Mathon Bertrand, Navarro Vincent, Pons Thomas, Lecas Sarah, Roussel Delphine, Charpier Stéphane, Carpentier Alexandre
Sorbonne University, Department of Neurosurgery, APHP, La Pitié-Salpêtrière Hospital 75013 Paris, France; Paris Brain Institute, ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne University, UMRS 1127 75013 Paris, France; Sorbonne University, GRC 23, Brain Machine Interface, APHP, La Pitié-Salpêtrière Hospital 75013 Paris, France; Sorbonne University, Advanced Surgical Research Technology Lab 75013 Paris, France.
Paris Brain Institute, ICM, INSERM U 1127, CNRS UMR 7225, Sorbonne University, UMRS 1127 75013 Paris, France; Sorbonne University, Department of Neurology, Epileptology Unit, APHP, La Pitié-Salpêtrière Hospital 75013 Paris, France.
Ultrasonics. 2025 Nov;155:107734. doi: 10.1016/j.ultras.2025.107734. Epub 2025 Jun 20.
Given the limitations of current treatment options for drug-resistant mesial temporal lobe epilepsy (MTLE), the development of novel, nonablative and minimally invasive surgical techniques is essential.
In this study, low-intensity pulsed ultrasound (LIPU)- and microbubble-induced (henceforth LIPU) blood-brain barrier (BBB) opening combined with selenium-nanoparticle (SeNP) intravenous injection in a mouse model of mesial temporal lobe optimized the latter's bioavailability in the brain epileptic tissue of the kainic acid (KA) mouse model of MTLE. We aimed to assess the safety and antiepileptic potential of LIPU-enhanced SeNP delivery against KA-induced seizures using long-term intracranial electroencephalogram video recordings and evaluating neuroinflammation, astrogliosis, neuronal apoptosis and neurogenesis in the hippocampal tissues of mice.
First, we established that SeNP intravenous injection combined with LIPU-induced BBB disruption was the most effective method to achieve high and sustained selenium levels in the brain. The safety of this treatment was demonstrated after three treatment sessions, 1-week apart, with no adverse effects observed. Our results further showed a significantly lower frequency of epileptic seizures (-90 %, P = 0.001) in KA mice treated with LIPU + SeNPs compared to sham-treated controls. Short- and long-term histological changes were seen after that combined regimen, including less aberrant neurogenesis in the hippocampus hilum, less neuronal death throughout the hippocampus and less hippocampal microglial activation, which might collectively contribute to the observed antiseizure effect.
SeNP injection combined with LIPU-induced BBB disruption demonstrated potential as a promising approach to reduce seizure activity in MTLE; however, statistical comparison did not conclusively establish superiority over SeNPs alone. Further investigations are necessary to consider translational studies in humans.
鉴于目前耐药性内侧颞叶癫痫（MTLE）治疗方案的局限性，开发新型、非消融性和微创外科技术至关重要。
在本研究中，低强度脉冲超声（LIPU）与微泡诱导（以下简称LIPU）的血脑屏障（BBB）开放相结合，并在内侧颞叶小鼠模型中静脉注射硒纳米颗粒（SeNP），优化了其在红藻氨酸（KA）诱导的MTLE小鼠模型脑癫痫组织中的生物利用度。我们旨在通过长期颅内脑电图视频记录评估LIPU增强的SeNP递送对KA诱导的癫痫发作的安全性和抗癫痫潜力，并评估小鼠海马组织中的神经炎症、星形胶质细胞增生、神经元凋亡和神经发生。
首先，我们确定静脉注射SeNP并结合LIPU诱导的BBB破坏是在脑中实现高且持续硒水平的最有效方法。在间隔1周进行三次治疗后，证明了这种治疗的安全性，未观察到不良反应。我们的结果进一步表明，与假手术对照组相比，接受LIPU + SeNPs治疗的KA小鼠癫痫发作频率显著降低（-90%，P = 0.001）。联合治疗方案后观察到短期和长期的组织学变化，包括海马门异常神经发生减少、整个海马神经元死亡减少以及海马小胶质细胞活化减少，这些可能共同促成了观察到的抗癫痫作用。
静脉注射SeNP并结合LIPU诱导的BBB破坏显示出作为一种有前景的方法来降低MTLE癫痫发作活动的潜力；然而，统计学比较并未最终确定其优于单独使用SeNPs。需要进一步研究以考虑在人类中进行转化研究。
