MITOCHONDRIAL ROS ARE ESSENTIAL FOR BRAIN REPAIR AFTER STROKE

Minimizing brain damage and stimulating endogenous repair mechanisms are crucial for functional recovery after stroke. Preclinical studies identified reactive oxygen species (ROS) as significant mediators of ischemic injury. However, antioxidant therapies have failed clinically, likely due to their focus on acute, neuron-specific targets rather than the broader and prolonged pathophysiological responses. By using genetically engineered mice expressing mitochondrial-targeted antioxidant catalase, we downmodulated mitochondrial H₂O₂ generation in vivo aiming to evaluate the role of ischemia-induced ROS in the transition from the acute phase to brain repair following stroke. Despite the neuroprotective effects observed both in vitro, following oxygen and glucose deprivation protocol, and in vivo, 24 hours after the occlusion of middle cerebral artery (MCAO), an imbalance in the redox response during reoxygenation phase and a persistent inflammatory state were observed in mito-catalase mice. Vascular and adjacent tissue repair were also impaired after MCAO, compromising the long-term recovery of motor and cognitive functions, as evidenced by the behavioral tests. Our results revealed mitochondrial ROS as key players on functional recovery after stroke and provide new clues for establishing novel and efficient antioxidant therapies to be successfully transferred to the clinic.
Funded by ISCIII (PI24/00810, RD24/0009/0005; co-funded by the EU); Junta de Castilla y León (CSI011P23) and FEDER.