Study of the Mechanism by Which MSCs Combined with LITUS Treatment Improve Cognitive Dysfunction Caused by Traumatic Brain Injury

Abstract

Traumatic brain injury (TBI) substantially affects the quality of life of patients, and an effective therapy for TBI is unavailable. Previous studies have shown that mesenchymal stem cells (MSCs) and low-intensity transcranial ultrasound (LITUS) are effective treatments for neurological damage, the inflammatory response, edema and cognitive impairment caused by TBI. However, researchers have not clearly determined whether the combination of the two exerts a synergistic effect. In this study, a rat TBI model was established using the controlled cortical impact (CCI) method, neurological function was assessed by determining the rat modified neurological score (mNSS), and cognitive function was assessed using the Y-maze. Pathological changes in the injured tissue and hippocampus were observed using hematoxylin-eosin (HE) staining, and immunohistochemistry (IHC) and Western blotting were performed to detect the expression of Nestin, neuron-specific enolase (NSE), glial fibrillary acidic protein (GFAP), growth-associated protein-43 (GAP-43), postsynaptic density protein (PSD-95), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-α (TNF-α), and aquaporin-4 (AQP-4), and real-time fluorescence quantitative polymerase chain reaction (RT–PCR) was performed to detect the expression of the GAP-43, PSD-95, BDNF, TNF-α, and AQP-4 mRNAs to investigate whether MSC combined with LITUS exerts a synergistic therapeutic effect on cognitive dysfunction caused by TBI and the possible mechanisms involved. Rats exhibited cognitive dysfunction 28 days after TBI, and MSC combined with LITUS treatment ameliorated the cognitive deficits caused by TBI by increasing Nestin, NSE, GAP-43, PSD-95, and BDNF expression and attenuated the inflammatory response and edema caused by TBI by reducing TNF-α and AQP-4 expression. Based on these results, MSC combined with LITUS treatment exerts a synergistic therapeutic effect on TBI, and its mechanism may be related to ameliorating the spatial learning memory impairment caused by TBI, promoting neuronal proliferation and differentiation, and attenuating the inflammatory response and edema. MSC combined with LITUS treatment represents a new approach for the clinical treatment of patients with TBI.

Note:
Funding Information: This research was funded by grants from the National Natural Science Foundation (81871029 and 61901100) and Hebei Science and Technology Project (172 77718D and 199477142G).

Declaration of Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Ethics Approval Statement: The animal study was reviewed and approved by the Medical Ethics Committee of First Hospital of Qinhuangdao in China (ID Number: 20140018).

Keywords: Traumatic brain injury, Mesenchymal stem cells, Low-intensity transcranial ultrasound, Cognitive dysfunction, Combined therapy