TLR2 and TLR4 in Parkinson’s disease pathogenesis: the environment takes a toll on the gut DOI Creative Commons
Anastazja M. Gorecki, Chidozie C. Anyaegbu, Ryan S. Anderton

et al.

Translational Neurodegeneration, Journal Year: 2021, Volume and Issue: 10(1)

Published: Nov. 17, 2021

Abstract Parkinson’s disease (PD) is an incurable, devastating disorder that characterized by pathological protein aggregation and neurodegeneration in the substantia nigra. In recent years, growing evidence has implicated gut environment gut-brain axis pathogenesis progression of PD, especially a subset people who exhibit prodromal gastrointestinal dysfunction. Specifically, perturbations homeostasis are hypothesized to contribute α-synuclein enteric neurons, which may spread brain over decades eventually result characteristic central nervous system manifestations including motor impairments. However, mechanisms linking disturbances still unclear. A plethora research indicates toll-like receptors (TLRs), TLR2 TLR4, critical mediators homeostasis. Alongside their established role innate immunity throughout body, studies increasingly demonstrating TLR4 signalling shapes development function system. Notably, dysregulated patients with thus be early dysfunction PD. To better understand putative contribution intestinal we critically discuss normal as well for altered reviewing clinical, animal model vitro research. Growing on immunological aetiology also discussed, focus interactions TLR4. We propose conceptual PD microbial dysbiosis alters permeability barrier signalling, ultimately leading positive feedback loop chronic promoting vagal neurons. turn, aggregates then migrate via peripheral nerves, such nerve, neuroinflammation typically associated

Language: Английский

Parkinson’s disease: etiopathogenesis and treatment DOI Open Access
Joseph Jankovic,

Eng King Tan

Journal of Neurology Neurosurgery & Psychiatry, Journal Year: 2020, Volume and Issue: 91(8), P. 795 - 808

Published: June 23, 2020

The concept of ‘idiopathic’ Parkinson’s disease (PD) as a single entity has been challenged with the identification several clinical subtypes, pathogenic genes and putative causative environmental agents. In addition to classic motor symptoms, non-motor manifestations (such rapid eye movement sleep disorder, anosmia, constipation depression) appear at prodromic/premotor stage evolve, along cognitive impairment dysautonomia, progresses, often dominating advanced stages disease. key molecular mechanisms include α-synuclein misfolding aggregation, mitochondrial dysfunction, protein clearance (associated deficient ubiquitin-proteasome autophagy-lysosomal systems), neuroinflammation oxidative stress. involvement dopaminergic well noradrenergic, glutamatergic, serotonergic adenosine pathways provide insights into rich variable phenomenology associated PD possibility alternative therapeutic approaches beyond traditional dopamine replacement therapies. One biggest challenges in development potential neuroprotective therapies lack reliable sensitive biomarkers progression. Immunotherapies such use vaccination or monoclonal antibodies directed against aggregated, toxic α-synuclein.as anti-aggregation strategies are currently investigated trials. application glucagon-like peptide one receptor agonists, specific gene target agents GBA LRRK2 modifiers) other modifying drugs cautious optimism that more effective on horizon. Emerging therapies, new symptomatic drugs, innovative drug delivery systems novel surgical interventions give hope patients about their future outcomes prognosis.

Language: Английский

Citations

797
Fluid transport in the brain DOI
Martin Kaag Rasmussen, Humberto Mestre, Maiken Nedergaard

et al.

Physiological Reviews, Journal Year: 2021, Volume and Issue: 102(2), P. 1025 - 1151

Published: May 5, 2021

The brain harbors a unique ability to, figuratively speaking, shift its gears. During wakefulness, the is geared fully toward processing information and behaving, while homeostatic functions predominate during sleep. blood-brain barrier establishes stable environment that optimal for neuronal function, yet imposes physiological problem; transcapillary filtration forms extracellular fluid in other organs reduced to minimum brain. Consequently, depends on special [the cerebrospinal (CSF)] flushed into along perivascular spaces created by astrocytic vascular endfeet. We describe this pathway, coined term glymphatic system, based dependency endfeet their adluminal expression of aquaporin-4 water channels facing CSF-filled spaces. Glymphatic clearance potentially harmful metabolic or protein waste products, such as amyloid-β, primarily active sleep, when drivers, cardiac cycle, respiration, slow vasomotion, together efficiently propel CSF inflow periarterial brain's space contains an abundance proteoglycans hyaluronan, which provide low-resistance hydraulic conduit rapidly can expand shrink sleep-wake cycle. system brain, meets requisites maintain homeostasis similar peripheral organs, considering blood-brain-barrier paths formation egress CSF.

Language: Английский

Citations

331
The NLRP3 Inflammasome Pathway: A Review of Mechanisms and Inhibitors for the Treatment of Inflammatory Diseases DOI Creative Commons

Hallie Blevins,

Yiming Xu,

Savannah Biby

et al.

Frontiers in Aging Neuroscience, Journal Year: 2022, Volume and Issue: 14

Published: June 10, 2022

The NLRP3 inflammasome is a multiprotein complex that plays pivotal role in regulating the innate immune system and inflammatory signaling. Upon activation by PAMPs DAMPs, oligomerizes activates caspase-1 which initiates processing release of pro-inflammatory cytokines IL-1β IL-18. most extensively studied to date due its array activators aberrant several diseases. Studies using small molecules biologics targeting pathway have shown positive outcomes treating various disease pathologies blocking chronic inflammation. In this review, we discuss recent advances understanding mechanism, pathology, provide broad review therapeutics discovered target their challenges.

Language: Английский

Citations

267
The microbiome–gut–brain axis in Parkinson disease — from basic research to the clinic DOI
Ai Huey Tan, Shen‐Yang Lim, Anthony E. Lang

et al.

Nature Reviews Neurology, Journal Year: 2022, Volume and Issue: 18(8), P. 476 - 495

Published: June 24, 2022

Language: Английский

Citations

213
The role of gut dysbiosis in Parkinson’s disease: mechanistic insights and therapeutic options DOI Creative Commons
Qing Wang, Yuqi Luo, К. Ray Chaudhuri

et al.

Brain, Journal Year: 2021, Volume and Issue: 144(9), P. 2571 - 2593

Published: April 12, 2021

Parkinson's disease is a common neurodegenerative disorder in which gastrointestinal symptoms may appear prior to motor symptoms. The gut microbiota of patients with shows unique changes, be used as early biomarkers disease. Alterations the composition related cause or effect non-motor symptoms, but specific pathogenic mechanisms are unclear. and its metabolites have been suggested involved pathogenesis by regulating neuroinflammation, barrier function neurotransmitter activity. There bidirectional communication between enteric nervous system CNS, microbiota-gut-brain axis provide pathway for transmission α-synuclein. We highlight recent discoveries about alterations focus on current mechanistic insights into pathophysiology. Moreover, we discuss interactions production α-synuclein inflammation neuroinflammation. In addition, draw attention diet modification, use probiotics prebiotics faecal transplantation potential therapeutic approaches that lead new treatment paradigm

Language: Английский

Citations

189
Inflammasomes as therapeutic targets in human diseases DOI Creative Commons
Yangxin Li, Hui Huang, Bin Liu

et al.

Signal Transduction and Targeted Therapy, Journal Year: 2021, Volume and Issue: 6(1)

Published: July 2, 2021

Abstract Inflammasomes are protein complexes of the innate immune system that initiate inflammation in response to either exogenous pathogens or endogenous danger signals. Inflammasome multiprotein composed three parts: a sensor protein, an adaptor, and pro-caspase-1. Activation inflammasome leads activation caspase-1, which cleaves pro-inflammatory cytokines such as IL-1β IL-18, leading pyroptosis. Effectors not only provide protection against infectious pathogens, but also mediate control over sterile insults. Aberrant signaling has been implicated development cardiovascular metabolic diseases, cancer, neurodegenerative disorders. Here, we review role double-edged sword various outcomes can be good bad depending on disease, well genetic background. We highlight memory two-shot process. propose M- N-type model, discuss how pathway may targeted for novel therapy.

Language: Английский

Citations

170
Motor and non-motor circuit disturbances in early Parkinson disease: which happens first? DOI
Javier Blesa, Guglielmo Foffani, Benjamin Dehay

et al.

Nature reviews. Neuroscience, Journal Year: 2021, Volume and Issue: 23(2), P. 115 - 128

Published: Dec. 14, 2021

Language: Английский

Citations

161
Neurodegenerative Disease and the NLRP3 Inflammasome DOI Creative Commons
Jonathan Holbrook, Heledd Jarosz-Griffiths, Emily A. Caseley

et al.

Frontiers in Pharmacology, Journal Year: 2021, Volume and Issue: 12

Published: March 10, 2021

The prevalence of neurodegenerative disease has increased significantly in recent years, and with a rapidly aging global population, this trend is expected to continue. These diseases are characterised by progressive neuronal loss the brain or peripheral nervous system, generally involve protein aggregation, as well metabolic abnormalities immune dysregulation. Although vast majority neurodegeneration idiopathic, there many known genetic environmental triggers. In past decade, research exploring low-grade systemic inflammation its impact on development progression increased. A particular focus been whether arises only secondary effect also cause pathology. inflammasomes, more specifically NLRP3 inflammasome, crucial component innate usually activated response infection tissue damage. Dysregulation inflammasome implicated several disorders, such Alzheimer’s disease, Parkinson’s Huntington’s amyotrophic lateral sclerosis, prion diseases. This review aims summarise current literature role pathogenesis diseases, work investigating inhibition potential future therapy.

Language: Английский

Citations

149
The Nrf2-NLRP3-caspase-1 axis mediates the neuroprotective effects of Celastrol in Parkinson's disease DOI Creative Commons
Chenyu Zhang, Miao Zhao, Bingwei Wang

et al.

Redox Biology, Journal Year: 2021, Volume and Issue: 47, P. 102134 - 102134

Published: Sept. 22, 2021

Parkinson's disease (PD) is a chronic neurodegenerative disorder that characterized by motor symptoms as result of loss dopaminergic neurons in the substantia nigra pars compacta (SNc), accompanied neuroinflammation, oxidative stress, formation α-synuclein aggregates. Celastrol, potent anti-inflammatory and anti-oxidative pentacyclic triterpene, has emerged neuroprotective agent. However, mechanisms which celastrol PD remain elusive. Here we show protects against dopamine neuron loss, mitigates relieves deficits MPTP-induced mouse model AAV-mediated human overexpression model. Whole-genome deep sequencing analysis revealed Nrf2, NLRP3 caspase-1 SNc may be associated with actions PD. By using multiple genetically modified mice (Nrf2-KO, NLRP3-KO Caspase-1-KO), identified inhibits inflammasome activation, nigrostriatal degeneration through Nrf2-NLRP3-caspase-1 pathway. Taken together, these findings suggest axis serve key target treatment, highlight favorable properties for neuroprotection, making promising disease-modifying agent

Language: Английский

Citations

121
The Potential Role of Cinnamon in Human Health DOI Open Access
Natalia Błaszczyk, Angelina Rosiak, Joanna Kałużna‐Czaplińska

et al.

Forests, Journal Year: 2021, Volume and Issue: 12(5), P. 648 - 648

Published: May 20, 2021

Cinnamon is an unusual tropical plant belonging to the Lauraceae family. It has been used for hundreds of years as a flavor additive, but it also in natural Eastern medicine. extracts are vital oils that contain biologically active compounds, such cinnamon aldehyde, cinnamic alcohol, acid, and cinnamate. antioxidant, anti-inflammatory, antibacterial properties treat diseases diabetes cardiovascular disease. In folk medicine, species have medicine respiratory digestive disorders. Their potential prophylactic therapeutic use Parkinson’s Alzheimer’s disease discovered. This review summarizes available isolation methods analytical techniques identify compounds present bark leaves influence these treatment

Language: Английский

Citations

120