Subclinical Doses of ATP-Sensitive Potassium Channel Modulators Prevent Alterations in Memory and Synaptic Plasticity Induced by Amyloid-β

Abstract

In addition to coupling cell metabolism and excitability, ATP-sensitive potassium channels (KATP) are involved in neural function and plasticity. Moreover, alterations in KATP activity and expression have been observed in Alzheimer's disease (AD) and during amyloid-β (Aβ)-induced pathology. Thus, we tested whether KATP modulators can influence Aβ-induced deleterious effects on memory, hippocampal network function, and plasticity. We found that treating animals with subclinical doses (those that did not change glycemia) of a KATP blocker (Tolbutamide) or a KATP opener (Diazoxide) differentially restrained Aβ-induced memory deficit, hippocampal network activity inhibition, and long-term synaptic plasticity unbalance (i.e., inhibition of LTP and promotion of LTD). We found that the protective effect of Tolbutamide against Aβ-induced memory deficit was strong and correlated with the reestablishment of synaptic plasticity balance, whereas Diazoxide treatment produced a mild protection against Aβ-induced memory deficit, which was not related to a complete reestablishment of synaptic plasticity balance. Interestingly, treatment with both KATP modulators renders the hippocampus resistant to Aβ-induced inhibition of hippocampal network activity. These findings indicate that KATP are involved in Aβ-induced pathology and they heighten the potential role of KATP modulation as a plausible therapeutic strategy against AD.

Single amyloid‐beta injection exacerbates 4‐aminopyridine‐induced seizures and changes synaptic coupling in the hippocampus

“…As previously shown, a single Aβ injection does not induce a significant effect on CA1‐Schaffer collateral synaptic transmission, as classically assessed through the I/O relationship (Salgado‐Puga et al, ), which is similar to the lack of effect of the long‐term presence of Aβ in basal synaptic transmission (Chapman et al, ; Giacchino, Criado, Games, & Henriksen, ; Peña et al, ; Sun & Alkon, ). However, like other reports, we also found indirect evidence of a decrease in synaptic release probability (i.e., increase in PPR; Peña et al, ; Peña et al, ) and a decrease in CA1‐Schaffer collateral coupling (i.e., reduced fEPSP slope/fEPSP area relationship) (Hsieh et al, ; Jo et al, ; Kurudenkandy et al, ; Pourbadie et al, ; Wang et al, ), which may contribute to the induction of hyperexcitability.…”

“…The arrangement of electrodes and screws were fixed to the skull with dental acrylic. The animals were allowed to recover from the surgical procedure, and the incubation time for the Aβ pre‐treatment was set to 3 weeks before any behavioral or electrophysiological evaluation (Salgado‐Puga, Rodríguez‐Colorado, Prado‐Alcalá, & Peña‐Ortega, ).…”

“…Three weeks after Aβ or F12m were administered (Salgado‐Puga et al, ), the group of animals that were not implanted with any electrode were anesthetized with an intraperitoneal injection of sodium pentobarbital (50 mg/kg) and perfused transcardially with a cold, protective saline solution containing 238 mM sucrose, 3 mM KCl, 2.5 mM MgCl 2 , 25 mM NaHCO 3 , and 30 mM D‐glucose, pH 7.4 and bubbled with carbogen (95% O 2 and 5% CO 2 ). Then, animals were decapitated, and their brains were removed and dissected in ice‐cold artificial cerebrospinal fluid (aCSF) containing 119 mM NaCl, 3 mM KCl, 1.5 mM CaCl 2 , 1 mM MgCl 2 , 25 mM NaHCO 3 , and 30 mM D‐glucose, pH 7.4 and bubbled with carbogen.…”

Diazoxide affects mitochondrial bioenergetics by the opening of mKATP channel on submicromolar scale

“…High sensitivity of mK ATP -channel to diazoxide in the absence of ATP observed in this study allows us hypothesize that under pathophysiological states and conditions marked by ATP deficiency (such as hypoxia and ischemia) affinity of mK ATP -channel to this drug can increase several times, which might contribute to the high effectiveness of diazoxide in cardio-and neuroprotection. This may be of relevance for health care practice, based on the report of successful application of sub-maximal doses of diazoxide for neuroprotection published in the literature [40].…”

Direct and Off-Target Effects of ATP-Sensitive Potassium Channels Opener Diazoxide

“…It appears that lowering of commonly used pharmacological doses of DZ and other KCOs [67] would help discriminate between therapeutic effects of mK ATP channel opening and those caused by off-target effects of DZ Nevertheless, under appropriate conditions bioenergetic effects produced by DZ on isolated mitochondria could be ascribed to the opening of mK ATP channel showing DZ to be a suitable pharmacological tool to assess physiological diversity of mK ATP channel functions.…”