Alzheimer's disease (AD) is a common neurodegenerative disease characterized by cognitive decline
According to the "World Alzheimer's Disease Report 2021" recently released by the International Alzheimer's Disease Association, more than 55 million people worldwide suffer from dementia
Regrettably, in the face of the ever-increasing number of people suffering from the disease, scientists still know very little about the cause of this complex disease, and the prevention and treatment of the disease has little effect
Recently, researchers from Tianjin University and Tianjin Medical University General Hospital have developed an antioxidant multi-target nano-drug that can efficiently cross the blood-brain barrier, bringing hope to defeating the "memory killer"
The Innovation Taking oxidative stress in the brain as a breakthrough
Taking oxidative stress in the brain as a breakthrough The pathogenesis of Alzheimer's disease is very complicated, and the development of effective therapeutic drugs is still a difficult point in the prevention and treatment of the disease
Therefore, the scientific research team focused on the deeper and more basic pathogenesis of Alzheimer's disease
On the one hand, brain activity has a large demand for oxygen.
In other words, the appearance of oxidative damage markers can be observed in the brains of patients in the early onset of Alzheimer's disease, and the levels gradually increase as the disease worsens, indicating that oxidative stress is the early stage of Alzheimer's disease Event, and gradually worsened as the course of the disease progressed
"Oxidative stress can interact with other pathogenesis and throughout the course of the disease, ultimately leading to a decline in learning and memory
Efficiently cross the blood-brain barrier
Efficiently cross the blood-brain barrier Because the pathogenesis of Alzheimer’s disease is complex and affects each other, and involves multiple pathways, drug treatment with a single target ignores the interaction between the mechanisms.
While antioxidants can actively affect other related pathogenesis while fighting oxidative stress, their effects are relatively mild, and they have the advantages of improving curative effects and reducing side effects
However, "the biggest problem that existing antioxidant drugs face in fighting Alzheimer's disease is that they cannot cross the blood-brain barrier and enter the brain
The blood-brain barrier is a natural barrier between the blood system and brain tissue.
Therefore, it is possible to develop an antioxidant multi-target nanomedicine that can efficiently cross the blood-brain barrier and adjust the drug delivery strategy according to different degrees of oxidative stress levels to achieve the prevention and treatment of Alzheimer's disease
Based on this idea, after several years of arduous exploration, the Tianjin University research team led by Chang Jin and the research team of the General Hospital of Tianjin Medical University finally constructed an antioxidant multi-target nano-drug PTCN that can efficiently cross the blood-brain barrier
Experimental verification of "good news" again and again
Experimental verification of "good news" again and again In order to verify the specific effects of the new nano-drug PTCN, the research team launched a series of experiments
.
The research team first proved that PTCN has two major functions through in vivo and in vitro experiments
.
First, in vitro experiments on mouse brain microvascular endothelial cells have confirmed that the transferrin-mediated transcytosis pathway plays a key role in PTCN crossing the blood-brain barrier.
At the same time, bio-electron microscopy and other techniques have confirmed that PTCN is effectively enriched in the hippocampus of the brain
.
Second, in vivo and in vitro specific fluorescence imaging proved that Congo red can guide the specific binding of PTCN and amyloid aggregates, exert the antioxidant effect of Prussian blue nanoparticles, and effectively remove reactive oxygen species
.
Then, the research team confirmed that PTCN has low cytotoxicity through cell experiments, and that PTCN pretreatment and post-treatment can significantly reduce oxidative stress and improve cell survival, and exert anti-oxidative stress and neuroprotective effects
.
In terms of in vivo research in mice, the research team designed a gradient drug delivery strategy based on the level of oxidative stress in different courses of disease, and conducted prevention and treatment experiments for the early and late stages
.
Behavioral and brain magnetic imaging results show that PTCN can effectively improve the cognitive impairment of Alzheimer's disease model mice and inhibit the atrophy of the hippocampus of the brain
.
Finally, Western blot results show that PTCN can improve oxidative stress, mitochondrial dysfunction and synaptic damage throughout Alzheimer's disease
.
In the early stage, PTCN will significantly inhibit inflammation and mildly inhibit neuronal apoptosis, while in the late stage, PTCN will more significantly inhibit neuronal apoptosis
.
"This is a new combination drug based on traditional biological materials with good biosafety
.
" Chang Jin pointed out that the early prevention and late treatment of Alzheimer's disease can be achieved through the PTCN gradient drug delivery strategy, and it is expected to develop into a clinical clinic.
Personalized drugs have the potential to prevent and treat other oxidative stress-related diseases, such as Parkinson's disease, ischemic stroke, and frostbite
.
Schematic diagram of PTCN prevention and treatment of Alzheimer's disease (photo courtesy of Changjin)
Schematic diagram of PTCN prevention and treatment of Alzheimer's disease (photo courtesy of Changjin)
Characterization of PTCN and its two performance tests (Photo courtesy of Changjin)
Characterization of PTCN and its two performance tests (Photo courtesy of Changjin)
Behavioral and hippocampal volume detection in in vivo prevention and treatment experiments (photo courtesy of Changjin)
Behavioral and hippocampal volume detection in in vivo prevention and treatment experiments (photo courtesy of Changjin)
Work towards clinical application
Efforts towards clinical application Efforts towards clinical application Starting from the start of therapeutic experiments using 6-month-old APP/PS1 transgenic mice as animal models in mid-2019, results were finally achieved in 2021.
It took 3 years for Chang Jin and team members to finally "bring" PTCN
.
It is not easy to make this result
.
At the beginning of December 2019, the research team purchased a large number of APP/PS1 mice to start preventive experiments at the animal level.
According to the experimental plan, it is necessary to give low-month-old mice continuous administration for 3 months
.
Unfortunately, in January 2020, the new crown epidemic broke out.
“At that time, we just started to administer the drug for less than a month.
According to the epidemic prevention and control requirements, we did not travel unless necessary, and students could not return to school temporarily.
This should be what we encountered.
The most difficult situation
.
” Mentioning the past in the research, Dou Yan, an assistant researcher at the Medical Imaging Department of Tianjin Medical University General Hospital, still feels vividly vivid
.
On the one hand, it is impossible to synthesize the required nano-medicine, on the other hand, it cannot enter the animal breeding unit for administration
.
It was not until June 2020 that the students returned to school smoothly.
At this time, the age of the mice did not meet the experimental requirements.
They had to buy the mice again and start the experiment again
.
"We have encountered some big or small problems in all aspects of the progress of the project.
Thanks to the team members for their concerted efforts to overcome the difficulties and have today's results
.
" Chang Jin is very grateful to his research team and scientific research partners for their dedication.
.
Clinical application is the ultimate goal of this research, but there is still a lot of basic work to be done in the early stage
.
"At present, we have only evaluated the macroscopic effects of oxidative stress on other pathogenesis, and we lack more detailed molecular-level investigations on the pathways through which other mechanisms are regulated
.
Next, we will be anti-oxidant multi-target nano-drugs.
Carry out in-depth research on the metabolic distribution in mice, the mechanism of Alzheimer's disease pathways and clinical transformation
.
" Chang Jin said in the end
.
(Source: Ni Weibo, China Science News)
Group photo of PTCN research team members (photo courtesy of Changjin)
Group photo of PTCN research team members (photo courtesy of Changjin) Related paper information: https://doi.
org/10.
1016/j.
xinn.
2021.
100160
https://doi.
org/10.
1016/j.
xinn.
2021.
100160
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