Novel adamantane-nitrone hybrids: design, synthesis, and their multi-target neuroprotective effects against ischemic stroke

Ischemic stroke involves interconnected pathological processes, including calcium overload, oxidative stress, apoptosis, and inflammation. This complexity challenges therapies directed at a single target, while limited blood-brain barrier (BBB) permeability can restrict drug delivery to the brain. This study aimed to develop hybrid compounds with favorable BBB permeability and multi-target neuroprotective activity.

Four adamantane-nitrone hybrids (TA1-TA4) were synthesized and screened for cytotoxicity and neuroprotective activity, leading to the selection of TA1. TA1 was then evaluated for its effects on calcium overload, oxidative stress, mitochondrial function, and BBB permeability in vitro, and for therapeutic efficacy and related signaling pathways in MCAO mice. Single-dose safety was assessed separately.

TA1 showed the highest neuroprotective activity and lowest cytotoxicity among the four hybrids. It reduced calcium overload, scavenged ROS and ONOO^-, and stabilized mitochondrial membrane potential. TA1 exhibited favorable BBB permeability (P_app = 6.73 × 10^-6 cm/s) and ameliorated ischemia-induced barrier disruption. In MCAO mice, intravenous TA1 reduced cerebral infarct volume from 32.97% to 14.33%, outperforming the positive control TBN. It also alleviated brain edema and improved neurobehavioral outcomes. TA1 modulated the Bax/Bcl-2/caspase-3, Nrf2/HO-1, and NF-κB pathways. No overt abnormalities were observed in the measured hematological, biochemical, or histopathological indices 48 h after a single intravenous dose of 136 μmol/kg.

TA1 combines favorable BBB permeability with multi-target anti-apoptotic, antioxidant, and anti-inflammatory effects, supporting its further investigation as a candidate for ischemic stroke treatment.