A Novel Synthetic Precursor of Styryl Sulfone Neuroprotective Agents Inhibits Neuroinflammatory Responses and Oxidative Stress Damage through the P38 Signaling Pathway in the Cell and Animal Model of Parkinson's Disease.

A novel class of styryl sulfones were designed and synthesized as CAPE derivatives by our work team, which showed a multi-target neuroprotective effect, including antioxidative and anti-neuroinflammatory properties. However, the underlying mechanisms remain unclear. In the present study, the anti-Parkinson's disease (PD) activity of 10 novel styryl sulfone compounds was screened by the cell viability test and the NO inhibition test in vitro. It was found that 4d exhibited the highest activity against PD among them. In a MPTP-induced mouse model of PD, the biological activity of 4d was validated through suppressing dopamine neurotoxicity, microglial activation, and astrocytes activation. With compound 4d, we conducted the mechanistic studies about anti-inflammatory responses through inhibition of p38 phosphorylation to protect dopaminergic neurons, and antioxidant effects through promoting nuclear factor erythroid 2-related factor 2 (Nrf2). The results revealed that 4d could significantly inhibit 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine/1-methyl-4-phenylpyridinium (MPTP/MPP+)-induced p38 mitogen-activated protein kinase (MAPK) activation in both in vitro and in vivo PD models, thus inhibiting the NF-κB-mediated neuroinflammation-related apoptosis pathway. Simultaneously, it could promote Nrf2 nuclear transfer, and upregulate the expression of antioxidant phase II detoxification enzymes HO-1 and GCLC, and then reduce oxidative damage.

Updates on immunity and inflammation in Parkinson disease pathology.

Studies in the last decade have suggested the association of both neuroinflammatory processes and immune responses in Parkinson disease (PD) pathology. PD pathology is related to depleted dopamine levels, α-synuclein aggregation, and death of nigrostriatal dopaminergic neurons. Reports have suggested central and peripheral inflammation in the prodromal stage of the disease, which is sustained during disease progression. Alongside the activation of peripheral immune system exacerbates the dissonant central inflammatory responses and could contribute in synergistic neurodegeneration. Activated glial cells contribute significantly in the neuroinflammatory process during the occurrence of the disease and are also acknowledged as a hallmark of disease progression. However, the contribution of glial cells is not well defined in the context of neurodegeneration and neuroprotection. This review provides an overview of the roles of immune and inflammatory responses and their consequences in PD disease pathogenesis and also discusses possible therapeutic strategies for PD based on these findings.

Paraquat-activated BV-2 microglia induces neuroinflammatory responses in the neuron model through NF-κB signaling pathway.

Paraquat (PQ), a non-selective contact herbicide, has been generally accepted as one of the environmental neurotoxicants. Despite the direct evidence that PQ could induce inflammation responses in microglia, little is known about the effects of the inflammatory microglia on neurons. Thus in the present study, mouse primary cortical neurons and PC12 cells, widely-used in vitro neuron models for neurotoxicity research were applied to investigate the neuroinflammatory effects of PQ-activated microglia on neurons. We observed that the secretion levels of TNF-α and IL-6 in PC12 cells were markedly increased upon treatment with the supernatants of inflammatory BV2 microglia, and NF-κB p65 protein expression was also elevated. Specific inhibition of NF-κB by PDTC dramatically attenuated the increase of TNF-α and IL-6 release. These results suggested that PQ-induced inflammatory microglia exerts secondary inflammatory effects on neurons through activation of NF-κB pathway.

Role of metallic pollutants in neurodegeneration: effects of aluminum, lead, mercury, and arsenic in mediating brain impairment events and autism spectrum disorder.

Autism spectrum disorder (ASD) is a developmental disorder of the brain characterized by shortfall in the social portfolio of an individual and abbreviated interactive and communication aspects rendering stereotypical behavior and pitfalls in a child's memory, thinking, and learning capabilities. The incidence of ASD has accelerated since the past decade, portraying environment as one of the primary assets, comprising of metallic components aiming to curb the neurodevelopmental pathways in an individual. Many regulations like Clean Air Act and critical steps taken by countries all over the globe, like Sweden and the USA, have rendered the necessity to study the effects of environmental metallic components on ASD progression. The review focuses on the primary metallic components present in the environment (aluminum, lead, mercury, and arsenic), responsible for accelerating ASD symptoms by a set of general mechanisms like oxidative stress reduction, glycolysis suppression, microglial activation, and metalloprotein disruption, resulting in apoptotic signaling, neurotoxic effects, and neuroinflammatory responses. The effect of these metals can be retarded by certain protective strategies like chelation, dietary correction, certain agents (curcumin, mangiferin, selenium), and detoxification enhancement, which can necessarily halt the neurodegenerative effects.

Knockdown of TLR4 Represses the Paraquat-Induced Neuroinflammation and Microglial M1 Polarization.

Paraquat (PQ) is associated with multiple nervous system disorders including Parkinson's disease. Despite the evidence that PQ could induce inflammatory responses in the central nervous system and largely contribute to neurotoxicity, the mechanisms of PQ-induced neuroinflammation are not yet fully understood. Toll-like receptor 4 (TLR4) could recognize various pathogens and initiate inflammation processes. Therefore, we investigated the role of TLR4 in PQ-induced neuroinflammation by using murine microglial immortalized BV-2 cell line. Normal microglia and TLR4-knockdown microglia were treated with PQ to evaluate signal transduction molecular expression, inflammatory responses, and microglial functions. Compared with normal microglia, PQ-induced production of pro-inflammatory cytokines was significantly reduced in TLR4-knockdown microglia. Levels of M1 markers were decreased, while levels of M2 markers were increased upon PQ exposure, confirming that TLR4 depletion inhibited the microglial M1 polarization. Besides, the migration and phagocytosis capability reduced by PQ were to some extent recovered in TLR4-knockdown microglia. Taken together, our results suggested that TLR4 mediated the neuroinflammatory responses in microglia and the depletion of TLR4 protects against PQ neurotoxicity.

HMGB1 Mediates Paraquat-Induced Neuroinflammatory Responses via Activating RAGE Signaling Pathway.

Paraquat (PQ), a widely characterized neurotoxicant, has been generally accepted as one of the environmental factors in the etiology of Parkinson's disease (PD). Despite the direct evidence that PQ could induce inflammatory responses in central nervous system, the putative adverse effects of PQ on the neuroimmune interactions have rarely been investigated. High-mobility group box 1 (HMGB1) has been proven to be relevant to the neuroinflammation involved in PD; however, whether and how HMGB1 exerts modulatory effects in nervous system upon PQ exposure remain elusive. Therefore, the present study investigated the underlying association between HMGB1 and PQ exposure in SH-SY5Y cells, which is a well-established in vitro model for PD research. We observed that HMGB1 was markedly increased in a concentration and time-dependent manner upon PQ exposure, and the elevated HMGB1 could be translocated into cytosol and then released to the extracellular milieu of SH-SY5Y cells. Knockdown of HMGB1 inhibited the activation of RAGE-P38-NF-κB signaling pathway and the expression of inflammation cytokines such as TNF-α and IL-6. These results suggested that HMGB1 is involved in the PQ-induced neuron death via activating RAGE signaling pathways and promoting neuroinflammatory responses.