Han Hongbin's team has made important progress in treating brain diseases using new technology for regulating extracellular space molecular

Release date: August 7, 2024 Views:

Stroke is the second leading cause of death in the world and the leading cause of death in China1 . In the past two decades, Han Hongbin's team has been committed to the diagnosis and treatment of major brain diseases through the extracellular space ( ECS ) of the brain. The brain ECS occupies 15-20% of the volume of the living brain , far exceeding the 3-5% occupied by the cerebral blood vessels that have been highly valued in the past ; in particular, the molecular transport within the ECS is closely related to important processes such as sleep, memory, and sensory formation2 . The brain ECS not only plays an important role in the occurrence and development of brain diseases, but also is the only way for drugs to reach the target of nerve cells after entering the brain parenchyma and exert their effects. The development of new stroke drugs through the vascular route must first overcome the obstruction of the blood-brain barrier to drug entry into the brain. Drug administration through the brain ECS route can effectively avoid the blood-brain barrier and exert its effects directly in the brain, providing a new approach for the treatment of brain diseases. In 2011 , the team published a research paper in SCIENCE CHINA Life Sciences magazine, proposing a new drug delivery technology through the brain ECS pathway - simple diffusion delivery ( SDD ) . The application of this technology solved the technical bottleneck of the patented technology owned by the US side, that is, it overcame the technical difficulties of drug reflux and precise quantitative analysis caused by pressure delivery. It is encouraging that the new ECS delivery method can achieve an improvement effect on the ischemic area that is more than 6 times more effective with only 1/800 of the traditional drug delivery method3 , thus confirming the possibility and high efficiency of minimally invasive drug delivery through the ECS pathway for the treatment of major brain diseases.

To further solve the technical difficulties of invasive treatment of brain diseases through the ECS pathway, Han Hongbin's team, after 13 years of scientific research, proposed and established a new minimally invasive treatment method that does not require the destruction of the dura mater - epidural artery implantation ( EAI ) . Without the need to introduce neuroprotective drugs, it achieved the same neuroprotective effect and confirmed that this neuroprotective effect is achieved by accelerating the drainage of interstitial fluid ( ISF ) in the deep brain area . The research and development found that after ischemic attacks, toxins accumulated in the ECS are cleared faster, thereby achieving the recovery of the ischemic area4 . This study proved for the first time that the active regulation technology of molecular transport in the ECS can be applied to the treatment of brain diseases, opening up a new direction for the neural regulation of the central nervous system and the treatment of major brain diseases.

Recently, Han Hongbin's team from Peking University published a research paper titled "A novel neuroprotective method against ischemic stroke by accelerating the drainage of brain interstitial fluid" in SCIENCE CHINA Life Sciences . The study found that m-EAI can alleviate ischemic stroke brain damage by accelerating the drainage of brain interstitial fluid and reducing the clearance of proinflammatory cytokines.

treats ischemic stroke through mEAI , a minimally invasive technique for actively accelerating brain ISF drainage . The improvement effect of ISF drainage acceleration on the inflammatory response in the ischemic penumbra area and the protective effect on ischemic damage in tMCAO model rats at different time points were compared . In the experiment , TTC staining, pathological staining, brainstem wet weight method and T2WI were used to evaluate the therapeutic effect; mNSS score, water maze and open field test were used to evaluate the changes in neurological function before and after treatment. The results showed that compared with the tMCAO model group, the infarct volume of the mEAI-Pre group and the mEAI-0 group was reduced, the degree of cerebral edema was alleviated, and the cognitive and motor functions were significantly improved. That is, m-EAI surgery alleviated ischemic damage and improved neurocognitive function in tMCAO rats.

The research team further used magnetic tracing methods to clarify the effect of m-EAI on ISF drainage within the brain ECS , confirming that m-EAI can accelerate ISF drainage in the superficial cortex and deep caudate nucleus of the brain . The experiment found that the half-life of the tracer injected into the caudate nucleus in the mEAI-Pre group and the mEAI-0 treatment group was significantly reduced compared with the tMCAO model group. In addition, the application of DECS-Mapping technology found that compared with the tMCAO group, the ECS microstructure in the caudate nucleus region of the mEAI-Pre group changed, its molecular diffusion and clearance rate increased, its volume share increased, and its tortuosity decreased. The study further explored the inflammatory mechanism of ischemia and found that m-EAI reduced the accumulation of IL-1β , IL-6 and TNF-α in brain ECS and improved the overactivation of microglia and astrocytes. These evidences indicate that m-EAI can accelerate the clearance of proinflammatory cytokines and alleviate the inflammatory response in tMCAO rats.

In summary, this study shows that m-EAI can achieve brain protection in ischemic stroke by accelerating ISF drainage, promoting the clearance of proinflammatory cytokines, and alleviating inflammatory response. This work not only confirms the theoretical hypothesis that inflammatory response will aggravate ischemic damage in the acute phase of stroke, but also provides a new method for brain protection in stroke (Figure 1 ) .

Fig. 1 Schematic diagram of the mechanism of m-EAI in treating ischemic stroke.

Professor Han Hongbin, Dr. Gao Yajuan and Researcher Tong Zhiqian from Peking University Third Hospital are the co-corresponding authors of the paper; Postdoctoral fellow Lian Jingge and doctoral student Yang Liu from Peking University Third Hospital are the co-first authors. The research was funded by a major project of the National Natural Science Foundation of China.

【References】

1. Xu, J., Zhang, X., Jin, A., Pan, Y., Li, Z., Meng, X., & Wang, Y. (2022). Trends and Risk Factors Associated With Stroke Recurrence in China, 2007-2018. JAMA network open, 5(6), e2216341.

2. Lei, Y., Han, H., Yuan, F., Javeed, A., & Zhao, Y. (2017). The brain interstitial system: Anatomy, modeling, in vivo measurement, and applications. Progress in neurobiology, 157, 230–246. https://doi.org/10.1016/j.pneurobio.2015.12.007

3. Han, H., Xia, Z., Chen, H., Hou, C., and Li, W. (2011). Simple diffusion delivery via brain interstitial route for the treatment of cerebral ischemia. Sci China Life Sci 54, 235-239.

4. Shi K, Tian DC, Li ZG, Ducruet AF, Lawton MT, Shi FD. Global brain inflammation in stroke. Lancet Neurol. 2019 Nov;18(11):1058-1066.