Synergistic effects of influenza and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) can be eliminated by the use of influenza therapeutics: experimental evidence for the multi-hit hypothesis

Abstract

Central Nervous System inflammation has been implicated in neurodegenerative disorders including Parkinson’s disease (Ransohoff, Science 353: 777–783, 2016; Kannarkat et al. J. Parkinsons Dis. 3: 493–514, 2013). Here, we examined if the H1N1 influenza virus (Studahl et al. Drugs 73: 131–158, 2013) could synergize with the parkinsonian toxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (Jackson-Lewis et al. in Mark LeDoux (ed) Movement Disorders: Genetics and Models: 287–306, Elsevier, 2015) to induce a greater microglial activation and loss of substantia nigra pars compacta dopaminergic neurons than either insult alone. H1N1-infected animals administered 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine exhibit a 20% greater loss of substantia nigra pars compacta dopaminergic neurons than occurs from the additive effects of H1N1 or 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine alone (p < 0.001). No synergistic effects were found in microglial activation. The synergistic dopaminergic neuron loss is eliminated by influenza vaccination or treatment with oseltamivir carboxylate. This work shows that multiple insults can induce synergistic effects; and even these small changes can be significant as it might allow one to cross a phenotypic disease threshold that would not occur from individual non-interacting exposures. Our observations also have important implications for public health, providing impetus for influenza vaccination or prompt treatment with anti-viral medications upon influenza diagnosis.

Infections or Sepsis Preceding Clinically Diagnosed α‐Synucleinopathies: A Case‐Control Study

“…30 Studies assessing LPS/viral exposure and PD in animal models assess results over days rather than years. 6,28 Individuals may require multiple hits of severe infection/sepsis to develop α-synucleinopathy. Our study, however, did not demonstrate increased odds of α-synucleinopathy among those hospitalized more than once.…”

Leucine Rich Repeat Kinase 2 and Innate Immunity

“…Model pathogens such as S. typhimurium or M. leprae are certainly of interest for understanding LRRK2 function in a defined context, but from an epidemiological viewpoint these would seem unlikely major initiators of PD or IBD. This in turn raises the question of how LRRK2 may modulate the response to more ubiquitous pathogens implicated in PD and IBD, such as gut microbiota (Houser and Tansey, 2017;Ni et al, 2017), periodontal microbes (Vavricka et al, 2013;Chen et al, 2017) or influenza virus (Sadasivan et al, 2017). This is likely an interesting area of future research.…”

Microglial Phenotypes and Their Relationship to the Cannabinoid System: Therapeutic Implications for Parkinson’s Disease

“…Olsen et al [114] also demonstrated that viral neuroinflammatory priming in the substantia nigra significantly exacerbated α-synuclein aggregate-induced neuroinflammation and neurodegeneration. Another group likewise observed an enhanced neurodegenerative effect by combination of the H1N1 influenza virus and MPTP [115]. However, it is not yet known how or if the response differs between different neurodegenerative conditions or different priming agents.…”