Inhibition of neuronal Kv7 channels ameliorates MK-801-induced cognitive dysfunction in mice via up-regulating NAMPT expression

Copyright © 2023 Elsevier B.V. All rights reserved..

PURPOSE: Abnormal energy metabolism affects cognitive function in schizophrenia. Nicotinamide phosphoribosyltransferase (NAMPT), as the rate-limiting enzyme of nicotinamide adenine dinucleotide (NAD+), is involved in energy metabolism by regulating the synthesis of NAD+. This study aims to clarify whether inhibition of Kv7 channels improves cognitive impairment by up-regulating NAMPT expression to increase the level of NAD+.

METHODS: The dominant negative pore mutation of KCNQ2 in transgenic mice was achieved by mutating residual 279-Gly to Ser (rQ2-G279S). A cognitive deficit model was established by injecting MK-801 into C57BL/6J mice. Y-maze and prepulse inhibition (PPI) tests were performed to evaluate cognitive ability. Gene and protein expression of NAMPT in the mouse hippocampus, cortex, and PC-12 cells were measured by qRT-PCR and Western blot. The level of NAD+ was measured by a WST-8 assay.

RESULTS: The Y-maze and PPI results showed that genetic or pharmacological inhibition of Kv7 channels by XE991 enhanced cognitive function in mice. Furthermore, inhibition of Kv7 channels increased the gene and protein expression of NAMPT and the level of NAD+ in the hippocampus and cortex of the above animal model. Similarly, XE991 treatment increased NAMPT expression and NAD+ levels in PC-12 cells. NAMPT inhibitor FK866 and Kv7 channel opener retigabine reversed the effects of XE991 in vivo and in vitro. In addition, XE991 increased pAMPK protein expression in PC-12 cells, while AMPK inhibitor Compound C counteracted the effect of XE991 on increasing NAMPT expression and NAD+ levels.

CONCLUSIONS: Suppression of Kv7 channel function improved spatial working memory and PPI impairment. This result may be achieved by activating AMPK to up-regulate NAMPT expression and thus increase NAD+ levels.

Medienart:

E-Artikel

Erscheinungsjahr:

2023

Erschienen:

2023

Enthalten in:

Zur Gesamtaufnahme - volume:814

Enthalten in:

Neuroscience letters - 814(2023) vom: 25. Sept., Seite 137471

Sprache:

Englisch

Beteiligte Personen:

Han, Shuo [VerfasserIn]
Zhuang, Dongpei [VerfasserIn]
Wang, Jing [VerfasserIn]
Ju, Chuanxia [VerfasserIn]

Links:

Volltext

Themen:

0U46U6E8UK
6LR8C1B66Q
AMP-Activated Protein Kinases
AMPK
Dizocilpine Maleate
EC 2.4.2.12
EC 2.7.11.31
Journal Article
Kv7 channels
Memory deficits
NAD
NAD(+)
NAMPT
Nicotinamide Phosphoribosyltransferase
Research Support, Non-U.S. Gov't

Anmerkungen:

Date Completed 25.09.2023

Date Revised 03.10.2023

published: Print-Electronic

Citation Status MEDLINE

doi:

10.1016/j.neulet.2023.137471

funding:

Förderinstitution / Projekttitel:

PPN (Katalog-ID):

NLM361710178