# Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease

> **NIH VA I01** · RALPH H JOHNSON VA MEDICAL CENTER · 2020 · —

## Abstract

Parkinson's disease (PD), a progressive degenerative disorder, affects almost 80,000 Veterans. Since there is
no cure, new therapies must be developed to halt disease progression. While the mechanisms of this degen-
erative process remain elusive, chronic inflammation may be involved. Calpain activates microglia and T cells,
induces T cell migration/chemotaxis, plays a pivotal role in spinal cord (SC) degeneration, and may be a driver
of inflammation and disease progression. Preliminary data from MPTP mice and human PD samples showed
infiltration of CD4+ and CD8+ T cells into SC and SN, increased CD4+ T cells in mouse splenocytes, and
elevated serum cytokines/chemokines. An expanded subpopulation of cytotoxic CD4+ T cells was detected in
splenocytes from MPTP mice and DSP-4/6OHDA-induced rats. Calpeptin (calpain inhibitor) treatment
abolished this CD4+ subtype in MPTP mice, suggesting calpain's role in T cell activation and the CD4+ subtype
may be critical in the inflammatory process. Chemokine receptor CCR-1 is a Ca2+ mobilizer and, importantly,
can activate calpain. Since CCR-1 ligands (MIP-1α, RANTES) promote trafficking of T cells in SC, their role in
inflammation was assessed. They were significantly reduced following treatment of MPTP mice with calpeptin,
and behavioral function was remarkably improved. SC from PD patients revealed activation of microglia and
astrocytes, infiltration of CD4+/CD8+ T cells, and increased calpain. Inhibition of primary microglia activation by
Ca2+ ionophore by calpeptin and CCR-1 antagonist (BX471) produced marked reduction in cytokines/
chemokines, suggesting their potential as agents for treatment of MPTP-induced neurotoxicity. Thus, we
hypothesize that calpain activation, infiltration of inflammatory T cells (Th1/Th17, CD8+), and released
cytokines/chemokines are involved in progressive degeneration in PD, and calpain inhibitor and CCR-1
antagonist treatment may reduce degeneration, slow disease progression, and improve function. Three
specific aims are proposed: (1) investigate the role of calpain regulation and T cell infiltration in SC degenera-
tion and disease progression in MPTP mice, characterize infiltrating T cells, assess cytokine/chemokine levels
in sera, and determine cell death parameters and calpain activation in SC; (2) examine infiltration of T cells and
activation of microglia in SC from PD patients, characterize T cell subpopulations, and correlate with Specific
Aim 1, determine chemokines/cytokines in serum from PD patients; and (3) examine whether treatment of
MPTP mice with calpain inhibitors (calpeptin, SNJ1945) and BX471 alone or in combination will reduce inflam-
matory events and degeneration and improve function, correlate with DigiGait analysis, and examine whether
primary microglia activated by calcium ionophore upregulate chemokines/cytokines and can be controlled by
calpeptin and BX471. The key finding of a CD4-subtype in MPTP mice will also be verified in rotenone and
DSP-4/6O...

## Key facts

- **NIH application ID:** 9918754
- **Project number:** 5I01BX004269-02
- **Recipient organization:** RALPH H JOHNSON VA MEDICAL CENTER
- **Principal Investigator:** NAREN L BANIK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-04-01 → 2023-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9918754

## Citation

> US National Institutes of Health, RePORTER application 9918754, Attenuation of Inflammatory Response in Progressive Neurodegeneration in Parkinson's Disease (5I01BX004269-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9918754. Licensed CC0.

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