NO-delivery Dinitrosyl Iron Complex (DNIC-1) Ameliorates the Cognitive Impairment in Neurodegenerative Disease Models 

Chih-Chieh Yu (余至傑)1, Tzai-Wen Chiu (曲在雯) 2,3, Tsai-Te Lu (魯才德) 4, Yun-Ming Wang (王雲銘) 1,2, and Chih-Fei Kao (高智飛) 1,2,3,*

1Institute of Molecular Medicine and Biochemical Engineering, 2Department of Biological Science and Technology, 3Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Taiwan

3Department of Biological Science and Technology, College of Biological Science and Technology, National Yang Ming Chiao Tung University, Hsinchu, Taiwan 4Institute of Biomedical Engineering, National Tsing Hua University, Taiwan

Neurodegenerative diseases are devastating disorder that results in progressive degeneration of the nervous system. Undoubtedly, the unmet need is the medical interventions that can effectively mitigate/prevent the progression of the disease. In this study, we characterized the neuroprotective capability of the Dinitrosyl Iron Complexes (DNIC-1), an inorganic and steady nitric oxide (NO)-releasing compound. Our findings indicate that DNIC-1 can effectively ameliorate abnormal protein aggregation and emerging brain cell death in polyQ disease model. Additionally, we observed that DNIC-1 can also ameliorate cognitive dysfunction in models of Huntington's disease, Alzheimer's disease (AD), and Parkinson's disease (PD). Furthermore, interferences of either the endogenous NO generation or the known NO-mediated signaling pathway markedly jeopardize the neuroprotective functions of DNIC-1. Mechanistic studies further suggest the treatment of DNIC-1 activates the ubiquitin-proteasome system, a major intracellular protein degradation system, in the target cells possibly through the up-regulation of multiple proteasomal genes. While our results imply that increased proteasome activity may compromise cognitive function and mitigate neurodegeneration, further experiments are needed to elucidate the precise role of the ubiquitin-proteasome system in DNIC-1-mediated neuroprotection. Together, our results suggest the DNIC-1 possesses the capability to confer protection to the cognitive impairment in distinct neurodegenerative disease models.