Targeting Nurr1 With Amodiaquine Preserves Dendritic Spines and Cognitive Function After Chronic Cerebral Hypoperfusion
Background Nurr1, an orphan nuclear receptor that lacks an endogenous ligand, plays a key role in hippocampal function, synaptic plasticity, and cognitive processes. It is linked to various central nervous system diseases; however, its association with chronic cerebral hypoperfusion (CCH)-induced cognitive impairment remains unclear. This study investigated whether the Nurr1 agonist, amodiaquine (AQ), can enhance synaptic plasticity and alleviate cognitive deficits caused by CCH. Methods A CCH rat model was created using the bilateral common carotid arterial occlusion method, followed by a 2-week AQ treatment (20 mg/kg, every 12 h, through intraperitoneal injection). Learning and spatial memory were assessed using the Morris water maze (MWM), Y-maze, and object recognition tests. Cerebral blood flow (CBF) in the cortex and hippocampus was measured using arterial spin labeling (ASL) with 3.0T magnetic resonance imaging (MRI), and white matter fiber density was assessed using diffusion tensor imaging (DTI). Hippocampal neuron morphology and count were examined using Nissl and NeuN staining, while dendritic spine morphology and density in CA1 and CA3 hippocampal regions were analyzed using Golgi staining. Results Experiments with the water maze, Y-maze, and object recognition tests demonstrated that CCH rats treated with AQ exhibited improved long-term and short-term memory and spatial recognition compared to the control group, with benefits persisting after two and 6 weeks. MRI DTI sequences revealed that AQ reversed the decline in white matter fiber density observed in CCH model rats compared to the sham group. Golgi staining confirmed that AQ protected the dendritic spines of the neurons damaged in the CCH model. Conclusion Administrating Nurr1 agonist AQ demonstrated a sustained ameliorative effect on cognitive deficits in CCH rats. This effect is potentially mediated through the mitigation of hippocampal neuronal loss and improvement of dendritic spine integrity.
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