INVESTIGATION OF THE EFFECTS OF NEURONAL GROWTH REGULATOR-1 ON NEURONAL DAMAGE AND NEUROPLASTICITY AFTER ISCHEMIC INJURY

Ischemic stroke results from reduced blood flow and leads to severe neuronal damage and death. Current stroke treatments are performed within a limited timeframe. Although research about acute stroke treatments is extensive, studies focusing on neuroplasticity and long-term recovery remain scarce. This hinders the development of therapeutic approaches that can address the chronic consequences of stroke. Neuronal growth regulator-1 (NEGR1) is a cell adhesion molecule that plays role in plasticity of synaptic connections. We investigated the role of NEGR1 in ischemic neuronal injury using primary cortical neuronal cultures derived from postnatal day 1 (P1) mice. Ischemia modeled by 6 hours of oxygen–glucose deprivation (OGD) followed by 18 hours reperfusion. NEGR1 expression modulated by AAV-mediated gene delivery, resulting in 1,8-fold increase in protein levels in overexpression group and 2-fold reduction in inhibition group. Neuronal morphology, cell survival, and DNA fragmentation assessed. Reduced NEGR1 expression significantly decreased neuronal survival following OGD, whereas NEGR1 overexpression enhanced neuronal viability and improved neuronal arborization. Consistently, DNA fragmentation significantly reduced in overexpression group. Western blot analysis revealed increased phosphorylation of AKT after OGD in neurons overexpressing NEGR1, indicating activation of pro-survival signaling pathways. Collectively, our findings demonstrate that NEGR1 critically modulates neuronal vulnerability to ischemic injury and promotes neuroprotection and structural recovery, potentially through AKT/ERK-dependent mechanisms. These results identify NEGR1 as a novel regulator of post-ischemic neuronal survival and plasticity, with potential implications for long-term stroke recovery. This study was supported by the Scientific and Technological Research Council of Türkiye (TÜBİTAK) under grant number 223S912.