title: Novel spiroimidazopyridine derivative SAK3 improves methimazole-induced cognitive deficits in mice.
abstract: Methimazole (MMI) is a first-line therapy used to manage hyperthyroidism and Graves' disease. Despite its therapeutic benefit, chronic MMI administration can lead to hypothyroidism and perturb brain homeostasis in patients, resulting in neuropsychiatric disorders such as depression and cognitive dysfunction. We recently developed the spiroimidazopyridine derivative SAK3 as cognitive enhancer; however, mechanisms underlying its activity remained unclear. Here, we show that SAK3 potentially improves cognitive impairment seen following MMI-induced hypothyroidism. Twenty-four hours after MMI (75 mg/kg, i.p.) treatment, we administered SAK3 (0.1, 0.5 and 1 mg/kg, p.o.) to mice daily for 7 days. MMI treatment alone disrupted olfactory bulb (OB) glomerular structure, as assessed by staining with the olfactory marker protein (OMP), reduced the number of choline acetyl transferase (ChAT)-immunoreactive neurons in medial septum (MS), and significantly impaired cognition. SAK3 (0.5 and 1 mg/kg, p.o.) administration significantly restored the number of cholinergic MS neurons in MMI-treated mice, and SAK3 treatment at a higher dose significantly improved cognitive deficits seen in MMI-treated control mice. Overall, our study suggests that SAK3 treatment could antagonize such impairment in patients with hypothyroidism.
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Husain
authors.initials: H
authors.lastname: Noreen
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Yabuki
authors.affiliation: Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan. Electronic address: kfukunaga@m.tohoku.ac.jp.
authors.forename: Kohji
authors.initials: K
authors.lastname: Fukunaga
mesh_terms: D000818:Animals; D003072:Cognition Disorders / Q000139:chemically induced* / Q000188:drug therapy* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D007037:Hypothyroidism / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D018782:Maze Learning / Q000187:drug effects / Q000502:physiology; D008713:Methimazole / Q000633:toxicity*; D051379:Mice; D011725:Pyridines / Q000494:pharmacology / Q000627:therapeutic use*; D011897:Random Allocation; D013141:Spiro Compounds / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D007093:Imidazoles; D011725:Pyridines; C000622095:SAK3 compound; D013141:Spiro Compounds; C000619660:imidazopyridine; D008713:Methimazole
keywords: Cognitive function; Hypothyroidism; Methimazole (MMI); Olfactory sensory neurons (OSNs); SAK3