Rottlerin, BDNF, and the impairment of inhibitory avoidance memory
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ORIGINAL INVESTIGATION
Rottlerin, BDNF, and the impairment of inhibitory avoidance memory Wan-Ling Huang 1 & Ming-Heng Hsiung 1 & Wen Dai 1 & Sherry Shu-Jung Hu 1 Received: 30 April 2020 / Accepted: 23 October 2020 # Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract Rationale and objective As a eukaryotic elongation factor 2 kinase (eEF2K) inhibitor and a mitochondrial uncoupler, oncologists have extensively studied rottlerin. Neuroscientists, however, have accumulated scarce data on the role of rottlerin in affective and cognitive functions. Only two prior studies have, respectively, documented its antidepressant-like effect and how it impairs psychostimulant-supported memory. Whether or not rottlerin would affect aversive memory remains unknown. Hence, we sought to investigate the effects of rottlerin on aversive memory in the inhibitory avoidance (IA) task in mice. Materials and methods Male C57BL/6J mice were trained to acquire the IA task. Rottlerin (5 mg/kg, i.p. or 3 μg bilaterally in the hippocampus) or the vehicle was administered before footshock training (acquisition), after footshock training (consolidation), after the memory reactivation (reconsolidation), and before the test (retrieval) in the IA task. Results Systemic and intrahippocampal rottlerin impaired the acquisition, consolidation, and retrieval of IA memory, without affecting the reconsolidation process. Rottlerin (5 mg/kg, i.p.) induced a fast-onset and long-lasting increase in the brain-derived neurotrophic factor (BDNF) protein levels in the mouse hippocampus. Systemic injection of 7,8-dihydroxyflavone (7,8-DHF, 30 mg/kg), a BDNF tropomyosin receptor kinase B (TrkB) agonist impaired IA memory consolidation, and treatment with K252a (5 μg/kg), a Trk receptor antagonist, reversed the suppressing effect of rottlerin on IA memory consolidation. Conclusion Rottlerin impairs IA memory consolidation through the enhancement of BDNF signaling in the mouse hippocampus. Excessive brain BDNF levels can be detrimental to cognitive function. Rottlerin is likely to affect the original memory-associated neuroplasticity. Thus, it can be combined with exposure therapy to facilitate the forgetting of maladaptive aversive memory, such as post-traumatic stress disorder (PTSD). Keywords Rottlerin . Aversive memory . BDNF . Hippocampus . PTSD
Abbreviations IA Inhibitory avoidance BDNF Brain-derived neurotrophic factor eEF2K Eukaryotic elongation factor 2 kinase mTOR Mammalian target of rapamycin PKC Protein kinase C TrkB Tropomyosin receptor kinase B 7,8-DHF 7,8-Dihydroxyflavone DMSO Dimethyl sulfoxide PTSD Post-traumatic stress disorder Wan-Ling Huang and Ming-Heng Hsiung contributed equally to this work. * Sherry Shu-Jung Hu [email protected] 1
Cannabinoid Signaling Laboratory, Department of Psychology, National Cheng Kung University, 1 University Rd, Tainan 70101, Taiwan
Introduction Rottlerin (or mallotoxin) is involved in multiple signaling transduction pathways and exhibits a complex spectrum of pharmacology. It is a polyphen
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