# Neuroinflammatory Biomarkers for Nigrostriatal Injury

> **NIH NIH R01** · WASHINGTON UNIVERSITY · 2020 · $641,769

## Abstract

ABSTRACT.
Parkinson disease (PD) causes motor and nonmotor manifestations. Underlying pathology includes abnormal
deposition of α-synuclein (α-syn) starting in caudal brainstem (as well as olfactory tubercle and medial
temporal areas) and then spreads to more rostral brainstem and cortical areas. Initial motor manifestations
likely reflect degeneration to the nigrostriatal dopaminergic pathway but cortical dysfunction leading to
nonmotor and some motor manifestations may reflect direct α-syn involvement, neurotransmitter deficiencies
due to loss of projecting brainstem nuclei or secondary dysfunction of cortical or subcortical networks.
Currently, no treatment delays the relentless progression of PD. We have preliminary data (neuroinflammation,
increased reactive oxygen species) after nigrostriatal injury in nonhuman primates (NHPs) that suggests that
cortical dysfunction may occur from retrograde degeneration along cortico-striatal neurons. Here we will test
whether an anti-inflammatory compound, synoxizyme (previously called carboxyfullerene or C3), will reduce
the observed neuroinflammation, and prevent retrograde cortical injury as a potential mechanism which could
contribute to disability in people with PD. We will confirm this finding and validate in vivo PET measures of
neuroinflammation and reactive oxygen species. We also demonstrated that synoxizyme restores nigrostriatal
dysfunction after unilateral internal carotid (ic) infusion of the selective neurotoxin MPTP. Synoxizyme may act
through attenuation of neuroinflammation and reduce destructive reactive oxygen species. Another goal of this
study is to determine whether our new PET radiotracers can act as targets of engagement for synoxizyme.
These highly novel studies will determine whether nigrostriatal injury with MPTP in nonhuman primates leads
to cortical dysfunction which could provide the basis for investigations into another mechanism of cortical
dysfunction that occurs in people with PD. Furthermore, we will validate new PET measures of
neuroinflammation and reactive oxygen species that could be key for such studies. We will determine whether
diffusion tensor imaging MR measures of mean diffusivity identify cortical striatal tract dysfunction that could
support the notion of retrograde degeneration after nigrostriatal injury. We also will determine whether
systemically administered synoxizyme will attenuate the effects of MPTP and whether this corresponds with a
reduction in MPTP-induced neuroinflammation and increased reactive oxygen species – which may be
involved in the pathogenesis of human PD. Finally, we will be able to demonstrate whether the PET measures
may provide quantification of targets of engagement for synoxizyme, which would be critical information for a
subsequent clinical trial in humans of synoxizyme or any other treatment targeting these pathogenic
mechanisms in PD or other neurodegenerative conditions.

## Key facts

- **NIH application ID:** 9939726
- **Project number:** 5R01NS107281-02
- **Recipient organization:** WASHINGTON UNIVERSITY
- **Principal Investigator:** JOEL Synes PERLMUTTER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $641,769
- **Award type:** 5
- **Project period:** 2019-06-01 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9939726

## Citation

> US National Institutes of Health, RePORTER application 9939726, Neuroinflammatory Biomarkers for Nigrostriatal Injury (5R01NS107281-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9939726. Licensed CC0.

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