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

• Published in: CNS neuroscience & therapeutics 2017-10, Vol.23 (10), p.818-826
• Main Authors: Wang, Rui, Yin, Yi‐Xuan, Mahmood, Qaisar, Wang, Xiao‐Juan, Gao, Yin‐Ping, Gou, Guo‐Jing, Ahmed, Muhammad Masood, Kohji, Fukunag, Du, Yong‐Zhong, Han, Feng
• Format: Article
• Language: English
• Subjects: Amines; Animals; Biochemical markers; Ca2+/calmodulin-dependent protein kinase II; Calcium-binding protein; Calcium-Calmodulin-Dependent Protein Kinase Type 2 - metabolism; Calmodulin; Calmodulin - antagonists & inhibitors; calmodulin inhibitor; Carotid arteries; Carotid artery; Carotid Stenosis - drug therapy; Carotid Stenosis - physiopathology; Caspase; Caspase 1 - metabolism; Caspase-1; Cognitive ability; Cognitive Dysfunction - drug therapy; Cognitive Dysfunction - physiopathology; cognitive impairment; Dementia disorders; Dementia, Vascular - drug therapy; Dementia, Vascular - physiopathology; Disease Models, Animal; Drug Carriers; Drug therapy; Exploration; Hippocampus - drug effects; Hippocampus - metabolism; Indazoles - administration & dosage; inflammasome; Inflammasomes - drug effects; Inflammasomes - metabolism; Interleukin 1; Interleukin-1beta - metabolism; Latency; Male; Mice, Inbred C57BL; Micelles; Nitration; nitrosative stress; Nitrosative Stress - drug effects; Nitrosative Stress - physiology; NLR Family, Pyrin Domain-Containing 3 Protein - metabolism; Nootropic Agents - administration & dosage; Original; Phosphorylation; Piperazines - administration & dosage; Polysialic acid; Short term memory; Sialic Acids; Stenosis; Tyrosine; Vascular dementia
• ISSN: 1755-5930; 1755-5949
• DOI: 10.1111/cns.12726

Summary 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.