Rationale: Infections of the central nervous system (CNS) are the most common risk factor for acquired epilepsy. Over 100 viruses, including West Nile virus, Herpes Simplex virus, and SARS-CoV2, can infect the brain and cause encephalitis in humans, with surviving patients being 16 times more likely to develop seizures than the general population. Brain infiltrating immune cells like macrophages and inflammation play an important role in seizure development, and understanding these mechanisms can support the discovery of new treatments. Pioglitazone, a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist, is approved for the treatment of type 2 diabetes. In non-infectious models, Pioglitazone has been shown to polarize macrophages toward an anti-inflammatory (M2) phenotype and reduce seizure incidence. However, the effect of Pioglitazone in a virus-induced model remains unexplored.
Methods: Theiler’s murine encephalomyelitis virus (TMEV) is a single-stranded, non-enveloped, murine RNA virus that provides a unique opportunity to study mechanisms of infection-driven seizures and epilepsy. Following intracranial infection of adult C57BL/6J mice with TMEV, mice experience acute seizures 3-7 days post-infection (dpi), followed by viral clearance at 14 dpi, and epilepsy after 30 dpi. Mice were infected with TMEV and treated with Pioglitazone (30mg/kg), and seizures were observed and scored twice daily (3-7 dpi). At 7 dpi, mice were euthanized, and brain tissue was analyzed by flow cytometry and immunohistochemistry.
Results: We observed a greater seizure incidence and burden in Pioglitazone-treated mice. Pioglitazone-treated mice also had significantly fewer immune cells, including macrophages, infiltrating into the brain from the periphery. However, the microglia and macrophages present in the brains of Pioglitazone-treated mice expressed significantly more MHC-II, indicating a more inflammatory state. Current work is aimed at quantifying TMEV in the hippocampus and profiling chemokines and cytokines to understand the mechanism underlying these findings.
Conclusions:
Overall, we found that Pioglitazone treatment in a virus-induced seizure model led to an increased seizure incidence and burden, reduced brain infiltration by peripheral immune cells, and heightened inflammatory activity in resident microglia and macrophages. We speculate that Pioglitazone increases seizures by modulating chemokine production, which in turn reduces the recruitment of infiltrating immune cells, particularly lymphocytes, and allows for increased viral replication and inflammation in the brain. These findings highlight the potential risks of repurposing anti-inflammatory drugs like Pioglitazone in the context of CNS infections and underscore the need for careful consideration when treating patients with virus
-induced seizures and epilepsy.
Funding: NIH-NINDS K22NS123547-ABPS