Age-related microglial activation in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced dopaminergic neurodegeneration in C57BL/6 mice

2003 ◽  
Vol 964 (2) ◽  
pp. 288-294 ◽  
Author(s):  
Shuei Sugama ◽  
Lichuan Yang ◽  
Byung Pil Cho ◽  
Lorraine A DeGiorgio ◽  
Stefan Lorenzl ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Dopaminergic Neurodegeneration ◽  
Age Related

Microglial activation and age-related dopaminergic neurodegeneration in MPTP-treated SAMP8 mice

2010 ◽  
Vol 1345 ◽  
pp. 213-220 ◽  
Author(s):  
Jing Liu ◽  
Ming-Wei Wang ◽  
Ping Gu ◽  
Qin-Ying Ma ◽  
Yan-Yong Wang ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Dopaminergic Neurodegeneration ◽  
Age Related ◽  
Samp8 Mice

scholarly journals Multiple genetic pathways regulating lifespan extension are neuroprotective in a G2019S LRRK2 nematode model of Parkinson’s disease

2020 ◽  
Author(s):  
Megan M. Senchuk ◽  
Jeremy M. Van Raamsdonk ◽  
Darren J. Moore
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Late Onset ◽  
Lifespan Extension ◽  
Disease Manifestation ◽  
Genetic Pathways ◽  
Dopaminergic Neurodegeneration ◽  
Age Related ◽  
Increased Risk ◽  
Extended Longevity

AbstractBackgroundMutations in the leucine-rich repeat kinase 2 (LRRK2) gene are the most frequent cause of late-onset, familial Parkinson’s disease (PD), and LRRK2 variants are associated with increased risk for sporadic PD. While advanced age represents the strongest risk factor for disease development, it remains unclear how different age-related pathways interact to regulate LRRK2-driven late-onset PD.FindingsIn this study, we employ a C.elegans model expressing PD-linked G2019S LRRK2 to examine the interplay between age-related pathways and LRRK2-induced dopaminergic neurodegeneration. We find that multiple genetic pathways that regulate lifespan extension can provide robust neuroprotection against mutant LRRK2. However, the level of neuroprotection does not strictly correlate with the magnitude of lifespan extension, suggesting that lifespan can be experimentally dissociated from neuroprotection. Using tissue-specific RNAi, we demonstrate that lifespan-regulating pathways, including insulin/IGF-1 signaling, TOR, and mitochondrial respiration, can be directly manipulated in neurons to mediate neuroprotection. We extend this finding for AGE-1/PI3K, where pan-neuronal versus dopaminergic neuronal restoration of AGE-1 reveals both cell-autonomous and non-cell-autonomous neuroprotective mechanisms downstream of insulin signaling.ConclusionsOur data demonstrate the importance of distinct lifespan-regulating pathways in the pathogenesis of LRRK2-linked PD, and suggest that extended longevity is broadly neuroprotective via the actions of these pathways at least in part within neurons. This study further highlights the complex interplay that occurs between cells and tissues during organismal aging and disease manifestation.

scholarly journals A Possible Novel Anti-Inflammatory Mechanism for the Pharmacological Prolyl Hydroxylase Inhibitor 3,4-Dihydroxybenzoate: Implications for Use as a Therapeutic for Parkinson’s Disease

2012 ◽  
Vol 2012 ◽  
pp. 1-12 ◽  
Author(s):  
Shankar J. Chinta ◽  
Subramanian Rajagopalan ◽  
Abirami Ganesan ◽  
Julie K. Andersen
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Microglial Activation ◽  
Nitrosative Stress ◽  
Neurodegenerative Disorder ◽  
Oxidative And Nitrosative Stress ◽  
Prolyl Hydroxylases ◽  
Age Related

Parkinson’s disease (PD) is an age-related neurodegenerative disorder characterized in part by the preferential loss of nigrostriatal dopaminergic neurons. Although the precise etiology of PD is unknown, accumulating evidence suggests that PD involves microglial activation that exerts neurotoxic effects through production of proinflammatory cytokines and increased oxidative and nitrosative stress. Thus, controlling microglial activation has been suggested as a therapeutic target for combating PD. Previously we demonstrated that pharmacological inhibition of a class of enzymes known as prolyl hydroxylases via 3,4-dihydroxybenzoate administration protected against MPTP-induced neurotoxicity, however the exact mechanisms involved were not elucidated. Here we show that this may be due to DHB’s ability to inhibit microglial activation. DHB significantly attenuated LPS-mediated induction of nitric oxide synthase and pro-inflammatory cytokines in murine BV2 microglial cellsin vitroin conjunction with reduced ROS production and activation of NFκB and MAPK pathways possibly due to up-regulation of HO-1 levels. HO-1 inhibition partially abrogates LPS-mediated NFκB activity and subsequent NO induction.In vivo, DHB pre-treatment suppresses microglial activation elicited by MPTP treatment. Our results suggest that DHB’s neuroprotective properties could be due to its ability to dampen induction of microglial activation via induction of HO-1.

scholarly journals Nigrostriatal Proteomics of Cypermethrin-Induced Dopaminergic Neurodegeneration: Microglial Activation-Dependent and -Independent Regulations

2011 ◽  
Vol 122 (2) ◽  
pp. 526-538 ◽  
Author(s):  
Anand Kumar Singh ◽  
Manindra Nath Tiwari ◽  
Anubhuti Dixit ◽  
Ghanshyam Upadhyay ◽  
Devendra Kumar Patel ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Dopaminergic Neurodegeneration

scholarly journals Mechanism of Inflammation in Age-Related Macular Degeneration

2012 ◽  
Vol 2012 ◽  
pp. 1-16 ◽  
Author(s):  
Francesco Parmeggiani ◽  
Mario R. Romano ◽  
Ciro Costagliola ◽  
Francesco Semeraro ◽  
Carlo Incorvaia ◽  
...  
Keyword(s):  
Macular Degeneration ◽  
Microglial Activation ◽  
Vision Loss ◽  
Dietary Habits ◽  
The United States ◽  
Age Related Macular Degeneration ◽  
Age Related ◽  
Oxidized Lipoproteins ◽  
Severe Vision Loss

Age-related macular degeneration (AMD) is a multifactorial disease that represents the most common cause of irreversible visual impairment among people over the age of 50 in Europe, the United States, and Australia, accounting for up to 50% of all cases of central blindness. Risk factors of AMD are heterogeneous, mainly including increasing age and different genetic predispositions, together with several environmental/epigenetic factors, that is, cigarette smoking, dietary habits, and phototoxic exposure. In the aging retina, free radicals and oxidized lipoproteins are considered to be major causes of tissue stress resulting in local triggers for parainflammation, a chronic status which contributes to initiation and/or progression of many human neurodegenerative diseases such as AMD. Experimental and clinical evidences strongly indicate the pathogenetic role of immunologic processes in AMD occurrence, consisting of production of inflammatory related molecules, recruitment of macrophages, complement activation, microglial activation and accumulation within those structures that compose an essential area of the retina known as macula lutea. This paper reviews some attractive aspects of the literature about the mechanisms of inflammation in AMD, especially focusing on those findings or arguments more directly translatable to improve the clinical management of patients with AMD and to prevent the severe vision loss caused by this disease.

scholarly journals The pentose phosphate pathway regulates chronic neuroinflammation and dopaminergic neurodegeneration

2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Dezhen Tu ◽  
Yun Gao ◽  
Ru Yang ◽  
Tian Guan ◽  
Jau-Shyong Hong ◽  
...  
Keyword(s):  
Substantia Nigra ◽  
Pentose Phosphate Pathway ◽  
Microglial Activation ◽  
Redox Homeostasis ◽  
Pentose Phosphate ◽  
Transgenic Expression ◽  
Dopaminergic Neurodegeneration ◽  
Locomotor Impairment

Abstract Background Metabolic dysfunction and neuroinflammation are increasingly implicated in Parkinson’s disease (PD). The pentose phosphate pathway (PPP, a metabolic pathway parallel to glycolysis) converts glucose-6-phosphate into pentoses and generates ribose-5-phosphate and NADPH thereby governing anabolic biosynthesis and redox homeostasis. Brains and immune cells display high activity of glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme of the PPP. A postmortem study reveals dysregulation of G6PD enzyme in brains of PD patients. However, spatial and temporal changes in activity/expression of G6PD in PD remain undetermined. More importantly, it is unclear how dysfunction of G6PD and the PPP affects neuroinflammation and neurodegeneration in PD. Methods We examined expression/activity of G6PD and its association with microglial activation and dopaminergic neurodegeneration in multiple chronic PD models generated by an intranigral/intraperitoneal injection of LPS, daily subcutaneous injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 6 days, or transgenic expression of A53T α-synuclein. Primary microglia were transfected with G6PD siRNAs and treated with lipopolysaccharide (LPS) to examine effects of G6PD knockdown on microglial activation and death of co-cultured neurons. LPS alone or with G6PD inhibitor(s) was administrated to mouse substantia nigra or midbrain neuron-glia cultures. While histological and biochemical analyses were conducted to examine microglial activation and dopaminergic neurodegeneration in vitro and in vivo, rotarod behavior test was performed to evaluate locomotor impairment in mice. Results Expression and activity of G6PD were elevated in LPS-treated midbrain neuron-glia cultures (an in vitro PD model) and the substantia nigra of four in vivo PD models. Such elevation was positively associated with microglial activation and dopaminergic neurodegeneration. Furthermore, inhibition of G6PD by 6-aminonicotinamide and dehydroepiandrosterone and knockdown of microglial G6PD attenuated LPS-elicited chronic dopaminergic neurodegeneration. Mechanistically, microglia with elevated G6PD activity/expression produced excessive NADPH and provided abundant substrate to over-activated NADPH oxidase (NOX2) leading to production of excessive reactive oxygen species (ROS). Knockdown and inhibition of G6PD ameliorated LPS-triggered production of ROS and activation of NF-кB thereby dampening microglial activation. Conclusions Our findings indicated that G6PD-mediated PPP dysfunction and neuroinflammation exacerbated each other mediating chronic dopaminergic neurodegeneration and locomotor impairment. Insight into metabolic-inflammatory interface suggests that G6PD and NOX2 are potential therapeutic targets for PD.

Involvement of exosomes in dopaminergic neurodegeneration by microglial activation in midbrain slice cultures

2019 ◽  
Vol 511 (2) ◽  
pp. 427-433 ◽  
Author(s):  
Reiho Tsutsumi ◽  
Yuria Hori ◽  
Takahiro Seki ◽  
Yuki Kurauchi ◽  
Masahiro Sato ◽  
...  
Keyword(s):  
Microglial Activation ◽  
Dopaminergic Neurodegeneration

Age-related severity of dopaminergic neurodegeneration to MPTP neurotoxicity causes motor dysfunction in C57BL/6 mice

2006 ◽  
Vol 401 (1-2) ◽  
pp. 183-187 ◽  
Author(s):  
Satoshi Ohashi ◽  
Atsushi Mori ◽  
Naoki Kurihara ◽  
Yasuhide Mitsumoto ◽  
Masami Nakai
Keyword(s):  
Motor Dysfunction ◽  
Dopaminergic Neurodegeneration ◽  
Age Related
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