Protective effects of alpha-mangostin encapsulated in cyclodextrin-nanoparticle on cerebral ischemia

• Published in: Journal of controlled release 2023-01, Vol.353, p.216-228
• Main Authors: Oka, Natsumi, Doan, Van Thi Hong, Matsubara, Hirofumi, Imai, Takahiko, Yoshioka, Yukie, Katsuki, Jun, Fujii, Shota, Nakamura, Shinsuke, Shimazawa, Masamitsu, Hara, Hideaki, Sakurai, Kazuo
• Format: Article
• Language: English
• Subjects: Alpha-mangostin; Animals; Antioxidants - pharmacology; Apoptosis; Brain Ischemia - drug therapy; Brain Ischemia - metabolism; Cyclodextrins; Glucose - metabolism; Humans; Ischemic Stroke; Nano-formulated form; Neuroblastoma; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxygen - therapeutic use; Rats; Reactive Oxygen Species - metabolism; Reperfusion Injury - metabolism; β-cyclodextrin
• ISSN: 0168-3659; 1873-4995
• DOI: 10.1016/j.jconrel.2022.11.030

The production of reactive oxygen species (ROS) during and after the onset of an ischemic stroke induces neuronal cell death and severely damages brain function. Therefore, reducing ROS by administrating antioxidant compounds is a promising approach to improving ischemic symptoms. Alpha-mangostin (α-M) is an antioxidant compound extracted from the pericarp of the mangosteen fruit. Reportedly, α-M decreases neuronal toxicity in primary rat cerebral cortical neurons. In this study, we investigated the neuroprotective activity of α-M in both in vitro and in vivo assays. Pretreatment with α-M inhibited excessive cellular ROS production after oxygen-glucose deprivation/reoxygenation (OGD/R) in vitro using an SH-SY5Y (human neuroblastoma) cell line. In addition, α-M maintained mitochondrial membrane potential and suppressed mitochondrial-specific ROS production induced by OGD/R. Meanwhile, the low bioavailability of α-M due to its poor water solubility has been an insuperable obstruction impeding extensive investigations of the biological functions of α-M and its medical applications. To overcome this problem, we synthesized a cyclodextrin-based nanoparticle (CDNP) that is known to increase the loading efficiency and binding constant of α-M, compared with cyclodextrins themselves. This nano-formulated α-M (α-M/CDNP) was optimized for an in vivo ischemic stroke model. Our results indicated that α-M/CDNP (25 mg/kg/injection) reduced infarct volume and improved neurological behavior (p = 0.036 and p = 0.046, respectively). These in vivo results suggest that α-M appears to cross the blood-brain barrier (BBB) with the help of a nano-formulation with CDNP. Combining an in vitro BBB model and a physicochemical binding assay between α-M and albumin, it is speculated that α-M released from CDNP would interact with albumin during its prolonged circulation in the blood, and the resultant α-M/albumin complex may cross the BBB through the absorptive-mediated transcytosis pathway. These findings suggest the potential clinical application of α-M in ischemic stroke treatment. [Display omitted] •α-Mangostin protects the neuronal blastoma cells against ischemic stress.•α-Mangostin ameliorates mitochondrial dysfunction in the neuronal blastoma cells.•α-Mangostin enters the central nervous system to inhibit the cerebral ischemic injury.•α-Mangostin penetrates the brain by interacting with albumin.•β-cyclodextrin nanoparticles allows intravenous administration of α-Mangostin.