Authors :
Presenting Author: Hai-Ying Shen, MD, PhD – University of Nebraska Medical Center
Nicole Ferris, BS – University of Nebraska Medical Center
Guoku Hu, PhD – University of Nebraska Medical Center
Shefali Srivastava, BS – University of Nebraska Medical Center
Howard Gendelman, MD – University of Nebraska Medical Center
Sookyong Koh, MD, PhD – University of Nebraska Medical Center
Rationale:
New-onset refractory status epilepticus (NORSE) is a catastrophic neurological emergency marked by prolonged seizures that fail to respond to standard anti-seizure medications. The absence of a clear etiology, combined with rapid disease progression and resistance to conventional therapies, often necessitates intensive care involving continuous IV anesthetics and immunomodulatory interventions. Despite aggressive treatment, NORSE remains associated with high mortality and long-term neurological deficits. Neuroinflammation, particularly mediated by interleukin (IL)-1 and IL-6 signaling, plays a central role in the pathogenesis of NORSE. Extracellular vesicles (EVs), membrane-bound particles secreted by cells, including neurons and glia, are emerging as promising therapeutic agents due to their ability to modulate immune responses, support neuronal survival, and cross the blood-brain barrier. Colostrum-derived EVs (colosEVs) are rich in bioactive proteins and RNAs with potent anti-inflammatory and neuroprotective properties. This study investigates the potential of colosEVs as a novel therapeutic strategy for treating NORSE.
Methods:
A rodent model of NORSE was established using intrahippocampal kainic acid (IHKA) injection in 45 mice to induce status epilepticus. Mice were randomly assigned to receive either daily intraperitoneal injections of colosEVs or vehicle control for 21 days. Seizure burden was assessed through electroencephalography (EEG) at Week 1 and Week 3 post-IHKA. Hippocampal tissues were analyzed using immunohistochemistry to assess neuronal survival (NeuN), neuroinflammation (IBA1), and astrogliosis (GFAP). Peripheral immune modulation was evaluated by quantifying circulating regulatory T cell (Treg) frequencies via flow cytometry.
Results:
(i) Seizure Reduction: EV-treated mice demonstrated a significant reduction in seizure frequency at Week 1 compared to vehicle-treated controls (n=12 vs. n=8, P=0.0392). By Week 3, seizure frequency was further reduced in the EV group compared to both Week 1 EV-treated mice (P=0.0425) and Week 3 vehicle controls (n=10 vs. n=6, P=0.0013). Individual EEG traces indicated a consistent trend toward seizure mitigation. (ii) Neuroprotection and Anti-inflammatory Effects: EV treatment significantly decreased IBA1 expression (P=0.0104), increased NeuN expression (P=0.0496), and attenuated GFAP-associated glial responses in the CA3 region of the hippocampus compared to vehicle-treated NORSE mice. (iii) Immunomodulation: EV-treated mice exhibited a significant increase in circulating Treg frequencies compared to vehicle-treated counterparts (P=0.0268), suggesting systemic immunomodulatory effects.
Conclusions:
Colostrum-derived EV treatment significantly reduces seizure burden, suppresses neuroinflammation, preserves neuronal integrity, and modulates peripheral immune responses in a rodent model of NORSE. These findings support the therapeutic potential of EVs as a novel, non-invasive, and immune-targeted intervention for refractory epileptic syndromes like NORSE.
Funding: AES Seed grant