Low-Intensity Focused Ultrasound Ameliorates Cisplatin-Induced Cognitive Impairment by Attenuating Hippocampal Neuroinflammation and Enhancing Synaptic Plasticity in Rats

Background

Platinum can cause chemotherapy-related cognitive impairment. Low-intensity focused ultrasound (LIFUS) is a promising noninvasive physical stimulation method with a unique advantage in neurological rehabilitation. We aimed to investigate whether LIFUS can alleviate cisplatin-induced cognitive impairment in rats and explore the related neuropathological mechanisms.

Methods

After confirming the target position for LIFUS treatment in 18 rats, 64 rats were randomly divided into four groups: control, model, sham, and LIFUS groups. Before and after LIFUS treatment, detailed biological behavioral assessments and magnetic resonance imaging were performed. Finally, the rats were euthanized, and relevant histopathological and molecular biological experiments were conducted and analyzed.

Results

In the Morris water maze, the model group showed fewer platform crossings (1.25 ± 0.93 vs. 5.69 ± 1.58), a longer escape latency (41.65 ± 36.55 s vs. 6.38 ± 2.11 s), and a lower novel object recognition index (29.77 ± 11.83 vs. 83.69 ± 5.67) than the control group. LIFUS treatment improved these metrics, with more platform crossings (3.13 ± 0.34), a higher recognition index (65.58 ± 8.71), and a shorter escape latency (6.45 ± 2.27 s). Longitudinal analysis of the LIFUS group further confirmed these improvements. Neuroimaging revealed significant differences in diffusion tensor imaging metrics of specific brain regions pre- and post-LIFUS. Moreover, neuropathology showed higher dendritic spine density, less myelin loss, fewer apoptotic cells, more synapses, and less mitochondrial autophagy after LIFUS treatment. The neuroimaging indicators were correlated with behavioral improvements, highlighting the potential of LIFUS for alleviating cognitive impairment (as demonstrated through imaging and analysis). Our investigation of the molecular biological mechanisms revealed distinct protein expression patterns in the hippocampus and its subregions. In the model group, glial fibrillary acidic protein (GFAP) and ionized calcium-binding adaptor molecule 1 (IBA1) expression levels were elevated across the hippocampus, whereas neuronal nuclei (NeuN) expression was reduced. Subregional analysis revealed higher GFAP and IBA1 and lower NeuN, especially in the dentate gyrus subregion. Moreover, positive cell areas were larger in the cornu ammonis (CA)1, CA2, CA3, and dentate gyrus regions. In the CA2 and CA3, significant differences among the groups were observed in GFAP-positive cell counts and areas, and there were variations in NeuN expression.

Conclusions

Our results suggest that LIFUS can reverse cisplatin-induced cognitive impairments. The neuroimaging findings were consistent with the behavioral and histological results and suggest a neuropathological basis that supports further research into the clinical applications of LIFUS. Furthermore, LIFUS appeared to enhance the plasticity of neuronal synapses in the rat hippocampus and reduce hippocampal inflammation. These findings highlight the clinical potential of LIFUS as an effective, noninvasive therapeutic strategy and monitoring tool for chemotherapy-induced cognitive deficits.