Abstract
Vascular dementia (VD) is characterized with vascular cognitive impairment (VCI), which currently has few effective therapies in clinic. Neuronal damage and white matter injury are involved in the pathogenesis of VCI. Citicoline has been demonstrated to exhibit neuroprotection and neurorepair to improve cognition in cerebrovascular diseases. Nicotinamide adenine dinucleotide (NAD+)-dependent sirtuin (SIRT) signaling pathway constitutes a strong intrinsic defense system against various stresses including neuroinflammation in VCI. Our hypothesis is that the combined use of citicoline and the precursor of NAD+, nicotinamide mononucleotide (NMN), could enhance action on cognitive function in VCI. We investigated the synergistic effect of these two drugs in the rat model of VCI by bilateral common carotid artery occlusion (BCCAO). Citicoline significantly enhanced neurite outgrowth in Neuro-2a cells, and the combination of citicoline and NMN remarkably induced neurite outgrowth in Neuro-2a cells and primary cortical neuronal cells with an optimal proportion of 4:1. In the rat model of BCCAO, when two drugs in combination of 160 mg/kg citicoline and 40 mg/kg NMN, this combination administrated at 7 days post-BCCAO significantly improved the cognitive impairment in BCCAO rats compared with vehicle group by the analysis of the Morris water maze and the novel object recognition test. This combination also decreased microglial activation and neuroinflammation, and protected white matter integrity indicated by the increased myelin basic protein (MBP) expression through activation of SIRT1/TORC1/CREB signaling pathway. Our results suggest that the combination of citicoline and NMN has a synergistic effect for the treatment of VD associated with VCI.
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Data Availability
The data that support the findings are available from the corresponding author upon reasonable request.
Abbreviations
- AD:
-
Alzheimer’s disease
- ANOVA:
-
One-way analysis variance
- BCCAO:
-
Bilateral common carotid artery occlusion
- BDNF:
-
Brain-derived neurotrophic factor
- CBF:
-
Cerebral blood flow
- DEPC:
-
Diethyl pyrocarbonate
- DMEM/F12:
-
Dulbecco’s Modified Eagle Medium/F12
- DMSO:
-
Dimethyl sulfoxide
- FBS:
-
Fatal bovine serum
- IBA-1:
-
Ionized calcium binding adapter molecule 1
- IL-10:
-
Interleukin-10
- IL-1β:
-
Interleukin-1 beta
- IL-6:
-
Interleukin-6
- LDH:
-
Lactate dehydrogenase
- MBP:
-
Myelin basic protein
- MEM:
-
Minimum essential medium
- MWM:
-
Morris water maze
- NAD+ :
-
Nicotinamide adenine dinucleotide+
- NADH:
-
Nicotinamide adenine dinucleotide
- NMN:
-
Nicotinamide mononucleotide
- PBS:
-
Phosphate buffer saline
- PLL:
-
Poly-l-Lysine
- PSD95:
-
Postsynaptic density protein-95
- PVDF:
-
Polyvinylidene fluoride
- qRT-PCR:
-
Real-time quantitative polymerase chain reaction
- SEM:
-
Standard error of mean
- SIRT1:
-
Sirtuin 1
- TNF-α:
-
Tumor necrosis factor-alpha
- TORC1:
-
Transducer of regulated CREB activity 1
- VD:
-
Vascular dementia
- VCI:
-
Vascular cognitive impairment
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Funding
This work was supported by the National Natural Science Foundation of China (82174010, 81973512), the Natural Science Foundation of Zhejiang Province (LY18H310009), the Research project of Health Commission of Zhejiang Province (2018KY653), the Biomedical and Health Industry Development Support Science and Technology Project of Hangzhou (2022WJC139), the Major Science and Technology Plan Project of Xiaoshan (2020310), and the Science and Technology Plan Project of Hangzhou (20201231Y118).
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All authors listed contributed immensely to this study. NZ and XZ performed the experiments and wrote the paper. NZ, XZ, LX, XG, and LT performed animal experiments, in vitro experiments, immunostaining and molecular biology experiments, and analyzed the data. TP and GJ designed the research, discussed the results and reviewed the manuscript. All authors read and approved the final manuscript.
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Zhao, N., Zhu, X., Xie, L. et al. The Combination of Citicoline and Nicotinamide Mononucleotide Induces Neurite Outgrowth and Mitigates Vascular Cognitive Impairment via SIRT1/CREB Pathway. Cell Mol Neurobiol 43, 4261–4277 (2023). https://doi.org/10.1007/s10571-023-01416-7
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DOI: https://doi.org/10.1007/s10571-023-01416-7