TY - JOUR
T1 - Blockade of voltage-gated potassium channels ameliorates diabetes-associated cognitive dysfunction in vivo and in vitro
AU - Yan, Wenhui
AU - Zhang, Meng
AU - Yu, Ye
AU - Yi, Xinyao
AU - Guo, Tingli
AU - Hu, Hao
AU - Sun, Qiang
AU - Chen, Mingxia
AU - Xiong, Huangui
AU - Chen, Lina
N1 - Publisher Copyright:
© 2019
PY - 2019/10
Y1 - 2019/10
N2 - The voltage-gated potassium (Kv) channel blockers tetraethylammonium (TEA) and 4-aminopyridine (4-AP) have shown beneficial effects on some neurological disorders. But their involvements in diabetes-associated cognitive dysfunction are still unknown. The present study aims to investigate whether the blockade of Kv channels by TEA and 4-AP alleviate cognitive decline in diabetes. In vivo, the effects of TEA and 4-AP (5 mg/kg body weight per day, 1 mg/kg body weight per day intraperitoneal injected for 4 weeks, respectively) were investigated in streptozotocin-induced C57BL/6 diabetic mice. In vitro study, we investigated the effects of TEA and 4-AP on the high glucose (HG) -stimulated primary cortical neurons. The results showed that TEA and 4-AP ameliorated the cognitive decline of diabetic mice in the Morris water maze test, improved the ultrastructure of pancreatic β cells, hippocampal neurons and synapses, decreased oxidative stress, modulated apoptosis-related proteins, and activated phosphatidylinositol 3-kinase (PI3K)/ Protein kinase-B (PKB or Akt) signaling pathway. In the HG-stimulated primary cultured cortical neurons, TEA and 4-AP increased the cell viability, decreased oxidative stress; prevented apoptosis and activated PI3K/Akt signaling pathway. Additionally, the PI3K inhibitor LY294002 partially abolished the effects of TEA and 4-AP. These findings indicate that the blockade of Kv channels by TEA and 4-AP ameliorates the diabetes-associated cognitive dysfunction via PI3K/Akt pathway, suggesting that targeting Kv channels could be a promising strategy for the treatments of cognitive impairments in diabetes.
AB - The voltage-gated potassium (Kv) channel blockers tetraethylammonium (TEA) and 4-aminopyridine (4-AP) have shown beneficial effects on some neurological disorders. But their involvements in diabetes-associated cognitive dysfunction are still unknown. The present study aims to investigate whether the blockade of Kv channels by TEA and 4-AP alleviate cognitive decline in diabetes. In vivo, the effects of TEA and 4-AP (5 mg/kg body weight per day, 1 mg/kg body weight per day intraperitoneal injected for 4 weeks, respectively) were investigated in streptozotocin-induced C57BL/6 diabetic mice. In vitro study, we investigated the effects of TEA and 4-AP on the high glucose (HG) -stimulated primary cortical neurons. The results showed that TEA and 4-AP ameliorated the cognitive decline of diabetic mice in the Morris water maze test, improved the ultrastructure of pancreatic β cells, hippocampal neurons and synapses, decreased oxidative stress, modulated apoptosis-related proteins, and activated phosphatidylinositol 3-kinase (PI3K)/ Protein kinase-B (PKB or Akt) signaling pathway. In the HG-stimulated primary cultured cortical neurons, TEA and 4-AP increased the cell viability, decreased oxidative stress; prevented apoptosis and activated PI3K/Akt signaling pathway. Additionally, the PI3K inhibitor LY294002 partially abolished the effects of TEA and 4-AP. These findings indicate that the blockade of Kv channels by TEA and 4-AP ameliorates the diabetes-associated cognitive dysfunction via PI3K/Akt pathway, suggesting that targeting Kv channels could be a promising strategy for the treatments of cognitive impairments in diabetes.
KW - 4-Aminopyridine
KW - Apoptosis
KW - Diabetes-associated cognitive dysfunction
KW - Hippocampus
KW - Oxidative stress
KW - Tetraethylammonium
UR - http://www.scopus.com/inward/record.url?scp=85067870921&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85067870921&partnerID=8YFLogxK
U2 - 10.1016/j.expneurol.2019.112988
DO - 10.1016/j.expneurol.2019.112988
M3 - Article
C2 - 31254519
AN - SCOPUS:85067870921
SN - 0014-4886
VL - 320
JO - Experimental Neurology
JF - Experimental Neurology
M1 - 112988
ER -