RESUMO
Hyperexcitability of neuronal networks is central to the pathogenesis of Alzheimer's disease (AD). Pharmacological activation of Kv7 channels is an effective way to reduce neuronal firing. Our results showed that that pharmacologically activating the Kv7 channel with Retigabine (RTG) can alleviate cognitive impairment in mice without affecting spontaneous activity. RTG could also ameliorate damage to the Nissl bodies in cortex and hippocampal CA and DG regions in 9-month-old APP/PS1 mice. Additionally, RTG could reduce the Aß plaque number in the hippocampus and cortex of both 6-month-old and 9-month-old mice. By recordings of electroencephalogram, we showed that a decrease in the number of abnormal discharges in the brains of the AD model mice when the Kv7 channel was opened. Moreover, Western blot analysis revealed a reduction in the expression of the p-Tau protein in both the hippocampus and cortex upon Kv7 channel opening. These findings suggest that Kv7 channel opener RTG may ameliorate cognitive impairment in AD, most likely by reducing brain excitability.
Assuntos
Doença de Alzheimer , Precursor de Proteína beta-Amiloide , Carbamatos , Disfunção Cognitiva , Modelos Animais de Doenças , Hipocampo , Camundongos Transgênicos , Fenilenodiaminas , Animais , Fenilenodiaminas/farmacologia , Carbamatos/farmacologia , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Camundongos , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Hipocampo/efeitos dos fármacos , Hipocampo/metabolismo , Disfunção Cognitiva/tratamento farmacológico , Disfunção Cognitiva/metabolismo , Presenilina-1/genética , Masculino , Placa Amiloide/tratamento farmacológico , Placa Amiloide/patologia , Placa Amiloide/metabolismo , Córtex Cerebral/efeitos dos fármacos , Córtex Cerebral/metabolismo , Córtex Cerebral/patologia , Proteínas tau/metabolismo , Comportamento Animal/efeitos dos fármacos , Camundongos Endogâmicos C57BLRESUMO
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.