Dexmedetomidine prevents hemorrhagic brain injury by reducing damage induced by ferroptosis in mice.

Intracerebral hemorrhage (ICH) is a devastating condition with significant morbidity and mortality for which few effective treatments are clinically available. After ICH, iron overload within the perihaematomal region can induce lethal reactive oxygen species (ROS) production and lipid peroxidation, which contribute to secondary brain injury. An iron-dependent form of non-apoptotic cell death known as ferroptosis was recently identified. Ferroptosis plays an important role in ICH pathology. It is characterized by an accumulation of iron-induced lipid ROS, which leads to intracellular oxidative stress. Dexmedetomidine (DEX), an α2-adrenergic agonist, is widely used for anesthesia, pain control, and intensive care unit sedation. DEX has numerous beneficial activities, including anti-inflammatory, anti-oxidative, and anti-cell death activities. Here, we established a mouse model of ICH using collagenase VII and evaluated the effect of DEX in preventing ICH-induced brain injury. Our study showed that administering DEX reduced the damage induced by ferroptosis after ICH by regulating iron metabolism, amino acid metabolism and lipid peroxidation processes.

Dexmedetomidine Alleviates Intracerebral Hemorrhage-Induced Anxiety-Like Behaviors in Mice Through the Inhibition of TRPV4 Opening.

Post-stroke anxiety severely affects recovery in patients with intracerebral hemorrhage (ICH). Dexmedetomidine (Dex), a highly selective alpha 2 adrenal receptor (α2-AR) agonist, was recently found to exert an excellent protective effect against mental disorders including anxiety. The transient receptor potential vanilloid 4 (TRPV4) channel is involved in a series of diseases such as asthma, cancer, anxiety, and cardiac hypertrophy. This study examines whether Dex improved ICH-induced anxiety via the inhibition of TRPV4 channel opening. A rodent model of moderate ICH in the basal ganglia was established using autologous blood injection (20 µl). Mice were treated with Dex (25 µg/kg, intraperitoneal injection) every day for 3 days post-ICH. GSK1016790A (1 µmol/2 µl), an agonist of TRPV4, was administered via the left lateral ventricle. Thirty days post-ICH, post-stroke anxiety was evaluated by elevated plus-maze and open-field tests. Following behavioral tests, superoxide dismutase (SOD), malondialdehyde (MDA), astrocytic activation, and A1-and A2-type astrocytes were determined. Primary astrocytes were exposed to hemin to simulate ICH in vitro. Compared with sham-treated mice, Dex administration ameliorates ICH-induced decreases of distance and time in the open-arm, reduces distance and time in the central zone, increases astrocytic activation and A1-type astrocytes, elevates MDA content, downregulates total SOD contents, and decreases A2-type astrocytes. However, GSK1016790A partially reversed the neuroprotective effects of Dex. In addition, Dex significantly inhibited hemin-induced astrocytic activation in vitro. Dex improves ICH-induced anxiety-like behaviors in mice, and the mechanism might be associated with the inhibition of TRPV4-channel opening.