Parkinson's disease is a disease characterized by neuronal death that spreads throughout the brain, often over decades. The disease is best known for causing tremors in the hands, muscle stiffness, slowness of gait and disturbance of other normal movements. But it affects a wide range of brain regions, leading to many different symptoms, including dementia in advanced stages. In the United States, approximately 1 million people have Parkinson's disease. Existing treatments can alleviate some movement abnormalities, but cannot stop disease progression -- mostly because scientists don't fully understand the process.
A key finding that has emerged in Parkinson's disease research over the past few decades is that neuronal death in the disease occurs as abnormal aggregates of alpha-synuclein in neurons spread throughout the brain of. This spread is an infection-like chain reaction process in which these abnormal alpha-synuclein aggregates lure normal alpha-synuclein to join them and, as they grow, And break into smaller aggregates continue to spread. Experiments in mice and nonhuman primates have shown that injecting these abnormal alpha-synuclein aggregates into their brains can initiate this transmission, as well as some Parkinson's-like neurodegeneration . But the details of how neurons pass them on to other neurons had not been well understood until now.
In this article, we will summarize recent research related to Parkinson's disease for your reference:
【1】British Pharmacology: Icariin Ⅱ predosing has potent neuroprotective effect against ischemic stroke
Reported on 2022-10-27, recently, researchers from Zunyi Medical University published a paper entitled "Icariside Ⅱ preconditioning evokes robust neuroprotection against ischemic stroke: Targeting Nrf2 mediated by OXPHOS/NF-κB/ferroptosis pathway" in Br J Pharmacol ” article, the study found that ICSⅡ preconditioning provided strong neuroprotection against ischemic stroke through the astrocytic Nrf2-mediated OXPHOS/NF-κB/ferroptosis axis, therefore, ICSⅡ would be a promising method to rescue ischemic stroke Nrf2 activators in stroke.
Our results reveal for the first time that ICS II preconditioning exerts a potent neuroprotective effect in ischemic stroke by targeting astrocyte NRF2. ICS II preconditioning suppresses ischemic stroke-induced mitochondrial oxidative stress and neuroinflammation by mediating the OXPHOS/NF-κB/ferroptosis axis. Thus, in the field of preconditioning methods, ICS II may be a powerful weapon in the fight against ischemic stroke and expand the possibility of new strategies to achieve neuroprotection.
Original: doi: 10.1111/bph.15961.
【2】Med Res Rev: Research progress of dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders
2022-10-18, recently, researchers from the National Institute of Mental Health of the United States published a review article entitled "Recent advances in dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders" in Med Res Rev. This study summarizes the research progress of dopamine D2 receptor ligands in the treatment of neuropsychiatric disorders.
Dopamine is a bioactive amine synthesized in the central and peripheral nervous systems. This biosourced monoamine works by activating five types of dopamine receptors (D1-5Rs) belonging to the G protein-coupled receptor family. Antagonists and partial agonists of D2Rs are used to treat schizophrenia, Parkinson's disease, depression and anxiety. A typical pharmacophore with high D2R affinity consists of four main regions, namely, the aromatic part, the cyclic amine, the central linker, and the aromatic/heteroaromatic lipophilic segment.
A chain of four to six atoms is the sweet spot for D2R affinity, with 4-butoxy being the most obvious one. Bicyclic aromatic/heteroaromatic systems most often occur as lipophilic appendages to maintain high D2R affinity. In this review, we provide a comprehensive overview of the therapeutic potential of D2R modulators in the treatment of the above diseases. In addition, this review summarizes the latest knowledge about these disorders with a focus on the dopaminergic pathways underlying them. The structure, function and pharmacological effects of novel D2R ligands belonging to 1,4-disubstituted aromatic cyclic amines developed in the past ten years (2010-2021) are highlighted.
Original: doi: 10.1002/med.21923.
[3] Nat Commun: Revealing that α-synuclein aggregates in Parkinson's disease diffuse in the brain through lysosomal exocytosis
2022-09-29 In a new study, researchers from Weill Cornell Medical College and the University of Pennsylvania proposed that aggregates of alpha-synuclein play a role in Parkinson's disease through a process of cellular waste removal. spread in the patient's brain. In a process called lysosomal exocytosis (also known as lysosomal efflux, or lysosomal secretion), neurons shed protein waste that they cannot break down and recycle. The discovery could solve one of the mysteries of Parkinson's disease and lead to new strategies to treat or prevent the neurological disorder. Relevant research results were recently published in the journal Nature Communications, titled "Lysosomal exocytosis releases pathogenic α-synuclein species from neurons in synucleinopathy models".
"Our results also suggest that lysosomal exocytosis may be a general mechanism for processing aggregated and refractory proteins in neurons," said senior author Manu Sharma, Ph.D., assistant professor of neuroscience at Weill Cornell Medical College. This is true in normal, healthy conditions and in neurodegenerative diseases."
Original: doi:10.1038/s41467-022-32625-1.
【4】Pharmacology and Therapeutics: Current status and prospects of insulin-based drug therapy for neurodegenerative diseases
2022-09-22, recently, researchers from the University of Pavia in Brazil published a review article entitled "Incretin-based drugs as potential therapy for neurodegenerative diseases: Current status and perspectives" in the journal Pharmacol Ther. , the study summarizes the current status and prospects of insulin-based drug therapy for neurodegenerative diseases.
This article will first describe the experimental, pathophysiological, and clinical approaches to insulin therapy in AD and PD. Then, the main pharmacological properties of GLP-1RAs and DPPIVis will be discussed, detailing their ability to cross the blood-brain barrier and enter the brain, and new strategies for blood-brain barrier crossing of DPP-IVIS. The focus will be on key findings regarding the neuroprotective effects of these agents in experimental models of AD and PD. For AD, improvements in learning and memory with insulin-based agents have been associated with attenuation of chronic inflammation, brain A plaques, tau hyperphosphorylation, mitochondrial protection, and improved energy utilization. For Parkinson's disease, both GLP-1RAs and DPP-IVIS can reverse the loss process of nigrostriatal dopaminergic neurons, restore dopamine synthesis, exert anti-inflammatory activity, and improve motor function.
Original: doi: 10.1016/j.pharmthera.2022.108277.
[5] PNAS: Mouse study reveals that irisin blocks Parkinson's disease symptoms
2022-09-18 reported that in a new study, researchers from the Johns Hopkins University School of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute found in mice that endurance or A hormone secreted into the blood during aerobic exercise can lower levels of a protein linked to Parkinson's disease and prevent movement problems. If confirmed in more laboratory studies and clinical trials, their study of mice with symptoms of Parkinson's disease could pave the way for Parkinson's disease treatments based on the exercise hormone irisin. The relevant research results will be published online in the PNAS journal on August 31, 2022. The title of the paper is "Amelioration of pathologic α-synuclein-induced Parkinson's disease by irisin".
"If irisin's utility is proven, we could envision it being developed as a gene or recombinant protein therapy," Dawson said, referring to the field of drug development that aims to use cytogenetics to expand the treatment of disease. Spiegelman added, "Given that irisin is a naturally occurring polypeptide hormone that appears to have evolved to cross the blood-brain barrier, we believe it is worth continuing to evaluate irisin as a potential treatment for Parkinson's disease and other forms of neurodegeneration."
Original: doi:10.1073/pnas.2204835119.
[6] New revelation: activation of BDNF transcription can improve Parkinson's disease-like pathology
2022-08-29, recently, researchers from Jinan University published an article entitled "Suppression of abnormal a-synuclein expression by activation of BDNF transcription ameliorates Parkinson's disease-like pathology" in the journal Molecular Therapy: Nucleic Acids , the results of this study demonstrate that inhibition of α-Syn by α-Syn-HDO protects dopaminergic neurons from degeneration by activating BDNF transcription. Therefore, α-Syn-HDO may be used as a new drug for the treatment of Parkinson's disease.
This study suggests that overexpression of α-Syn induces dopaminergic neuron degeneration by inhibiting BDNF transcription, and that the novel nucleic acid preparation α-SynHDO can alleviate dopaminergic neuron degeneration in PD model mice by activating BDNF transcription. Therefore, α-Syn-HDO is expected to become a new drug for the treatment of Parkinson's disease.
Original: doi: 10.1016/j.omtn.2022.05.037.
[7] Nat Med: Using artificial intelligence to detect Parkinson's disease by reading people's breathing patterns
2022-08-24 Reported that Professor Dina Katabi and her team from the Department of Electrical Engineering and Computer Science at the Massachusetts Institute of Technology in the United States have developed an artificial intelligence model that can detect Parkinson's disease just by reading a person's breathing patterns . The relevant research results were published online in the journal on August 22, 2022, with the title of the paper "Artificial intelligence-enabled detection and assessment of Parkinson's disease using nocturnal breathing signals".
The tool is a neural network, a series of associated algorithms that mimic the way the human brain works, that can assess whether a person has Parkinson's disease from their nocturnal breathing -- breathing patterns during sleep. The neural network, trained by MIT doctoral student Yuzhe Yang and postdoc Yuan Yuan, was also able to discern the severity of Parkinson's disease that people had and track the progression of their disease.
Original: doi:10.1038/s41591-022-01932-x.
【8】Science: Increased concentration of GPNMB in blood samples may be a biomarker for Parkinson's disease
2022-08-23 reported that in a new study, researchers from the University of Pennsylvania found evidence that the transmembrane protein GPNMB (Glycoprotein Nonmetastatic Melanoma Protein B, Glycoprotein Nonmetastatic Melanoma Protein B) in blood samples ) may be an early biomarker of Parkinson's disease. The relevant research results were published in the journal Science on August 19, 2022. The title of the paper is "GPNMB confers risk for Parkinson's disease through interaction with α-synuclein". In the paper, they describe how they investigated potential risk factors associated with chromosome 7 in Parkinson's disease patients, and what they found in relation to the link to GPNMB. Brit Mollenhauer and Christine AF von Arnim of the University Medical Center Göttingen in Germany outline the new research in an opinion-type article titled "Toward preventing Parkinson's disease" in the concurrent issue of Science.
In the new study, the authors began their work by noting that while multiple genes thought to contribute to the risk had been identified, the genes actually involved were still unknown. For this reason, they chose to focus their research on the production of alpha-synuclein (αSyn) fibrils, which form in Parkinson's patients and are a hallmark of the disease feature.
Original: doi:10.1126/science.abk0637.
【9】Brain: Extracellular vesicle biomarkers of cognitive impairment in Parkinson's disease
2022-07-25, recently, researchers from the American Clinical Investigation Laboratory published an article entitled Extracellular vesicle biomarkers for cognitive impairment in Parkinson's disease in the Brain magazine. The study showed that α-synuclein and Tau pathology and impaired insulin signaling underlie cognitive impairment in Parkinson's disease. Plasma neuronal extracellular vesicle biomarkers predict cognitive outcomes in patients with Parkinson's disease.
The study used plasma samples from 271 participants: 103 cognitively normal Parkinson's patients, 121 cognitively impaired Parkinson's patients (81 with mild cognitive impairment, 40 with dementia), and 49 age- and sex-matched controls. Neuron-enriched plasma extracellular vesicles were immunocaptured by targeting L1 cell adhesion molecules, followed by quantification of biomarkers by immunoassay. α-synuclein was lower in Parkinson's patients than controls (p=0.004), and lower in cognitively impaired patients than in cognitively normal Parkinson's patients (p<0.001) and controls (p<0.001) . Amyloid-beta protein 42 did not differ between groups. Phosphorylated Tau (T181) was higher in patients with Parkinson's disease than in controls (p=0.003), and was higher in patients with cognitively impaired than in Parkinson's patients with normal cognitive function (p<0.001) and control group (p<0.001). There was no difference in total tau between groups.
The results of this study reveal a potential synergistic relationship between PTAU and α-synuclein in the generation of cognitive impairment in Parkinson's disease, which deserves further study. Future studies of longitudinal changes in NeV biomarkers after transition from PD-N to PD-MCI or PDD in Parkinson's disease patients are needed to establish a relative timeline of Parkinson's disease biomarker changes.
Original: doi: 10.1093/brain/awac258.
【10】Pharmaceutical Journal! Design, mechanism of action and application of mitochondria-targeted drugs for neurodegenerative diseases
2022-07-06, recently, researchers from Nanjing University of Science and Technology published a review article entitled "Mitochondria targeting drugs for neurodegenerative diseasesdDesign, mechanism and application" in the journal "Acta Pharmaceutica Sinica B".
Mitochondrial dysfunction is an important part of the pathogenesis of NDDS. Mitochondrial dysfunction leading to energy depletion, oxidative stress, calcium overload, and activation of caspase-aspartate aminotransferase is the main cause of neuronal death in NDDS. Therefore, mitochondria are the preferred target for NDDS intervention. So far, various mitochondria-targeted drugs have been developed. Fortunately, some of these drugs have shown good effects, but there are still some obstacles, such as targeting, delivery ability, etc., that hinder the development of drugs. In this article, the researchers discussed in detail the design strategies of mitochondrial-targeted drugs, the rescue mechanism of each mitochondrial-targeted drug, and how to evaluate the therapeutic effect.
Original: doi: 10.1016/j.apsb.2022.03.001.
【11】Exosomes: microRNA-124-3p-rich extracellular vesicles for Parkinson's disease
2022-06-16 Reported that recently, researchers from Beira University of Internal Affairs published an article entitled "MicroRNA-124-3p-enriched small extracellular vesicles as a therapeutic approach for Parkinson's disease" in the journal Mol Ther. The findings reveal a new promising therapeutic application of extracellular vesicles as delivery agents of miR-124-3p in Parkinson's disease.
In this study, the researchers reported for the first time the therapeutic potential of microRNA-124-3p-enriched SEVs for Parkinson's disease. SEV carrying miR-124-3p induced SVZ neural stem cells to differentiate into neurons under physiological conditions in vitro. In vivo, we found that intracerebroventricular injection of miR-124-3p SEV protected the nigrostriatal pathway from 6-OHDA-induced neurodegeneration and significantly improved exercise capacity in injured mice. Our findings support the use of miR-124-3p SEV as a new and effective therapeutic approach to arrest the progression of PD and open new perspectives for the treatment of other neurodegenerative diseases.
Original: doi: 10.1016/j.ymthe.2022.06.003.
[12] Cell: Discovery of the dual function of α-synuclein
2022-06-11 Reported that in a new study, researchers from Brigham and Women's Hospital, Harvard Stem Cell Institute, Broad Institute have a new understanding of the role of alpha-synuclein, A new function of the protein related to Parkinson's disease and related diseases was revealed. The relevant research results were published in the journal Cell on June 9, 2022, with the title of the paper "The Parkinson's disease protein alpha-synuclein is a modulator of processing bodies and mRNA stability".
"Our research provides new insights into alpha-synuclein, a protein thought to play a role in Parkinson's disease and related disorders," said senior author Vikram Khurana, Ph. The nucleus produced. Current therapeutics target this protein, but its function has been unclear. Traditionally, alpha-synuclein was thought to play a role in binding to cell membranes and transporting structures called vesicles. But our study shows that alpha-synuclein has a dual identity."
"If we want to be able to develop therapeutics that target alpha-synapsin, we need to understand what the protein does and how to reduce its level or activity," said first author Erinc Hallacli, PhD, of the Department of Neurology at Brigham and Women's Hospital. Potential consequences. This paper provides important information that fills a gap in our knowledge about this protein, which may benefit clinical translation."
Original: doi:10.1016/j.cell.2022.05.008.
【13】A new drug for advanced Parkinson's disease (PD)! AbbVie's ABBV-951 has applied for marketing in the United States: the curative effect is significantly better than oral levodopa/carbidopa!
2022-05-27 reported that AbbVie (AbbVie) recently announced that it has submitted a New Drug Application (NDA) to the U.S. Food and Drug Administration (FDA) for ABBV-951 (foscarbidopa/foslevodopa), a levodopa A solution of the prodrug (foslevodopa) and the carbidopa prodrug (foscarbidopa) by continuous subcutaneous administration for the treatment of motor fluctuations (MF) in patients with advanced Parkinson's disease (PD).
[14] Ruijian Pharmaceutical "Qingqi" IND acceptance of the first pluripotent stem cell-derived drug in the field of Parkinson's in China
It was reported on April 11, 2022 that on the "World Parkinson's Day" in 2022, Wuhan Ruijian Pharmaceutical Technology Co., Ltd. (referred to as "Ruijian Pharmaceutical") officially submitted the IND application for Parkinson's R&D pipeline NouvNeu001 to the National Drug Evaluation Center , April 27, the National Drug Evaluation Center officially accepted the application. Preclinical data show that NouvNeu001 can be efficiently transformed into mature dopaminergic neurons after transplanted into the body through the high-efficiency chemical small molecule-induced functional cell regeneration technology developed by Ruijian Medicine, which can secrete dopamine transmitters and form with the original neurons in the body. Neural connections produce comprehensive therapeutic functions and improve Parkinson's symptoms. It provides a new clinical treatment path of cell medicine for Parkinson's disease. It is worth mentioning that the acceptance of the NouvNeu001 IND also makes Ruijian Pharmaceuticals officially become the first biopharmaceutical company in China and the second in the world to receive clinical applications for pluripotent stem cell-derived drugs in the field of Parkinson’s disease, second only to Bayer Its BlueRock.