CN-121987797-A - Application of SAA1 protein inhibitor in preparation of drug for treating methamphetamine addiction withdrawal syndrome

Abstract

The invention belongs to the technical field of intersection of biological medicine and neuropsychiatric medicine, and particularly relates to application of an SAA1 protein inhibitor in preparation of a drug for treating methamphetamine addiction withdrawal syndrome. The invention discloses that the mesenteric white adipose tissue plays a key role in negative emotions such as anxiety, depression and the like induced by the withdrawal of methamphetamine through secretion of SAA1 protein for the first time, so that the drug-seeking behavior and the relapse risk are obviously increased. By inhibiting or reducing the expression or activity of SAA1 protein from mesenteric white fat, the negative emotion related to withdrawal can be effectively relieved, thereby reducing psychological craving and relapse rate. The invention provides an inhibitor, an antibody, a gene silencing tool or application thereof which take SAA1 protein as a target spot, and the inhibitor, the antibody and the gene silencing tool are used for preparing medicines or preparations for treating methamphetamine addiction withdrawal syndrome and preventing relapse. The target and the treatment method provide a brand new way and strategy for substance use disorder, in particular for clinical intervention dependent on methamphetamine.

Inventors

• LIAO YANHUI
• FANG YEHONG
• Gao Yanpan
• WANG LIANGLIANG
• TANG JINSONG

Assignees

• 浙江大学医学院附属邵逸夫医院

Dates

Publication Date

20260508

Application Date

20260330

Claims (10)

1. Use of a saa1 protein inhibitor for the preparation of a medicament for the treatment of methamphetamine addiction withdrawal syndrome.
2. 2. The use according to claim 1, wherein the SAA1 protein is a human SAA1 protein or a mammalian homolog thereof.
3. 3. The use according to claim 2, wherein the SAA1 protein inhibitor is at least one of the following: An antibody or antigen-binding fragment thereof that specifically binds to a SAA1 protein; small molecule inhibitors of SAA1 proteins; siRNA, shRNA, antisense oligonucleotide or miRNA targeting mRNA of SAA1 protein; CRISPR/Cas9 gene editing system of coding genes of targeted SAA1 proteins; A carrier system for mesenteric white adipose tissue-specific delivery of said SAA1 protein inhibitor.
4. 4. The use according to claim 3, wherein the vector system is an adeno-associated viral vector comprising a white adipose tissue-specific promoter; The white adipose tissue-specific promoter is a murine AP2 promoter or a human FABP4 promoter.
5. 5. The use according to claim 4, wherein the adeno-associated viral vector is an AAV8 serotype vector.
6. 6. The use according to claim 3, wherein the shRNA targeting mRNA of SAA1 protein comprises a sense strand having the nucleotide sequence shown in SEQ ID No. 2 and an antisense strand having the nucleotide sequence shown in SEQ ID No. 3.
7. 7. The use according to claim 3, wherein the antibody is a monoclonal or polyclonal antibody; wherein the monoclonal antibody is selected from humanized antibody, murine monoclonal antibody or chimeric antibody.
8. 8. The use according to any one of claims 1 to 7, wherein the medicament is a liquid formulation.
9. 9. The use according to any one of claims 1 to 7, wherein the medicament is for topical or systemic administration to mesenteric white adipose tissue.
10. 10. The use according to any one of claims 1 to 7, wherein the methamphetamine addiction withdrawal syndrome includes anxiety, depression, irritability or other negative mood symptoms arising during withdrawal.

Description

Application of SAA1 protein inhibitor in preparation of drug for treating methamphetamine addiction withdrawal syndrome Technical Field The invention belongs to the technical field of intersection of biological medicine and neuropsychiatric medicine, and particularly relates to application of an SAA1 protein inhibitor in preparation of a drug for treating methamphetamine addiction withdrawal syndrome. Background Methamphetamine (METH) addiction withdrawal syndrome refers to a series of clinical symptoms of psychoaffective symptoms, which appear after sudden withdrawal or decrement of a long-term abuser, and is characterized by a central appearance of negative emotion (lack of pleasure, anxiety, depression), strong psychological craving and cognitive impairment (attention loss, somnolence, etc.), relatively mild somatic symptoms, and a course of illness generally divided into acute withdrawal (most serious emotional symptoms within 1 to 2 weeks after withdrawal) and prolonged periods (lasting weeks to months, residual anxiety depression and psychological craving, high risk stages of relapse). Prevention of relapse is the biggest problem in the clinical treatment of METH addiction. Studies have shown that even after forced or voluntary detoxification treatment, the annual relapse rate of METH addicts exceeds 60%. The key factors responsible for this serious challenge are mainly derived from the strong negative emotional states that persist during long-term withdrawal, including anxiety, depression, hedonia, and irritability (i.e., methamphetamine addiction withdrawal syndrome described above). These negative emotions constitute the central driving force for "negative reinforcement" -the individual is forced to seek and re-inhale the drug in order to relieve or evade this intolerable negative emotion experience. Thus, withdrawal-period negative emotion is the core psychological cause driving the behavior of relapse, and is a key link for the transformation of addiction from acute substance dependence to chronic recurrent encephalopathy. Currently, because the symptoms of METH withdrawal are centered on negative emotions (e.g., anxiety, depression, hedonia), doctors often attempt symptomatic treatment with conventional antidepressants (e.g., selective 5-hydroxytryptamine reuptake inhibitors, SSRIs) or anxiolytics. However, these drugs are originally directed to primary mood disorders whose pharmacological mechanisms are directed primarily to the classical monoamine neurotransmitter system, and are difficult to cover the complex pathological processes driven by METH neurotoxicity involving peripheral-central interactions. Therefore, the current clinically used drugs often have the conditions of slow onset, low response rate and even ineffective in METH withdrawal groups. Disclosure of Invention In order to develop a new therapeutic strategy for METH withdrawal syndrome and solve the problems of slow onset of action, low response rate and even ineffectiveness of medicines clinically used in METH withdrawal groups in the prior art, the invention provides application of a SAA1 protein inhibitor in preparing medicines for treating METH addiction withdrawal syndrome. In order to achieve the above purpose, the present invention adopts the following technical scheme. The invention provides an application of SAA1 protein inhibitor in preparing medicines for treating METH addiction withdrawal syndrome. The SAA1 protein is Serum Amyloid A1 (Serum Amyloid A1). The SAA1 protein is taken as acute phase reaction protein, is abnormally and highly expressed in the process of METH withdrawal and is combined with brain-activated microglial cell-mediated neuroinflammatory reaction to influence synaptic plasticity and finally aggravate withdrawal symptoms such as anxiety, depression and craving, and the SAA1 protein can be specifically inhibited to block neuroinflammatory cascade reaction from the source and rapidly relieve core symptoms, so that the defect of low or even ineffective reaction rate caused by dispersed targets, slow onset of action or incapacity of blocking inflammatory pathways of traditional medicines is overcome. Further, the medicament acts by inhibiting or reducing the expression level or biological activity of SAA1 protein in mesenteric white adipose tissue. Further, the SAA1 protein is a human SAA1 protein or a mammalian homolog thereof. Further, the mammal is selected from the group consisting of mice, rats, rabbits, dogs, pigs, and non-human primates. Further, the mammal is a mouse, the amino acid sequence of the SAA1 protein is shown in SEQ ID NO.1, and the sequence is a precursor protein sequence comprising a signal peptide: MKLLTGLVFCSLAVLGVSAQQWTAFISHEARQAGVQDMIRAYQDMKEANWKNSTVLVSKGNGDAAVLVPGGPEAWAAEVVSNAKENGIKAALTGRGEDSLADQAANKWGR SGKDPNRFRP KGLPDKY, Wherein amino acids (MKLLTGLVFC SLAVLGVSA) at positions 1 to 18 are signal peptide sequences, and amino acids (QQWTAFISHE..to the end) at positions 19 to 1