动物造模,药效评价,急性癫痫 z-bio 2024-09-04 777

　　[Overview] Acute epilepsy models are often single episode models that can induce epilepsy with a single treatment. Including the maximal electroconvulsive epilepsy model and the pentylenetetrazole epilepsy model.

　　（1） Maximum Electric Shock Epilepsy Model

　　[Modeling mechanism] Electrodes are placed in the ears or eyeballs of animals, and a strong current is passed through the electrodes to stimulate the brain for a short period of time, causing the animal to produce strong convulsions in both hind limbs.

　　[Modeling Method] Using an electroconvulsive apparatus or a multi-purpose device for pharmacological and physiological experiments, an alternating current is led out through a wire, and the output wire is connected to a crocodile clip. After being moistened with physiological saline, the clip is placed on both ears of a mouse or rat, or a slightly concave disc-shaped corneal electrode is used to contact both corneas (the cornea is anesthetized with tetracaine). Then, electricity is applied to induce typical rigid convulsions of forelimb flexion and hind limb extension in the mouse or rat. The electrical stimulation parameters are generally 50mA for mice, 150mA for rats, 60Hz, 80-120V (180V for rats), and the stimulation time is 0.2-0.3 seconds. The process of convulsions can be divided into latent period, rigidity period, spasm period, and post seizure inhibition period. Observation indicators: The occurrence of hind limb stiffness in animals is used as the observation indicator. If a certain drug can prevent its occurrence, it indicates that the drug has an anti MES effect.

　　The MES model is one of the most widely used and thoroughly researched models. Commonly used to simulate human tonic clonic seizures and for drug screening for anti tonic clonic seizures. The classic antiepileptic drug phenytoin sodium was discovered through the MES model.

　　The MES epilepsy model preparation method is simple and has a relatively high efficiency in screening antiepileptic compounds. The acute epilepsy model also has its shortcomings: the MES model has a significant effect on drugs that act on ion channels, and may overlook other drugs with antiepileptic effects (such as aminocaproic acid, thiamethoxam, etc.); The MES epilepsy model is not suitable for screening drugs that can prevent partial epileptic seizures. For example, the MES model suggests that antagonists of N-methyl-D-aspartic acid (NMDA) receptors are effective, but this antagonist has not shown clear antiepileptic effects in both the lighting model and clinical trials. It should be emphasized that acute epilepsy models cannot simulate the entire process of human epilepsy occurrence and development, nor can they simulate the pathological and physiological changes of refractory epilepsy and drug resistant epilepsy.

　　（2） Pentylenetetrazine epilepsy model

　　[Modeling mechanism] PTZ is a derivative of tetrazole, which has a constant convulsive effect in mice, rats, cats, and primates when administered systemically. The intravenous injection dose of PTZ for inducing spasms in mice is 50mg/kg, while for tonic clonic seizures it is 90mg/kg. Subcutaneous administration causes spasms in mice at 85mg/kg and in rats at 70mg/kg.

　　[Modeling Method] PTZ mainly acts on the brainstem and forebrain, enhancing the facilitation process of excitatory synapses and causing seizures. Method: 18-25g mice were given a free diet before the experiment and fasted during the experiment. 0.5% PTZ physiological saline (38mg/kg) was rapidly injected through the tail vein, which caused 97% of the mice to experience tetanic attacks. Observation indicators: Ankylosis of the hind limbs is an observation indicator, and medication is effective if it can prevent its occurrence.

　　[Model Features] The PTZ model can simulate the generalized seizures of human myoclonic epilepsy, and the clinical use of ethylsuccinate was discovered through this model.

　　The preparation method of PTZ epilepsy model is simple and has a relatively high efficiency in screening antiepileptic compounds. In the past few decades, MES model and PTZ model have been the gold standards for the initial screening of epilepsy drugs. The PTZ model, as a classic animal model for screening non spastic seizures, also has its drawbacks: it has not been able to discover the anti spastic seizure effect of lamotrigine; However, tigerbin and aminocaproic acid showed significant anti seizure effects in the PTZ model, but clinically manifested as exacerbating non seizure seizures.