Beta2-adrenergic agonists, also known as adrenergic β2 receptor agonists, are a class of drugs that act on the β2 adrenergic receptor. Like other β adrenergic agonists, they cause smooth muscle relaxation leading dilatation of bronchial passages, vasodilation in muscle and liver, relaxation of uterine muscle, and release of insulin. They are primarily used to treat asthma and other pulmonary disorders, such as Chronic obstructive pulmonary disease (COPD). Yet β2 agonists are used by athletes and bodybuilders as anabolic performance-enhancing drugs. They are also used illegally to try to promote the growth of livestock.

Scientists from Bergen, Norway, were interested in the association between Parkinson's disease and the use of beta2-adrenoreceptor (β2AR) agonists vary among groups of short-, long-, and ultra-long-acting β2AR agonists (SABA, LABA, and ultraLABA).

There is evidence supporting the use of β2AR agonists in synucleinopathies is rapidly growing. Molecular and immunological data suggest that adrenergic stimulation may decrease both α-synuclein (α-syn) deposition and pro-inflammatory/neurotoxic molecules release.

Small open-label clinical trials including a total number of 25 Parkinson's disease (PD) patients, in which the β2AR agonist salbutamol was added to levodopa, suggest a promising symptomatic benefit.

However, other mechanisms might explain this apparent association. Some persons with prodromal PD symptoms of anxiety and tremor might avoid β2AR agonists due to the potential of these drugs to exacerbate such symptoms. A study in a UK cohort of 2,430,884 patients found that apparent association of β2-agonists with a decreased risk of PD was likely the result of reverse causality rather than a biological effect of these drugs on the risk of PD.

In the Norwegian study the scientists searched for Parkinson disease cases and prescriptions in a population of 3.2 million people. This was facilitated by the fact that in Norway, drugs for treating certain diseases, such as PD, asthma, and chronic obstructive pulmonary disease (COPD), are covered by the national insurance system, and the reimbursement codes indicate the disease for which the medicine was prescribed.

Beta2-adrenergic agonists can be classified in short-acting β2 agonists (SABAs), long-acting β2 agonists (LABAs), and ultra-long-acting β2 agonists (ultraLABA). A dose-response analysis was conducted on β2AR agonists and separately on groups of SABA, LABA, and ultraLABA.

Evidence for a negative association between β2AR agonists and PD. All three subgroups of β2AR agonists remained inversely associated with PD risk in the fully adjusted model and after stratification by indication of use, with ultraLABA displaying the overall strongest association. The observed dose-response relationships are also consistent with a protective effect.

There is an inverse association between β2AR agonists and PD attributed to smoking habits. This is an important source of potential bias. β2AR agonists are commonly used for conditions associated with smoking, such as COPD, and smoking has consistently been associated with a reduced PD risk.

Adjusting for level of education in the present study did not notably influence the risk estimates. These results were surprising given the markedly decreased risk of PD among individuals with lowest education who smoke more and use more β2AR agonists, than those with highest education after adjustment for sex and age.

Parkinson’s disease has traditionally been primarily associated with a nigrostriatal dopamine deficit resulting in the characteristic motor symptoms of tremor, rigidity, and bradykinesia. Nowadays, the involvement of other brain circuits is widely recognized, as the majority of patients also present numerous non-motor symptoms such as dementia, depression, sleep disorders, or apathy. Nevertheless, the mechanistic basis for neuropathological and symptomatic heterogeneity remains unclear. Indeed differential neurotransmitter and receptor expression may underpin the selective vulnerability of several neuronal populations. So the lack of whole-brain spatial distribution maps of neurotransmitter receptors in patients with PD hampers research progress.

In a new medRXiv publication, scientists from Canada use patient-specific generative brain modeling to identify neurotransmitter receptor-mediated mechanisms involved in PD progression.

Multifactorial causal modeling (MCM) is a mechanistic modeling approach that is able to identify contributions of interacting factors to longitudinal changes. Combining multi-modal neuroimaging with spatial distribution templates of 15 neurotransmitter receptors from post-mortem autoradiography in an MCM-based approach may significantly improve the explanation of degenerative changes in individual patients’ neuroimaging data, and linked specific receptor-pathology interactions to clinical symptoms.

Thus the authors combined receptor maps with longitudinal neuroimaging (PPMI data), to detect a diverse set of receptors influencing gray matter atrophy, microstructural degeneration, and dendrite loss in PD. Importantly, identified receptor mechanisms correlate with symptomatic variability along two distinct axes, representing motor/psychomotor symptoms with large GABAergic contributions, and cholinergically-driven visuospatial dysfunction.

Furthermore, the authors map cortical and subcortical regions where receptors exert significant influence on neurodegeneration.

Their work constitutes the first personalized causal model linking the progression of multi-factorial brain reorganization in PD across spatial scales, including molecular systems, accumulation of neuropathology in macroscopic brain regions, and clinical phenotypes.

Biomedical research has revealed many similarities between neurodegenerative diseases at the cellular level, including atypical protein assemblies. These similarities suggest that therapeutic advances against one neurodegenerative disease might ameliorate other diseases as well. In each disease, neurons gradually lose function as the disease progresses with age. It is though that repeated viral exposures, even seemingly innocuous, can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.

Yet the search for a specific viral or auto-immune origin in these diseases have mostly failed. This article published on medRxiv by scientists from Netherlands, aims at identifying overlap at genetic level between four investigated neurodegenerative disorders (Alzheimer’s disease, amyotrophic lateral sclerosis, Lewy body dementia, and Parkinson’s disease).

As these diseases are mostly associated with age, they have a poor heritability, so it would be difficult to associate with some gene.

As in previous studies, the authors failed to identify any region, gene, gene-set, cell or tissue type that was shared between all four neurodegenerative diseases. However, they found that HLA locus was significantly associated with these traits. It is not clear how it is associated because the scientists used a tool named FUMA. FUMA is an automatic tool which annotates GWAS findings and prioritizes the most likely causal SNPs and genes. Yet it is a bit obscure like all these "ontological" tools, like too often in molecular biology it is a qualitative, not quantitative tool.

HLA is a part of the genome which plays an important role in immune systems. The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. This genetic complex is called HLA in humans.

These cell surface proteins are called MHC molecules. The proteins encoded by HLAs are those on the outer part of body cells that are (in effect) unique to that person. The immune system uses the HLAs to differentiate self cells and non-self cells. Any cell displaying that person's HLA type belongs to that person and is therefore not an invader.

While this study does not try to explain what is the relation between those diseases and the HLA region, it is possible to make some guesses.

If aging (and DNA) degradation is a function of the number of viral attacks during life, then it makes sense to find a correlation between immune system and these non-communicable diseases.

But again many studies have not found any relations between viral or auto-immune insults and neurodegenarative diseases.

Parkinson patients sometimes complain that their symptoms are not due to their disease, but to their medication. This review shed some light on this problem.

For patients with Parkinson’s disease, dopamine replacement is the treatment of choice, and the most commonly used drug is levodopa (L-dopa), a dopamine precursor. Because dopamine itself cannot cross the blood-brain barrier (BBB) owing to its large molecular weight, L-dopa is administered.

However, L-dopa can easily convert to other structures, such as 3-O-methyldopa catalyzed by the enzyme catechol-O-methyl transferase (COMT) before it crosses the BBB or reaches the brain. To prevent this undesirable conversion, L-dopa is often prescribed along with COMT inhibitors, such as entacapone. Moreover, it can cause serious side effects, such as dyskinesia. It accelerates PD progression by inducing neuronal cell death through self-oxidation.

These treatments of Parkinson's disease tends to further elevate circulating homocysteine levels and peripheral nerves damage. High levels of homocysteine in the blood have been associated with certain pathologies, cardiac, neurological, rheumatic or psychiatric. Evidence exists linking elevated homocysteine levels with vascular dementia and Alzheimer's disease.

There is also evidence that elevated homocysteine levels and low levels of vitamin B6 and B12 are risk factors for mild cognitive impairment and dementia. Oxidative stress induced by homocysteine may also play a role in schizophrenia.

Accumulating deficiencies of B12, B6 vitamins and folic acid are presumed to be the substrate for the homocysteine elevation.

So B-vitamin therapy may reduce homocysteine levels. This begs the question of whether Parkinson's disease patients on levodopa should be concurrently treated with ongoing B-vitamin therapy. There is a substantial literature on this topic that has accumulated over the last quarter-century, and this topic is still debated.

This review summarizes the relevant literature with the aim of approximating closure on this issue. Also, noteworthy is that Parkinson's disease patients with renal insufficiency may not tolerate cyanocobalamin, the standard oral B12 supplement due to facilitation of renal decline.

Here are some key points: • Levodopa treatment of Parkinson's disease (PD) elevates circulating homocysteine levels. • Elevated homocysteine and/or B-vitamin depletion correlates with an increased risk of cognitive decline. • Lifetime monitoring of B-vitamin levels could address this problem. • It may be necessary to prescribe oral B12, B6, folic acid to levodopa-treated PD patients. • Levodopa-treated PD patients with renal insufficiency should take methylcobalamin rather than cyanocobalamin.

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La dérégulation du fer a été impliquée dans de multiples maladies neurodégénératives, y compris la maladie de Parkinson et la sclérose latérale amyotrophique (SLA). Les cellules constituant la microglie se trouvent fréquemment chargées de fer dans les régions cérébrales touchées, mais la façon dont l'accumulation de fer influence la physiologie de la microglie et contribue à la neurodégénérescence est mal comprise.

Dans une nouvelle publication, les auteurs montrent qu'une tri-culture de cellules de microglie dérivée de cellules souches pluripotentes humaines est très sensible au fer et sensible à la ferroptose, une forme de mort cellulaire dépendante du fer. La microglie est une population de cellules gliales — des macrophages que l'on retrouve dans le système nerveux central et qui en forme la principale défense immunitaire active grâce à ses capacités phagocytaires. Les cellules gliales sont les cellules qui forment l'environnement des neurones. Elles jouent un rôle de soutien et de protection du tissu nerveux en apportant les nutriments et l'oxygène, en éliminant les cellules mortes et en combattant les pathogènes.

Les cultures in vitro d'astrocytes et de microglies sont des outils puissants pour étudier les voies moléculaires spécifiques impliquées dans la neuroinflammation. Cependant, afin de mieux comprendre l'influence de la diaphonie cellulaire sur la neuroinflammation, de nouveaux modèles de culture multicellulaires sont nécessaires. En effet, les interactions entre les neurones, les astrocytes et la microglie influencent de manière critique les réponses neuro-inflammatoires à l'insulte dans le système nerveux central. La « tri-culture » composée à la fois de neurones, d'astrocytes et de microglie imite plus fidèlement les réponses neuro-inflammatoires in vivo que les mono-cultures standard.

Parmi les trois types de cellules, la microglie a eu la réponse transcriptionnelle la plus forte à la dérégulation du fer, et les scientifiques ont identifié un sous-ensemble de microglie avec une signature transcriptomique distincte associée à la ferroptose qui est enrichie dans la moelle épinière SLA post-mortem et la microglie du mésencéphale du patient PD post-mortem.

L'élimination de la microglie du système de tri-culture a considérablement retardé la neurotoxicité induite par le fer.

Dans la maladie, l'absorption microgliale de fer peut initialement être protectrice, mais, lorsque les cellules succombent à la ferroptose, elles entrent dans un état cellulaire neurotoxique qui entraîne des lésions et elles meurent en masse.

Pour élucider les mécanismes régulant la réponse du fer dans la microglie, les scientifiques ont effectué un criblage CRISPR à l'échelle du génome et identifié de nouveaux régulateurs de la ferroptose, y compris le gène de trafic de vésicule SEC24B. Enfin, les auteurs ont effectué un criblage de petites molécules pour identifier les inhibiteurs de la ferroptose de la microglie. Sur les 546 composés, ils ont trouvé 39 composés qui inhibaient la ferroptose dans la microglie. Parmi ceux-ci Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP ou encore sésamol. La rhapontigénine est un stilbénoïde. Il peut être isolé de la vigne du Japon (Vitis coignetiae) ou du Gnetum cleistostachyum. Il montre une action sur les cellules cancéreuses de la prostate. Il a été démontré qu'il inhibe le cytochrome humain P450 1A1, une enzyme impliquée dans la biotransformation d'un certain nombre de composés cancérigènes et immunotoxiques. Le xanthotoxol est une furanocoumarine. C'est l'un des principes actifs majeurs de Cnidium monnieri. Cnidium monnieri (L.) Cuss. est l'une des plantes médicinales traditionnelles les plus largement utilisées et ses fruits ont été utilisés pour traiter diverses maladies en Chine, au Vietnam et au Japon. Le sésamol est un composé organique naturel qui entre dans la composition des graines de sésame et de l'huile de sésame, aux propriétés anti-inflammatoires, antioxydantes, antidépressives et neuroprotectrices.

Malgré le fait que la ferroptose a été impliquée dans de nombreux troubles, on ne connait aucun traitement efficace pour atténuer la ferroptose. Les chélateurs du fer sont une approche potentielle, mais beaucoup od'entre eux peuvent perturber les fonctions redox homéostatiques. Cependant, les études précliniques existantes utilisant des inhibiteurs de la peroxydation lipidique, tels que lip-1, et les données présentées dans cette étude fournissent une justification solide pour le développement de thérapies ciblant la ferroptose. Plusieurs composés ciblant la peroxydation lipidique et le stress oxydatif sont d'ailleurs en cours d'essais cliniques, notamment le dérivé de la vitamine E vatiquinone, l'acide linoléique deutéré et les activateurs de la voie antioxydante NRF2.

Iron dysregulation has been implicated in multiple neurodegenerative diseases, including Parkinson's disease and amyotrophic lateral sclerosis (ALS).

Cells making up microglia are frequently found loaded with iron in affected brain regions, but how iron accumulation influences microglia physiology and contributes to neurodegeneration is poorly understood.

In a new publication, authors show that a tri-culture of microglia cells derived from human pluripotent stem cells is highly iron-sensitive and susceptible to ferroptosis, a form of iron-dependent cell death.

Microglia is a population of glial cells, macrophages that are found in the central nervous system and which form the main active immune defense thanks to their phagocytic abilities. Glial cells are the cells that form the environment of neurons. They play a role in supporting and protecting nervous tissue by providing nutrients and oxygen, eliminating dead cells and fighting pathogens.

In vitro cultures of astrocytes and microglia are powerful tools to study the specific molecular pathways involved in neuroinflammation. However, in order to better understand the influence of cell crosstalk on neuroinflammation, new multicellular culture models are needed. Indeed, interactions between neurons, astrocytes and microglia critically influence neuroinflammatory responses to insult in the central nervous system. The "tri-culture" composed of both neurons, astrocytes and microglia more closely mimics neuro-inflammatory responses in vivo than standard mono-cultures.

Of the three cell types, microglia had the strongest transcriptional response to iron dysregulation, and scientists identified a subset of microglia with a distinct transcriptomic signature associated with ferroptosis that is enriched in the spinal cord Postmortem ALS and midbrain microglia from postmortem PD patient.

Removal of microglia from the tri-culture system significantly delayed iron-induced neurotoxicity.

In the disease, microglial iron uptake may initially be protective, but when cells succumb to ferroptosis, they enter a neurotoxic cellular state that leads to damage and they die en masse.

To elucidate the mechanisms regulating the iron response in microglia, scientists performed a genome-wide CRISPR screen and identified novel regulators of ferroptosis, including the vesicle trafficking gene SEC24B. Finally, the authors performed a small molecule screen to identify inhibitors of microglia ferroptosis. Of the 546 compounds, they found 39 compounds that inhibited ferroptosis in microglia. Among these Rhapontigenin, Xanthotoxol, Tenovin-1, Curcumin, ATP or sesamol.

Rhapontigenin is a stilbenoid. It can be isolated from Japanese grapevine (Vitis coignetiae) or Gnetum cleistostachyum. It shows an action on prostate cancer cells. It has been shown to inhibit human cytochrome P450 1A1, an enzyme involved in the biotransformation of a number of carcinogenic and immunotoxic compounds. Xanthotoxol is a furanocoumarin. It is one of the major active principles of Cnidium monnieri. Cnidium monnieri (L.) Cuss. is one of the most widely used traditional herbal medicines and its fruits have been used to treat various diseases in China, Vietnam and Japan. Sesamol is a natural organic compound that is part of the composition of sesame seeds and sesame oil, with anti-inflammatory, antioxidant, antidepressant and neuroprotective properties.

Despite the fact that ferroptosis has been implicated in many disorders, no effective treatment is known to alleviate ferroptosis. Iron chelators are a potential approach, but many of them can disrupt homeostatic redox functions. However, the existing preclinical studies using lipid peroxidation inhibitors, such as lip-1, and the data presented in this study provide strong rationale for the development of therapies targeting ferroptosis. Several compounds targeting lipid peroxidation and oxidative stress are also in clinical trials, including the vitamin E derivative vatiquinone, deuterated linoleic acid and activators of the antioxidant pathway NRF2.

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Chez les patients atteints de la maladie de Parkinson, on pense depuis les travaux de Heiko Braak, que la pathologie de l'α-synucléine se propage au cerveau via le nerf vague. Le lien entre le microbiote intestinal et la maladie de Parkinson a été exploré dans diverses études. Un indice est que les patients sont souvent constipés.

Récemment, l'appendicectomie a été associée à un risque plus faible de maladie de Parkinson, probablement en raison du rôle de l'appendice dans la modification du microbiome intestinal. Cependant, le microbiote fécal chez les patients sans antécédent d'appendicectomie peut présenter des variations interindividuelles considérables qui rendent difficile toute conclusion.

Les auteurs d'un nouvel article publié dans Nature/Scientific reports, ont cherché à élucider si le microbiote intestinal affectait le développement de la maladie de Parkinson dans une cohorte d'appendicectomie.

Ces scientifiques japonais ont analysé la composition microbienne fécale d'une vingtaine de patients atteints de la maladie de Parkinson et de témoins sains avec et sans antécédent d'appendicectomie. 10 sujets avaient la maladie de Parkinson, tandis que 10 autres constituaient le groupe contrôle. Chacun de ces deux groupes a été subdivisé en deux groupes de 5 sujets, l'un pour les sujets n'ayant pas subi d'appendicectomie, l'autre groupe constitué de ceux ayant subi cette opération.

L'abondance de microbes de la famille des entérobactéries était plus élevée dans les échantillons de matières fécales de patients atteints de la maladie de Parkinson que dans les échantillons prélevés sur des témoins sains. Il convient de noter que les entérobactéries, telles que Escherichia coli et Salmonella, produisent des amyloïdes bactériens appelés curli. Par conséquent, les entérobactéries peuvent induire une pathologie de Parkinson.

Les microbes des groupes Proteobacteria, Gammaproteobacteria, Enterobacteriales et Enterobacteriaceae étaient plus enrichis chez les patients parkinsoniens que chez les témoins sains. Les scientifiques ont découvert que le genre Serratia, de l'ordre des entérobactéries, avait une abondance plus élevée dans les échantillons fécaux de patients atteints de maladie de Parkinson que dans les témoins sains.

On pensait que Serratia était une bactérie environnementale inoffensive jusqu'à ce que l'espèce la plus commune du genre, S. marcescens, soit découverte comme étant un pathogène opportuniste. Chez l'homme, S. marcescens est principalement associé à des infections nosocomiales ou nosocomiales, mais il peut également provoquer des infections des voies urinaires, une pneumonie et une endocardite. S. marcescens se trouve fréquemment dans les douches, les cuvettes de toilettes et autour des carreaux humides sous forme de biofilm rosâtre à rouge.

Certaines études ont démontré que le microbiote intestinal des patients atteints de maladie de Parkinson a une faible abondance de Prevotella, tandis que d'autres études ont montré des résultats contradictoires. Il est possible que l'abondance des Prevotellaceae dans le microbiote intestinal soit corrélée à la sévérité de la constipation, et non à la maladie de Parkinson.

Les individus du groupe en bonne santé avaient les indices de masse corporelle les plus élevés. Une réduction du ratio Firmicutes/Bacteroidetes chez les patients atteints de maladie de Parkinson a été observée entre les groupes maladie de Parkinson et contrôle dans une étude précédente.

De plus, il y avait une différence phylogénétique significative entre les patients atteints de la maladie de Parkinson et les témoins sains ayant subi une appendicectomie. Il y avait une différence phylogénétique significative entre les patients atteints de la maladie de Parkinson et les témoins sains qui avaient subi une appendicectomie. Ces résultats suggèrent la corrélation entre le microbiote intestinal et la maladie de Parkinson chez les patients ayant subi une appendicectomie.

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In patients with Parkinson's disease, it is believed since the work of Heiko Braak, that α-synuclein pathology spreads to the brain via the vagus nerve. The link between gut microbiota and Parkinson's disease has been explored in various studies. One clue is that patients are often constipated.

Recently, appendectomy has been associated with a lower risk of Parkinson's disease, possibly due to the appendix's role in altering the gut microbiome. However, the faecal microbiota in patients without a history of appendectomy may show considerable interindividual variation which makes any conclusion difficult.

The authors of a new paper published in Nature/Scientific reports, sought to elucidate whether gut microbiota affects the development of Parkinson's disease in an appendectomy cohort.

The Japanese scientists analyzed the fecal microbial composition in about twenty patients with Parkinson's disease and healthy controls with and without a history of appendectomy. 10 subjects had Parkinson's disease, while 10 others constituted the control group. Each of these two groups was subdivided into two groups of 5 subjects, one for subjects who had not undergone appendectomy, the other group consisting of those who had undergone this operation.

The abundance of microbes from the Enterobacteriaceae family was higher in fecal matter samples from patients with Parkinson's disease than in samples taken from healthy controls. It should be noted that Enterobacteriaceae, such as Escherichia coli and Salmonella, produce bacterial amyloids called curli. Therefore, Enterobacteriaceae can induce PD α-synuclein pathology.

Microbes from the Proteobacteria, Gammaproteobacteria, Enterobacteriales, and Enterobacteriaceae groups were more enriched in PD patients than in healthy controls. The scientists found that the genus Serratia, of the order Enterobacteriales, had a higher abundance in fecal samples from patients with PD than from healthy controls.

Serratia was thought to be a harmless environmental bacterium until the most common species of the genus, S. marcescens, was discovered to be an opportunistic pathogen. In humans, S. marcescens is primarily associated with nosocomial or nosocomial infections, but can also cause urinary tract infections, pneumonia, and endocarditis. S. marcescens is frequently found in showers, toilet bowls, and around wet tiles as a pinkish to red biofilm.

Some studies have demonstrated that the gut microbiota of patients with PD has a low abundance of Prevotella, while other studies have shown conflicting results. It is possible that the abundance of Prevotellaceae in the gut microbiota may be correlated with the severity of constipation, and not with PD.

Individuals in the healthy group had the highest body mass indices. A reduction in the Firmicutes/Bacteroidetes ratio in patients with PD was observed between the PD and control groups in a previous study.

Moreover, there was a significant phylogenetic difference between patients with Parkinson's disease and healthy controls who had undergone appendectomy. There was a significant phylogenetic difference between patients with Parkinson's disease and healthy controls who had undergone appendectomy. These results suggest the correlation between gut microbiota and Parkinson's disease in patients who have undergone appendectomy.

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