Calmodulin inhibitor ameliorates cognitive dysfunction via inhibiting nitrosative stress and NLRP3 signaling in mice with bilateral carotid artery stenosis

Autor:	Yi-Xuan Yin, Rui Wang, Xiao-Juan Wang, Yong-Zhong Du, Feng Han, Fukunag Kohji, Muhammad Masood Ahmed, Qaisar Mahmood, Guo-Jing Gou, Yin-Ping Gao
Rok vydání:	2017
Předmět:	Male 0301 basic medicine Indazoles Calmodulin Inflammasomes Interleukin-1beta Caspase 1 Hippocampus Pharmacology Piperazines 03 medical and health sciences 0302 clinical medicine Physiology (medical) NLR Family Pyrin Domain-Containing 3 Protein medicine Animals Carotid Stenosis Cognitive Dysfunction Pharmacology (medical) Amines Phosphorylation Vascular dementia Receptor Micelles Nootropic Agents Drug Carriers biology business.industry Dementia Vascular Inflammasome Original Articles medicine.disease Mice Inbred C57BL Disease Models Animal Psychiatry and Mental health 030104 developmental biology Nitrosative Stress Sialic Acids biology.protein Calcium-Calmodulin-Dependent Protein Kinase Type 2 Drug carrier business 030217 neurology & neurosurgery medicine.drug
Zdroj:	CNS Neuroscience & Therapeutics. 23:818-826
ISSN:	1755-5930
DOI:	10.1111/cns.12726
Popis:	Aims Vascular dementia (VaD) is a heterogeneous brain disorder for which there are no effective approved pharmacological treatments available. We aimed to evaluate the effect of calmodulin inhibitor, DY-9836, and its loaded nanodrug carrier system on cognitive impairment and gain a better understanding of the protective mechanisms in mice with bilateral carotid artery stenosis (BCAS). Results DY-9836 (0.5 or 1 mg/kg) or DY-9836 (0.25 mg/kg)-encapsulated polysialic acid-octadecylamine (PSA-ODA) micelles (PSA-ODA/DY) were given to BCAS mice for 4 weeks. Administration of DY-9836 or PSA-ODA/DY reduced escape latency in space exploration and working memory test compared with vehicle group. Vehicle-treated mice showed reduced phospho-CaMKII (Thr286/287) levels in the hippocampus, whereas partially restored by DY-9836 (1 mg/kg) or PSA-ODA/DY (0.25 mg/kg) treatment. In accordance with the pharmacological profile of DY-9836 observed during behavioral studies, experimental molecular and biochemical markers induced by BCAS, such as protein tyrosine nitration, Nod-like receptor protein 3 (NLRP3), caspase-1, and interleukin-1β, were reduced by DY-9836 and PSA-ODA/DY treatment. Conclusions These data disclose novel findings about the therapeutic potential of DY-9836, and its encapsulated nanodrug delivery system significantly enhanced the cognitive function via inhibitory effect on nitrosative stress and NLRP3 signaling in VaD mice.
Databáze:	OpenAIRE
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