The KCNH3 inhibitor ASP2905 shows potential in the treatment of attention deficit/hyperactivity disorder

Abstract

N-(4-fluorophenyl)-N'-phenyl-N"-(pyrimidin-2-ylmethyl)-1,3,5-triazine-2,4,6-triamine [ASP2905] is a potent and selective inhibitor of the potassium voltage-gated channel subfamily H member 3 (KCNH3) that was originally identified in our laboratory. KCNH3 is concentrated in the forebrain, and its overexpression in mice leads to cognitive deficits. In contrast, Kcnh3 knockout mice exhibit enhanced performance in cognitive tasks such as attention. These data suggest that KCNH3 plays important roles in cognition. Here we investigated the neurochemical and neurophysiological profiles of ASP2905 as well as its effects on cognitive function, focusing on attention. ASP2905 (0.0313 and 0.0625 mg/kg, po) improved the latent learning ability of mice, which reflects attention. Microdialysis assays in rats revealed that ASP2905 increased the efflux of dopamine and acetylcholine in the medial prefrontal cortex (0.03, 0.1 mg/kg, po; 0.1, 1 mg/kg, po, respectively). The activities of these neurotransmitters are closely associated with attention. We used a multiple-trial passive avoidance task to investigate the effects of ASP2905 on inattention and impulsivity in juvenile stroke-prone spontaneously hypertensive rats. ASP2905 (0.1 and 0.3 mg/kg, po) significantly prolonged cumulative latency as effectively as methylphenidate (0.1 and 0.3 mg/kg, sc), which is the gold standard for treating ADHD. Further, ASP2905, amphetamine, and methylphenidate significantly increased the alpha-band power of rats, suggesting that ASP2905 increases arousal, which is a pharmacologically important activity for treating ADHD. In contrast, atomoxetine and guanfacine did not significantly affect power. Together, these findings suggest that ASP2905, which acts through a novel mechanism, is as effective for treating ADHD as currently available drugs such as methylphenidate.

Fig 1. Effect of ASP2905 on the finding latency of mice in the water finding task.

Data are expressed as the mean ± SEM of finding latency. The numbers in parentheses indicate the number of mice in each group. *p<0.05, **p<0.01 vs vehicle group (Dunnett’s test).

Fig 2

Effect of ASP2905 (A) and methylphenidate (B) on cumulative latency in the 5-trial passive avoidance task administered to juvenile SHRSP. Cumulative latency data are expressed as the mean ± SEM. The numbers in parentheses indicate the number of rats in each group. *p <0.05, **p <0.01 vs the vehicle-treated SHRSP group (Dunnett’s test); ^##p <0.01 vs the WKY group (Student t test).

Fig 3

Effects of ASP2905 on the extracellular levels of DA (A, B) and ACh (C, D) in the rat mPFC. Data are expressed as the mean ± SEM of percentages of the baseline (A and C) and AUCs 60 min after administration of ASP2905 (B and D). The numbers in parentheses indicate the number of rats in each group. For DA, animals with basal levels differing by ± 10% from the mean were excluded from the analysis. The IPHC values for ACh were compensated by the IPHC value of the third point acquired before administering ASP2905, and the value of ACh was corrected using the compensated value of IPHC. When the basal level differed by >30% from the mean, the data for that animal were excluded from the analysis. *p<0.05, **p<0.01 vs vehicle-treated group (Dunnett’s test). A) Extracellular levels of DA after administration of ASP2905. B) AUCs of the levels of DA in the mPFC 60 min after administration of ASP2905. C) Extracellular ACh levels after administration of ASP2905. D) AUCs of the levels of Ach in the mPFC 60 min after administration of ASP2905.

Fig 4

Effect of ASP2905 (A), amphetamine (B), methylphenidate (C), atomoxetine (D), and guanfacine (E) on alpha power in rats. Alpha power is quantified as an AUC of the difference between powers before and after administering a drug. Data are expressed as the mean ± SEM. The numbers in parentheses indicate the number of rats in each group. *p<0.05, **p<0.01 vs vehicle-treated group (Dunnett’s test).

Fig 5. EEG spectra acquired before and after treatment of rats with ASP2905, amphetamine, or methylphenidate.

Representative EEG spectra. Each graph indicates EEG power spectra from 1 Hz to 13 Hz of each rat before and after treatment with A) ASP2905 (10 mg/kg po), B) amphetamine (3 mg/kg sc), and C) methylphenidate (3 mg/kg sc).