Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by deficits in social interaction and repetitive, stereotyped behaviors. There is no universally effective pharmacological treatment targeting its core symptoms. Oxytocin, an endogenous polypeptide known as the “social hormone”, has shown potential in improving emotional recognition and social interactions in individuals with ASD. However, its clinical application has been limited due to its short half-life and poor blood–brain barrier penetration. To address these challenges, we utilized peptide lipidation technology to enhance the pharmacokinetic properties and brain bioavailability of oxytocin. A series of lipidated oxytocin analogs was designed and synthesized, exhibiting superior brain distribution and pharmacokinetic profiles in valproic acid-induced autistic rat models compared to unmodified oxytocin. Among these analogs, C16-modified oxytocin (C16-OT), administered intrathecally, achieved the most extensive brain distribution with limited presence in the blood, resulting in long-lasting improvements in autistic behaviors. These improvements, including enhanced social behaviors and reduced stereotypical actions, were sustained for up to 42 days, contrasting with the brief effects typically reported in previous studies. Furthermore, a comparison of administration routes revealed that intrathecal injection achieved higher brain concentrations and more prolonged social behavioral improvements than intranasal delivery. These findings provide robust preclinical evidence that C16-OT, through optimized lipidation and intrathecal delivery, offers sustained central nervous system activity and significant, long-term reversal of social behavioral deficits in rats with autism.
Oxaliplatin (OXA) is a third-generation platinum compound with clinical activity in multiple solid tumors. Due to the repetition of chemotherapy cycle, OXA-induced chronic neuropathy presenting as paresthesia and pain. This study explored the neuropathy of chemotherapy pain and investigated the analgesic effect of 2-bromopalmitate (2-BP) on the pain behavior of OXA-induced rats. The chemotherapy pain rat model was established by the five consecutive administration of OXA (intraperitoneal, 4 mg/kg). After the establishment of OXA-induced rats, the pain behavior test, inflammatory signal analysis and mitochondrial function measurement were conducted. OXA-induced rats exhibited mechanical allodynia and spinal inflammatory infiltration. Our fluorescence and western blot analysis revealed spinal astrocytes were activated in OXA rats with up-regulation of astrocytic markers. In addition, NOD-, LRR- and pyrin domain-containing 3 (NLRP3) inflammasome mediated inflammatory signal cascade was also activated. Inflammation was triggered by dysfunctional mitochondria which represented by increase in cyclooxygenase-2 (COX-2) level and manganese superoxide dismutase (Mn-SOD) activity. Intrathecally injection of 2-BP significantly attenuated dynamin-related protein 1 (Drp1) mediated mitochondrial fission, recovered mitochondrial function, suppressed NLRP3 inflammasome cascade, and consequently decreased mechanical pain sensitivity. For cell research, 2-BP treatment significantly reversed tumor necrosis factor-α (TNF-α) induced mitochondria membrane potential deficiency and high reactive oxygen species (ROS) level. These findings indicate 2-BP decreases spinal inflammation and relieves OXA-induced neuropathic pain via reducing Drp1-mediated mitochondrial dysfunction.
危险品化学品经营许可证（带存储）