Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease

<p>Abstract</p> <p>Background</p> <p>The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease.</p> <p>Methods</p> <p>We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology.</p> <p>Results</p> <p>We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1β), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-α and interferon-γ and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration.</p> <p>Conclusion</p> <p>These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease.</p

Neuroinflammation Mediated by IL-1β Increases Susceptibility of Dopamine Neurons to Degeneration in an Animal Model of Parkinson's Disease

Background: The etiology of Parkinson's disease (PD) remains elusive despite identification of several genetic mutations. It is more likely that multiple factors converge to give rise to PD than any single cause. Here we report that inflammation can trigger degeneration of dopamine (DA) neurons in an animal model of Parkinson's disease. Methods: We examined the effects of inflammation on the progressive 6-OHDA rat model of Parkinson's disease using immunohistochemistry, multiplex ELISA, and cell counting stereology. Results: We show that a non-toxic dose of lipopolysaccharide (LPS) induced secretion of cytokines and predisposed DA neurons to be more vulnerable to a subsequent low dose of 6-hydroxydopamine. Alterations in cytokines, prominently an increase in interleukin-1beta (IL-1β), were identified as being potential mediators of this effect that was associated with activation of microglia. Administration of an interleukin-1 receptor antagonist resulted in significant reductions in tumor necrosis factor-α and interferon-γ and attenuated the augmented loss of DA neurons caused by the LPS-induced sensitization to dopaminergic degeneration. Conclusion: These data provide insight into the etiology of PD and support a role for inflammation as a risk factor for the development of neurodegenerative disease

Reducing Amyloid Plaque Burden via Ex Vivo Gene Delivery of an Aβ-Degrading Protease: A Novel Therapeutic Approach to Alzheimer Disease

Matthew Hemming and colleagues describe the ex vivo gene delivery of an Aβ-degrading protease that reduces amyloid plaque burden in transgenic mice expressing human amyloid precursor protein

Interleukin-1 receptor antagonist (IL-1ra) reduces the amount of tyrosine hydroxylase-immunoreactive (TH-ir) cell loss associated with LPS and 6-OHDA (t-test, * 0

05). Each animal received LPS into the substantia nigra (SN), 9 days later started on either IL-1ra or vehicle (Veh) which continued through the experiment, and all animals then received an intra-striatal injection of 6-OHDA (5.0 μg) and were allowed 21 days until post-mortem analyses. Magnification, 2.5×; scale bar, 1.0 mm. Error bars, ± SEM; n = 8 per condition.<p><b>Copyright information:</b></p><p>Taken from "Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/8</p><p>Journal of Neuroinflammation 2008;5():8-8.</p><p>Published online 27 Feb 2008</p><p>PMCID:PMC2292163.</p><p></p

Tyrosine hydroxylase positive (TH ) cell counts in the substantia nigra (SN)

Animals received, into the SN, saline (SAL) and 12 days later received an intra-striatal injection of SAL. Animals received lipopolysaccharide (LPS) into the SN and 12 days later received an intra-striatal injection of SAL. Animals received SAL into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). Animals received LPS into the SN and 12 days later received an intra-striatal injection of 6-OHDA (5.0 μg). Animals received an intra-striatal injection of 6-OHDA (5.0 μg) and 12 days later received LPS into the SN. Animals received an intra-striatal injection of 6-OHDA-h (high) (22.5 μg). Letters inside bars of panel represent respective images in panels below. 21 days was allowed following 6-OHDA injection in all conditions. There was an overall main effect across groups (ANOVA, < 0.001). LPS injection into the SN was non-toxic to TH+ neurons (, ). LPS injection prior to 6-OHDA administration increased the amount of TH+ cell loss compared to SAL prior to 6-OHDA (, *< 0.05, post-hoc Holm-Sidak). Intra-striatal injection of 6-OHDA followed by injection of LPS in the SN produced no greater cell loss (, ). The high dose of 6-OHDA produced cell loss that was not significantly different from a low dose of 6-OHDA with prior exposure to LPS (), however the high dose of 6-OHDA was significantly greater than other conditions receiving the lower dose of 6-OHDA (, # < 0.05, post-hoc Holm-Sidak). 1, first injection; 2, second injection; SNpc, pars compacta; SNpr, pars reticulata; VTA, ventral tegmental area; CP, cerebral peduncle; scale bar, 1.0 mm; magnification, 2.5×. Error bars, ± SEM; n = 6 per condition.<p><b>Copyright information:</b></p><p>Taken from "Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/8</p><p>Journal of Neuroinflammation 2008;5():8-8.</p><p>Published online 27 Feb 2008</p><p>PMCID:PMC2292163.</p><p></p

Representative coronal sections of microglia in the ventral midbrain at the level of the substantia nigra (SN) visualized by CD11b-immunoreactivity (-ir)

() activated microglia in the SN of a rat injected in the SN with LPS 12 days prior and () the contralateral side. () low level of microglia activation 12 days following an intra-striatal injection of 6-OHDA (5.0 μg) and () the contralateral side showing resting microglia. Insets are 20× images taken from the area outlined in lower magnification pictures. Scale bar of inset, 100 μm; scale bar of low magnification images (2.5×), 1.0 mm).<p><b>Copyright information:</b></p><p>Taken from "Neuroinflammation mediated by IL-1β increases susceptibility of dopamine neurons to degeneration in an animal model of Parkinson's disease"</p><p>http://www.jneuroinflammation.com/content/5/1/8</p><p>Journal of Neuroinflammation 2008;5():8-8.</p><p>Published online 27 Feb 2008</p><p>PMCID:PMC2292163.</p><p></p

The epidemiology of drowning in low- and middle-income countries: a systematic review

Abstract Background According to the World Health Organization, drowning is the 3rd leading cause of unintentional injury-related deaths worldwide, accounting for 370,000 annual deaths and 7% of all injury-related deaths. Low- and middle-income countries are the most affected, accounting for 91% of unintentional drowning deaths. Methods The authors performed a systematic review of literature indexed in EMBASE, PubMed, Web of Science, Cochrane Library, and Traumatology journals formerly indexed in PubMed in January 2014 and again in September 2016. Abstracts were limited to human studies in English, conducted in low- and middle-income countries, and containing quantitative data on drowning epidemiology. Results A total of 62 articles met inclusion criteria. The majority of articles originate from Asia (56%) and Africa (26%). Risk factors for drowning included young age (<17–20 years old), male gender (75% vs. 25% female), rural environment (84% vs. 16% urban), occurring in the daytime (95% vs. 5% night time), lack of adult supervision (76% vs. 18% supervised), and limited swimming ability (86% vs. 10% with swimming ability). There was almost equal risk of drowning in a small body of water versus a large body of water (42% ponds, ditches, streams, wells; 46% lakes, rivers, sea, ocean). Conclusion Drowning is a significant cause of injury-related deaths, especially in LMICs. Young males who are unsupervised in rural areas and have limited formal swimming instruction are at greatest risk of drowning in small bodies of water around their homes. Preventative strategies include covering wells and cisterns, fencing off ditches and small ponds, establishing community daycares, providing formal swimming lessons, and increasing awareness of the risks of drowning