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Updated: Jun 4, 2026
Determining Immune System Suppression versus CNS Protection for Pharmacological Interventions in Autoimmune Demyelination
Published on: September 12, 2016
PARP-1 inhibition prevents CNS migration of dendritic cells during EAE, suppressing the encephalitogenic response and
Leonardo Cavone1, Alessandra Aldinucci, Clara Ballerini
1Department of Pharmacology, University of Florence, Florence, Italy. leonardo.cavone@unifi.it
Background:
Pharmacological inhibitors of poly(ADP-ribose) polymerase-1 (PARP-1) are currently evaluated in clinical trials for various malignancies but, interestingly, also proved of remarkable efficacy in preclinical models of autoimmune disorders including experimental autoimmune encephalomyelitis (EAE).
Objectives:
The objectives of the study were to determine molecular mechanisms underlying suppression of the encephalitogenic response by these drugs; likewise, whether clinically-relevant post-treatment paradigms with PARP-1 inhibitors could prevent EAE relapses.
Methods:
Adopted both in vitro techniques (bone marrow-derived cultured DC) as well as in vivo models of chronic or relapsing-remitting (RR) EAE.
Results:
We report that two structurally unrelated PARP-1 inhibitors negatively regulated NFκB activation, as well as maturation, cytokine production and APC function of cultured mouse bone marrow-derived dendritic cells (DCs). PARP-1 inhibitors also reduced the number and APC function of DCs migrating in the draining lymph nodes of ovalbumin-immunized mice. In C57Bl mice with chronic EAE or SJL mice with RR EAE, pharmacological inhibition of PARP-1 reduced CNS DC migration and demyelination as well as neurological impairment to an extent similar to that achieved with the potent immunosuppressant cyclosporine A. Remarkably, PARP-1 inhibitors injected after the first phase of disease reduced relapse incidence and severity, as well as the spinal cord number of autoreactive Th17 cells. Under this clinically-relevant treatment paradigm, PARP inhibitors also suppressed epitope spreading of the encephalitogenic response.
Conclusions:
Overall, data underscore the potential relevance of PARP-1 inhibitors to MS therapy and suppression of autoimmunity.
Insights
Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors show promise for treating autoimmune diseases like multiple sclerosis (MS). These drugs suppress immune cell function and reduce disease severity and relapses in preclinical models.
Area of Science:
- Immunology
- Neuroscience
- Pharmacology
Background:
- Poly(ADP-ribose) polymerase-1 (PARP-1) inhibitors are investigated for cancer therapy.
- PARP-1 inhibitors demonstrate efficacy in preclinical models of autoimmune disorders, including experimental autoimmune encephalomyelitis (EAE).
Purpose of the Study:
- To elucidate the molecular mechanisms by which PARP-1 inhibitors suppress the encephalitogenic response.
- To assess the potential of post-treatment paradigms with PARP-1 inhibitors in preventing EAE relapses.
Main Methods:
- In vitro studies using bone marrow-derived dendritic cells (DCs).
- In vivo studies utilizing mouse models of chronic and relapsing-remitting (RR) EAE.
Main Results:
- PARP-1 inhibitors reduced NFκB activation, DC maturation, cytokine production, and APC function.
- Inhibition of PARP-1 decreased DC migration to the CNS, demyelination, and neurological deficits in EAE models.
- Post-disease treatment with PARP-1 inhibitors lowered relapse incidence, severity, and autoreactive Th17 cell counts, suppressing epitope spreading.
Conclusions:
- PARP-1 inhibitors hold significant therapeutic potential for multiple sclerosis (MS).
- These findings highlight the role of PARP-1 inhibition in suppressing autoimmune responses.
