# The Neuroimmune Hypothesis of Paraquat: Connecting the Periphery and Brain

> **NIH NIH R01** · INDIANA UNIVERSITY INDIANAPOLIS · 2021 · $348,235

## Abstract

Parkinson's disease (PD) is the second most prevalent neurodegenerative disease and a devastating
movement disorder characterized by the progressive loss of dopaminergic (DA) neurons in the substantia
nigra. Approximately 90-95% of PD cases are sporadic and pesticides have been implicated in sporadic PD
etiology. Paraquat (PQ) is a widely used herbicide and many epidemiology studies have associated PQ
exposure with increased PD risk. Mechanistic controversy exists regarding the DA neurotoxicity of PQ, as the
mechanisms through which PQ impacts the brain and the resulting neuropathology remains a point of debate.
Importantly, PD is linked to peripheral and brain immune perturbation. Microglia, the resident innate immune
cells in the brain, are chronically activated in PD. As a source of neurotoxic cytokines and reactive oxygen
species, chronic microglial activation and neuroinflammation have been implicated in the initiation and
augmentation of selective DA neurotoxicity in PD models in vivo and in vitro. The paraquat neuroimmune
hypothesis holds that microglia and neuroinflammation are culpable in PQ DA neuropathology. Paraquat
activates microglia both in vivo and in vitro, where research has shown that the reduction of pro-inflammatory
factors ameliorates PQ DA neuropathology. Despite low levels of PQ localized in the brain, previous research
has predominantly focused on the direct interaction of PQ with brain parenchymal cells, the neurons and glia.
Importantly, PQ accumulates prominently in the lung, kidney, and liver with toxicity. Here, we propose that
peripheral damage from PQ signals to the brain through circulating damage associated molecular patterns
(DAMPs) to exert deleterious central nervous system (CNS) effects. Preliminary data implicate an important
role for the circulating DAMP HMGB1 in how PQ impacts the brain. Thus, we hypothesize that PQ exposure
causes circulating HMGB1, which causes neuroinflammation and DA neuropathology. As such, our specific
AIMS are to: AIM1) Assess the role of HMGB1 in PQ–induced neuroinflammation & neuropathology; AIM2)
characterize the role of vascular endothelial cells and brain capillaries in PQ-induced HMGB1 and
neuroinflammation; AIM3) Define the role of myeloid cells in PQ-induced neuroinflammation and
neuropathology. If successful, these findings will reveal a novel peripheral mechanism of pesticide (PQ)-
induced CNS effects, implicate HMGB1 as a potential therapeutic target for chronic CNS effects after
PQ/pesticide exposure, and provide key insight into the role of the periphery in PD.

## Key facts

- **NIH application ID:** 10085636
- **Project number:** 5R01ES028104-04
- **Recipient organization:** INDIANA UNIVERSITY INDIANAPOLIS
- **Principal Investigator:** Michelle L Block
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $348,235
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10085636

## Citation

> US National Institutes of Health, RePORTER application 10085636, The Neuroimmune Hypothesis of Paraquat: Connecting the Periphery and Brain (5R01ES028104-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10085636. Licensed CC0.

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