The Research Team of Prof. Qi Xu Made Significant Progress in Researching Drug Target for Overexcited Nervous System

2017-05-22

Overexcited nervous system is common in patients with early Alzheimer's disease (AD), especially in the mild cognitive impairment (MCI) period. By implanting the electrodes, researchers has observed the epileptiform discharges originating in the hippocampus in patients with early AD (Nature Medicine, 2017). Epileptic seizure is also a common satellite phenomenon for AD patients. Abnormal discharge originating in hippocampus and temporal lobe is closely related to the cognitive impairment of AD patients.

 

Recently, the research team of Prof. Qi Xu made significant progress in researching drug target for overexcited nervous system. The researchers found that for patients with refractory epilepsy, the abnormal expression of astrocyte Hsp90β protein is a major cause of excessive accumulation of glutamate in epilepsy focus. The 17AAG, a Hsp90 inhibitor, has a significant anti-epileptic effect. The findings were summarized in the article titled Pharmacologic Inhibition of Hsp90 to Prevent GLT-1 Degradation as An Effective Therapy for Epilepsy, which was published on The Journal of Experimental Medicine on February 1, 2017 (Link to: http://jem.rupress.org/content/214/2/547). Prof. Qi Xu of Institute of Basic Medical Sciences is the corresponding author, and Dr. Longze Sha and Xueqin Wang are the co-first authors.

 

Many studies have demonstrated that the neural hyperexcitation is mainly caused by the abnormal intracephalic accumulation of glutamate, a excitatory neurotransmitter. Astrocyte can eliminate the extracellular glutamate and terminate the conduction of nerve excitability by Glutamate transporter-1 (GLT-1/EAAT2). The abnormal “deficiency” of GLT-1 is a major reason for the unusual accumulation of glutamate. However, the “deficiency” of GLT1 is still a mystery now. The research team found that Hsp90β protein expressing abnormal increase in the epilepsy focus excised from patients with temporal lobe epilepsy promoted the protein degradation of GLT-1 by collecting GLT-1 into the 20S proteasome. Hsp90 inhibitor can prevent the excessive degradation of GLT-1, greatly improve the protein level of GLT-1, and strengthen the capacity of astrocyte to eliminate extracellular glutamate. In the therapeutic study of model mouse with temporal lobe epilepsy, the researchers found that the Hsp90 inhibitor 17AAG had a significant anti-epileptic effect. Long-term medication could greatly reduce the seizure frequency of spontaneous epilepsy (the average inhibition rate is 73.4%), increase seizure-free days, and relieve the hyperplasia of astrocyte. An extended clinical experiment has been carried out on the 17AAG as an antitumor drug previously. This experiment based on a mouse model showed that alternate-day administration of a small dosage of 17AAG would have an anti-epileptic effect, and no significant toxic reaction was observed during the long-term medication.


The findings have not only expanded the physiopathologic mechanism of intractable epilepsy, but also provided new ideas for the treatment of diseases with nerve excitotoxicity (e.g. AD). Nature Reviews Drug Discovery reported the article as a “Research Highlight” titled HSP90 Inhibition Suppresses Seizures (Link to: http://www.nature.com/n-rd/journal/v16/n2/full/nrd.2017.9.html), and pointed out that the research had found the molecular mechanism of GLT1 “deficiency” and the HSP90-targeted inhibitors or other new therapies might be a potential treatment for nerve excitotoxicity.

 

This research is mainly carried out by the research team of Prof. Qi Xu and is sponsored by CAMS Innovation Fund for Medical Sciences and National Natural Science Foundation of China. Prof. Liwen Wu from the Neurology Department of PUMC Hospital participated in the research.

 



 

Figure A: 17AAG inhibits the spontaneous epilepsy seizure in mouse model

Figure B:  17AAG significantly inhibits theabnormal discharge of nerves

 

(Institute of Basic Medical Sciences)