Manganese exposure in juvenile C57BL/6 mice increases glial inflammatory responses in the substantia nigra following infection with H1N1 influenza virus.

Infection with Influenza A virus can lead to the development of encephalitis and subsequent neurological deficits ranging from headaches to neurodegeneration. Post-encephalitic parkinsonism has been reported in surviving patients of H1N1 infections, but not all cases of encephalitic H1N1 infection present with these neurological symptoms, suggesting that interactions with an environmental neurotoxin could promote more severe neurological damage. The heavy metal, manganese (Mn), is a potential interacting factor with H1N1 because excessive exposure early in life can induce long-lasting effects on neurological function through inflammatory activation of glial cells. In the current study, we used a two-hit model of neurotoxin-pathogen exposure to examine whether exposure to Mn during juvenile development would induce a more severe neuropathological response following infection with H1N1 in adulthood. To test this hypothesis, C57BL/6 mice were exposed to MnCl2 in drinking water (50 mg/kg/day) for 30 days from days 21-51 postnatal, then infected intranasally with H1N1 three weeks later. Analyses of dopaminergic neurons, microglia and astrocytes in basal ganglia indicated that although there was no significant loss of dopaminergic neurons within the substantia nigra pars compacta, there was more pronounced activation of microglia and astrocytes in animals sequentially exposed to Mn and H1N1, as well as altered patterns of histone acetylation. Whole transcriptome Next Generation Sequencing (RNASeq) analysis was performed on the substantia nigra and revealed unique patterns of gene expression in the dual-exposed group, including genes involved in antioxidant activation, mitophagy and neurodegeneration. Taken together, these results suggest that exposure to elevated levels of Mn during juvenile development could sensitize glial cells to more severe neuro-immune responses to influenza infection later in life through persistent epigenetic changes

Rotenone induces regionally distinct α-synuclein protein aggregation and activation of glia prior to loss of dopaminergic neurons in C57Bl/6 mice

Rotenone is a naturally occurring insecticide that inhibits mitochondrial complex I and leads to neurochemical and neuropathological deficits closely resembling those in Parkinson\u27s disease (PD). Deficits include loss of dopaminergic neurons (DAn) in the substantia nigra pars compacta (SNpc), decreased dopamine levels and aggregation of misfolded alpha-synuclein (p129). In rat models of rotenone-induced parkinsonism, the progression of neuronal injury has been associated with activation of microglia and astrocytes. However, these neuroinflammatory changes have been challenging to study in mice, in part because the systemic rotenone exposure model utilized in rats is more toxic to mice. To establish a reproducible murine model of rotenone-induced PD, we therefore investigated the progression of neuroinflammation, protein aggregation and DAn loss in C57Bl/6 mice by exposing animals to 2.5 mg/kg/day rotenone for 14 days, followed by a two-week period where neuroinflammation is allowed to progress. Our results indicate that initial cellular dysfunction leads to increased formation of proteinase K-resistant p129 aggregates in the caudate-putamen and SNpc. Clearance of these aggregates was region- and cell type-specific, with the early appearance of reactive astrocytes coinciding with accumulation of p129 in the SNpc. Phagocytic microglial cells containing p129 aggregates were observed proximal to p129+ DAn in the SNpc. The majority of neuronal loss in the SNpc occurred during the two-week period after rotenone exposure, subsequent to the peak of microglia and astrocyte activation, as well as the peak of p129 aggregation. A secondary peak of p129 coincided with neurodegeneration at later timepoints. These data indicate that systemic exposure to rotenone in C57Bl/6 mice causes progressive accumulation and regional spread of p129 aggregates that precede maximal loss of DAn. Thus, activation of glial cells and aggregation of p129 appear to drive neuronal loss following neurotoxic stress imposed by exposure to rotenone

Use of diindolylmethane (DIM) compounds and derivatives as neuroprotective agents

Presented herein are diindolylmethane derivative compounds useful for the prevention and or treatment of neurological conditions, including neurological conditions related to neuroinflammation. One such neurological condition is Parkinson's disease.U

Use of diindolylmethane (DIM) compounds and derivatives as neuroprotective agents

Presented herein are diindolylmethane derivative compounds useful for the prevention and or treatment of neurological conditions, including neurological conditions related to neuroinflammation. One such neurological condition is Parkinson's disease.U

Use of diindolylmethane (DIM) compounds and derivatives as neuroprotective agents

Presented herein are diindolylmethane derivative compounds useful for the prevention and or treatment of neurological conditions, including neurological conditions related to neuroinflammation. One such neurological condition is Parkinson's disease.U

Use of diindolylmethane (DIM) compounds and derivatives as neuroprotective agents

Presented herein are diindolylmethane derivative compounds useful for the prevention and or treatment of neurological conditions, including neurological conditions related to neuroinflammation. One such neurological condition is Parkinson's disease.U

Glial-neuronal signaling mechanisms underlying the neuroinflammatory effects of manganese

Abstract Background Exposure to increased manganese (Mn) causes inflammation and neuronal injury in the cortex and basal ganglia, resulting in neurological symptoms resembling Parkinson’s disease. The mechanisms underlying neuronal death from exposure to Mn are not well understood but involve inflammatory activation of microglia and astrocytes. Expression of neurotoxic inflammatory genes in glia is highly regulated through the NF-κB pathway, but factors modulating neurotoxic glial-glial and glial-neuronal signaling by Mn are not well understood. Methods We examined the role of NF-κB in Mn-induced neurotoxicity by exposing purified microglia, astrocytes (from wild-type and astrocyte-specific IKK knockout mice), and mixed glial cultures to varying Mn concentrations and then treating neurons with the conditioned media (GCM) of each cell type. We hypothesized that mixed glial cultures exposed to Mn (0–100 μM) would enhance glial activation and neuronal death compared to microglia, wild-type astrocytes, or IKK-knockout astrocytes alone or in mixed cultures. Results Mixed glial cultures treated with 0–100 μM Mn for 24 h showed the most pronounced effect of increased expression of inflammatory genes including inducible nitric oxide synthase (Nos2), Tnf, Ccl5, Il6, Ccr2, Il1b, and the astrocyte-specific genes, C3 and Ccl2. Gene deletion of IKK2 in astrocytes dramatically reduced cytokine release in Mn-treated mixed glial cultures. Measurement of neuronal viability and apoptosis following exposure to Mn-GCM demonstrated that mixed glial cultures induced greater neuronal death than either cell type alone. Loss of IKK in astrocytes also decreased neuronal death compared to microglia alone, wild-type astrocytes, or mixed glia. Conclusions This suggests that astrocytes are a critical mediator of Mn neurotoxicity through enhanced expression of inflammatory cytokines and chemokines, including those most associated with a reactive phenotype such as CCL2 but not C3