mother-infant separation can also lead to abnormal brain-gut axis function and induce irritable bowel syndrome (O'Mahony, SM; Hyland, NP; Dinan, TG; Cryan , JF, Maternal separation as a model of brain-gut axis dysfunction. Psychopharmacology (Berl) 2011, 214 (1), 71-88.); At the same time, it can also induce the abnormal function of the paraventricular nucleus of the hypothalamus and affect the norepinephrine Level and learning ability (Shionoya, K.; Moriceau, S.; Bradstock, P.; SULLIVAN, RM, Maternal Attenification of hypothalamic Paraventricular Nucleus NorePinephrine Switches Avoidan CE Learning to Preference Learning in Preweanling Rat Pups. Horm Behav 2007, 52 (3) , 391-400.), and the depression model constructed by repeated injections of corticosterone represents different pathological features. The P18-P20 age group that did not start sexual development and the pubertal P30-P45 age group that started sexual development were used to separate mothers and infants for modeling. After the depression model was implemented on the young mice, the mice were given normal saline and NRH-containing solutions respectively. Then two classic experiments of tail suspension and forced swimming were carried out.

The experimental results showed that the young rats given NRH showed a stronger desire to survive during puberty, and the struggling time when the tail was suspended was longer than that of the control group (Fig. 1 left). In the forced swimming test, the depression model (D) mice showed lower helpless abandonment behavior than the control mice (Control), however, the active survival behavior of the mice given NRH, regardless of the depression model, was higher than that of the control mice. The depression modeling group was strong (Fig. 1 right).

After the depression model was implemented in the young mice, the young mice showed a higher depression phenotype than the control group at puberty. In the same experiment, the mice given the same level of modeling and intraperitoneal NRH injection showed relief of the depression phenotype.

Embodiment 3 reduces the self-injury behavior experiment that anxiety brings

Drug-induced anxiety was administered to adolescent mice, and it was observed that more than 75% of the mice entered a state of high anxiety within 10 minutes after drug injection, and then exhibited self-biting to bleeding behavior (SIB) within 100 minutes, and self-injury was Extremely depressive/anxiety phenotype. Mice given NMN intraperitoneally half an hour before drug-induced anxiety had a greatly reduced rate of self-injury phenotype, similar to lithium, a known anxiety-relieving drug.

In the invention, self-injury is usually defined as intentional injury to body tissue, and there is a certain proportion among adolescents, and there is a trend of increasing incidence year by year, which includes self-injury and self-poisoning. The most common form of self-injury is skin cutting, but self-injury also covers a wide range of behaviors, including but not limited to burning, scratching, punching or knocking on body parts, interfering with wound healing (eg, compulsive skin scratching syndrome), hair pulling (such as trichotillomania), and ingestion of toxic substances or objects. Suicide is not usually the purpose or goal of self-injury, but self-injury can be potentially life-threatening. Although self-injury can occur at any age, it is especially common in adolescents and young adults, usually between the ages of 12 and 24. Motives for self-injury in adolescents vary and are often related to a history of childhood trauma.

The above examples demonstrate that NMN can inhibit self-injury behavior caused by anxiety in adolescent subjects through experiments on mice.

Claims (10)

Use of β-nicotinamide mononucleotide in the preparation of a drug for reducing the anxiety associated with self-injury thoughts and/or feelings in a subject, or in the preparation of a drug for reducing self-injury thoughts and/or feelings in a subject due to anxiety . The use according to claim 1, wherein the subject is a young subject. The use according to claim 2, wherein the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30 mice that have not yet started sexual development. -P45 mice. The use according to claim 3, characterized in that the reason for the subject to have self-injury thoughts and/or feelings is drug-induced anxiety. A method for reducing anxiety accompanied by self-harming thoughts and/or feelings or reducing self-harming thoughts and/or feelings due to anxiety, said method comprising administering beta - nicotinamide mononucleotide; Preferably, the subject is an adolescent subject; More preferably, the adolescent subjects are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development; More preferably, the cause of the subject's thoughts and/or feelings associated with self-harm is drug-induced anxiety. A drug for reducing anxiety accompanied by self-harm thoughts and/or feelings, characterized in that the drug uses β-nicotinamide mononucleotide as an active ingredient; Preferably, the medicine is oral medicine or injection medicine. Use of β-dihydronicotinamide riboside in the preparation of drugs for the treatment or prevention of adolescent depression; Preferably, the patient with puberty depression is a human being aged 12-24, a mouse in the P18-P20 age group that has not yet started sexual development, or a pubertal P30-P45 mouse that has not yet started sexual development; More preferably, said adolescent depression is induced by long-term stress event stress; More preferably, said adolescent depression is stress-induced due to stressful events in early life. The use of β-dihydronicotinamide riboside in the preparation of drugs for normal subjects' desire to survive; Preferably, the pubertal depression patients are humans aged 12-24, mice in the P18-P20 age group that have not yet started sexual development, or pubertal P30-P45 mice that have not yet started sexual development. A method for preventing or treating adolescent depression with β-dihydronicotinamide riboside, characterized in that the method comprises administering β-dihydronicotinamide riboside to subjects in need; Preferably, the patient with puberty depression is a human being aged 12-24, a mouse in the P18-P20 age group that has not yet started sexual development, or a pubertal P30-P45 mouse that has not yet started sexual development; More preferably, said adolescent depression is induced by long-term stress event stress; More preferably, said adolescent depression is stress-induced due to stressful events in early life. A drug for preventing or treating adolescent depression, characterized in that the drug uses β-dihydronicotinamide riboside as an active ingredient; Preferably, the medicine is oral medicine or injection medicine.