Therapeutic method for regulating hypoxic ischemic brain injury of newborn mouse through Prxl2b

Abstract

The invention discloses a treatment method for regulating hypoxic ischemic brain injury of newborn mice through Prxl2b, and relates to the technical field of hypoxic brain injury. Accurate timing of treatment intervention is achieved, an optimal treatment time window is defined by establishing an oxidative stress mechanical model, it is ensured that supplementation or activation of Prxl2b plays the maximum effect in the stage where oxidative stress is most active and strongest in destructiveness, blindness of empirical drug administration is overcome, and the treatment intervention accuracy is improved. The initial injury volume and the administration delay time are quantified into calculation parameters of a mathematical model, so that the initial load dose and the maintenance dose can be customized for each model mouse, and the treatment intensity is accurately matched with the injury severity; the curative effect is maximized; and the excessive risk is potentially reduced.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of hypoxic brain injury, in particular to a treatment method for regulating hypoxic-ischemic brain injury of newborn mice through Prxl2b. BACKGROUND

[0002] Hypoxic-ischemic encephalopathy is the leading cause of neonatal death and long-term neurological sequelae (such as cerebral palsy, mental retardation). Currently, there are limited supportive treatment measures in clinical practice, and there is a lack of specific neuroprotective drugs.

[0003] Although research has found that excessive reactive oxygen species produced after hypoxia-ischemia is a key factor leading to neuronal death. Therefore, targeting oxidative stress is a promising treatment strategy. Prxl2b is a member of the peroxiredoxin family and plays an important role in antioxidant defense. Previous studies have shown that Prxl2b is highly expressed in brain tissue and its expression changes in neural injury models.

[0004] However, there are several key challenges in developing Prxl2b as an effective treatment method: Timing of administration: After hypoxia-ischemia, oxidative stress is a dynamic process. Early or late intervention may not achieve the best results, and may even interfere with normal physiological redox signals. There is currently a lack of an accurate model to define the "treatment time window" based on pathophysiological changes.

[0005] Dose of administration: The severity of injury varies greatly from individual to individual. A uniform dose of administration may result in insufficient treatment for severe injury, or unnecessary exposure risk for mild injury. There is currently no scheme for individualized dose calculation based on injury severity.

[0006] Evaluation and feedback of efficacy: The evaluation of treatment effect is often delayed, which cannot provide real-time and quantitative basis for dose adjustment during treatment.

[0007] Therefore, there is an urgent need in the art for a strategy that can integrate injury severity, time kinetics and individual response to precisely regulate Prxl2b targeted therapy. SUMMARY

[0008] The purpose of the present application is to provide a treatment method for regulating hypoxic-ischemic brain injury of newborn mice through Prxl2b, to solve the technical problems presented in the background art.

[0009] To achieve the above-mentioned purpose, the present application provides the following technical solution: a treatment method for regulating hypoxic-ischemic brain injury of newborn mice through Prxl2b, at least comprising the following steps: S1: Establishing HIBD model and injury quantification baseline, unilateral carotid artery ligation and exposure to hypoxic environment in newborn mice (such as postnatal day 7-10, P7-P10) to establish hypoxic-ischemic brain injury model; within 24 hours after modeling, the volume of cerebral infarction is quantified by micro-magnetic resonance imaging technology as the initial injury baseline value V0; S2: Determining the treatment time window and intervention target, within a specific treatment time window after modeling, the treatment agent targeting Prxl2b is administered to the mice; the treatment time window is determined by an algorithm model based on injury dynamics; S3: Personalized calculation of treatment dose, according to the initial injury baseline value V0 measured in step S1 and the interval time T from modeling to first administration, the personalized administration scheme of first and subsequent maintenance dose is calculated through a pharmacokinetic-pharmacodynamic integrated model; S4: Dynamic evaluation and feedback adjustment of efficacy, during the treatment process, the recovery of neurological function is evaluated regularly through non-invasive physiological monitoring indicators, and the recovery rate parameters are fed back to the dose calculation model of step S3 to dynamically adjust the subsequent administration dose to optimize the efficacy.

[0010] Further, the treatment time window determination algorithm in step S2 is based on the expression dynamics of Prxl2b after HIBD and its correlation with the peak of oxidative stress: Through pre-experimental data determination, the function of brain oxidative stress level Sox(t) changing with time after HIBD can be approximated as Sox(t) = A · t · e^(-λt); The optimal treatment time window [Tstart, Tend] is defined as the time interval from when the oxidative stress level rises to 50% of the peak to when it drops to 70% of the peak; That is, the period when Sox(t) ≥ 0.5 · max(Sox) and Sox(t) ≥ 0.7 · max(Sox), during which exogenous supplementation of Prxl2b or its agonists can most effectively neutralize excess reactive oxygen species.

[0011] Further, the personalized administration dose calculation in step S3 is achieved by the following mathematical algorithm: Define the target drug exposure AUCtarget as positively correlated with the initial injury volume V0 and the delay time T; the calculation formula of the first loading dose Dloading is: Where k1 and k2 are model constants fitted through previous pharmacodynamic experiments; Subsequent maintenance dose Dmaintenance is calculated based on the target steady-state plasma concentration Css-target and drug clearance CL: .

[0012] Furthermore, the dynamic assessment of therapeutic efficacy in step S4 employs a neurological function recovery index based on multi-parameter fusion: Define the neurological function recovery index for: in, The thickness of brain tissue as measured by imaging. The scoring of neural reflexes such as the righting reflex. For autonomous activity level, Weighting coefficients; recovery rate Defined as The first derivative with respect to time; when When the value falls below the expected threshold, the feedback system will proportionally increase the value in step S3. This is to achieve adaptive adjustments in drug administration.

[0013] Compared with the prior art, the beneficial effects of the present invention are: 1. Achieved precise timing of treatment intervention: By establishing an oxidative stress kinetic model to define the optimal treatment time window, it ensures that the supplementation or activation of Prxl2b exerts its maximum efficacy during the most active and destructive phase of oxidative stress, overcoming the blindness of empirical dosing.

[0014] 2. Personalized and optimized dosing regimens are achieved: By quantifying the initial lesion volume and dosing delay time into mathematical model calculation parameters, this invention can "tailor-make" the initial loading dose and maintenance dose for each model mouse, so that the treatment intensity is precisely matched with the severity of the injury, maximizing the efficacy and potentially reducing the risk of overdose.

[0015] 3. A dynamic closed-loop feedback system of "assessment-treatment-reassessment" has been formed: By introducing the neurological function recovery index and its rate of change as real-time efficacy indicators, the system can automatically sense the treatment response. If the recovery does not meet expectations, the system will intelligently increase the concentration of the target drug, thereby achieving dynamic optimization of the treatment plan. This is an adaptive treatment strategy that can learn autonomously.

[0016] 4. Improved repeatability and translational potential of preclinical research: By reducing the difference of human experience judgment through algorithm, the method makes the treatment regimen more standardized and quantified. This research paradigm of precision medicine can provide more reliable data support and dose exploration basis for subsequent clinical research, significantly accelerating the drug development process.

[0017] 5. Provides a general framework for multi-target intervention: Although the present application takes Prxl2b as an example, the core "time window determination algorithm" and "dose dynamic optimization system" can be extended to the development of other neuroprotective agents with time dependence and dose effect relationship, with wide application prospects. DETAILED DESCRIPTION

[0018] The technical solutions in the embodiments of the present application will be described below. Obviously, the described embodiments are only a part of the embodiments of the present application, not all.

[0019] A treatment method for regulating hypoxic-ischemic brain injury in newborn mice through Prxl2b, at least comprising the following steps: S1: Establishing a HIBD model and an injury quantification baseline, unilateral carotid artery ligation and exposure to a hypoxic environment are performed on a newborn mouse (such as postnatal day 7-10, P7-P10) to establish a hypoxic-ischemic brain injury model; within 24 hours after modeling, the micro-magnetic resonance imaging technology is used to quantify the cerebral infarction volume as the initial injury baseline value V0; S2: Determining the treatment time window and intervention target, within a specific treatment time window after modeling, a treatment agent targeting Prxl2b is administered to the mouse; the treatment time window is determined by an algorithm model based on injury dynamics; S3: Individualized calculation of treatment dose, according to the initial injury baseline value V0 measured in step S1 and the interval time T from modeling to first administration, an integrated pharmacokinetic-pharmacodynamic model is used to calculate the individualized administration scheme of the first and subsequent maintenance doses; S4: Dynamic evaluation and feedback adjustment of efficacy, during the treatment process, the recovery of neurological function is evaluated regularly through non-invasive physiological monitoring indicators, and the recovery rate parameter is fed back to the dose calculation model of step S3 to dynamically adjust the subsequent administration dose to optimize the efficacy.

[0020] The treatment time window determination algorithm in step S2 is based on the expression dynamics of Prxl2b after HIBD and its correlation with the peak of oxidative stress: Through pre-experimental data determination, the function of the brain oxidative stress level Sox(t) changing with time after HIBD can be approximated as Sox(t) = A · t · e^(-λt); The optimal treatment window [Tstart, Tend] is defined as the time interval in which the oxidative stress level rises to 50% of the peak value to falls to 70% of the peak value; i.e. the time period in which the excess reactive oxygen species can be most effectively neutralized by exogenous supplementation of Prxl2b or its agonists, i.e. the time period in which Sox(t) ≥ 0.5 · max(Sox) and Sox(t) ≥ 0.7 · max(Sox).

[0021] The personalized dosing calculation in step S3 is achieved by the following mathematical algorithm: The target drug exposure AUCtarget is defined to be positively correlated with the initial lesion volume V0 and the delay time T. The calculation formula of the first loading dose Dloading is: where k1 and k2 are model constants fitted by previous pharmacodynamic experiments; The subsequent maintenance dose Dmaintenance is calculated based on the target steady-state blood drug concentration Css-target and the drug clearance rate CL: .

[0022] The efficacy dynamic assessment in step S4 adopts a neural function recovery index based on multi-parameter fusion: The neural function recovery index is defined as: wherein, is the brain tissue thickness measured by imaging, is the score of neural reflexes such as righting reflex, is the amount of autonomous activity, is the weight coefficient; the recovery rate is defined as the first order derivative with respect to time; When is lower than the expected threshold, the feedback system will proportionally increase in step S3 to achieve adaptive adjustment of dosing.

[0023] In different embodiments, different dose optimization systems can be constituted, which include a data input module, a calculation engine, a feedback adjustment module and an output module; The data input module is used to receive the initial lesion volume Vo and the dosing delay time T; ​a computing engine built-in the pharmacokinetics-pharmacodynamics integrated model for calculating the individualized dosing; a feedback adjustment module for dynamically adjusting the dosing regimen according to the neural function recovery index NRI(t) and its recovery rate R; an output module for providing clear dosing guidance to the user.

[0024] It is apparent for a person skilled in the art that the present application is not limited to the details of the above-described exemplary embodiments, but can be implemented in other concrete forms without departing from the spirit or essential characteristics of the present application. Therefore, the embodiments should be considered in all respects as illustrative and not restrictive, the scope of the present application being defined by the appended claims rather than the above description, and all changes falling within the meaning and range of equivalency of the claims are therefore intended to be embraced therein.

Claims

1. A method of treatment for regulating hypoxic-ischemic brain damage in neonatal mice through Prxl2b, characterized by: At least comprising the following steps: S1: Establishing HIBD model and injury quantification baseline, establishing a hypoxic-ischemic brain injury model by unilateral common carotid artery ligation and exposure to hypoxic environment in newborn mice; within 24 hours after modeling, the volume of cerebral infarction is quantified by micro-magnetic resonance imaging technology as the initial injury baseline value V0; S2: Determining the treatment time window and intervention target, administering a treatment agent targeting Prxl2b to the mice within a specific treatment time window after modeling; the treatment time window is determined by an algorithmic model based on injury dynamics; S3: Personalized calculation of treatment dose, according to the initial injury baseline value V0 measured in step S1 and the interval time T from modeling to first administration, the personalized dosing regimen of first and subsequent maintenance dose is calculated by a pharmacokinetic-pharmacodynamic integrated model; S4: Dynamic evaluation of efficacy and feedback adjustment, during the treatment, the recovery of neurological function is evaluated regularly by non-invasive physiological monitoring indicators, and the recovery rate parameters are fed back to the dose calculation model in step S3 to dynamically adjust the subsequent administration dose to optimize the efficacy.

2. The method of claim 1, wherein the treatment of neonatal mice with hypoxic-ischemic brain injury is modulated by Prxl2b. The treatment time window determination algorithm in step S2 is based on the expression dynamics of Prxl2b after HIBD and its correlation with the peak of oxidative stress: Through pre-experimental data determination, the function of brain oxidative stress level Sox(t) changing with time after HIBD can be approximated as Sox(t) = A · t · e^(-λt); The optimal treatment time window [Tstart, Tend] is defined as the time interval from when the oxidative stress level rises to 50% of the peak to when it drops to 70% of the peak; That is, the period when Sox(t) ≥ 0.5 · max(Sox) and Sox(t) ≥ 0.7 · max(Sox), during which exogenous supplementation of Prxl2b or its agonists can most effectively neutralize excess reactive oxygen species.

3. The method of claim 2, wherein the treatment of neonatal mice with hypoxic-ischemic brain injury is modulated by Prxl2b. The personalized dosing dose calculation in step S3 is achieved by the following mathematical algorithm: Define the target drug exposure AUCtarget as positively correlated with the initial injury volume V0 and the delay time T; the calculation formula of the first loading dose Dloading is: Where k1 and k2 are model constants fitted by previous pharmacodynamic experiments; The subsequent maintenance dose Dmaintenance is calculated based on the target steady-state drug concentration Css-target and the drug clearance rate CL: 。 4. The method of claim 2, wherein the treatment of neonatal mice with hypoxic-ischemic brain injury is modulated by Prxl2b. The dynamic evaluation of efficacy in step S4 uses a multi-parameter fusion-based neurological function recovery index: Defining a neurological recovery index is: wherein, is the brain tissue thickness measured by imaging, is the score of a neurological reflex such as a righting reflex, is the amount of autonomous activity, is the weight coefficient; recovery rate is defined as is the first derivative over time; When Below the expected threshold, the feedback system will proportionally up-regulate the dose in step S3 to achieve an adaptive adjustment of the administration.

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