Chronic administration of theobromine inhibits mTOR signal in rats

Abstract

Theobromine is a caffeine derivative and the primary methylxanthine in Theobroma cacao. We have shown previously that theobromine inhibits the Akt-mammalian target of rapamycin (mTOR) signal in vitro. In this study, we investigated whether orally administered theobromine could inhibit mTOR activity in rats. mTOR is phosphorylated by Akt. Thus, the level of phosphorylated mTOR was used as an index of mTOR activity. Male Wistar rats were divided into two groups. The control group (CN) was fed a normal diet, while the theobromine group (TB) was fed a diet supplemented with 0.05% theobromine for 40 days.We measured body-weights and tissue weights, food and water intake, blood count, concentrations of theobromine in the plasma, liver and brain, and the levels of phosphorylated mTOR in the liver and brain. Orally administered theobromine did not affect the body-weights and tissue weights, food and water intake, and blood count as determined by comparison with levels in rats that were fed standard chow. Theobromine was detected in the plasma, liver and brain obtained from TB rats, but was not detected in tissues obtained from CN rats. The phosphorylated mTOR levels in the liver and brain were significantly lower in TB rats than in CN rats. The results suggest that oral theobromine inhibits mTOR signalling in vivo. K E Y W O R D S4E-BP1, Akt, cerebral cortex, liver, mTOR, theobromine

Theobromine Improves Working Memory by Activating the CaMKII/CREB/BDNF Pathway in Rats

“…In our previous study, we confirmed that mice fed TB performed better on learning tasks and TB acted as a phosphodiesterase (PDE) inhibitor [9,10], by enhancing the cAMP/cAMP-response element-binding protein (CREB)/brain-derived neurotrophic factor (BDNF) pathway [7]. We also confirmed that TB supplemented chow-inhibited mTOR signaling in the brain and liver [11]. In the current experiment, we want to assess the effects of TB on rats, using a prolonged feeding period of 73 days, and to check whether different types of memory functions are affected by a variety of behavior experiments.…”

“…To exert material effects against cognitive disorders, TB must be taken up in the brain from the blood by crossing over the BBB. Our previous data showed that TB was detectable in rat plasma and the brain after 30 and 40 days of TB ingestion, and gradually increased in a time-dependent manner [11]. The concentration of TB in rat brain and plasma after 40 days of TB ingestion might have been sufficient to produce significant pharmacological effects, as described in [4,7,47].…”

“…Interestingly, Yabuki et al reported that deficits in working memory in ADHD model rats and spontaneously hypertensive rats (SHR), were closely associated with dysfunction of CaMKII in the mPFC, but not in the hippocampus [91]. Since the accumulation of TB in the cortex has been clearly detected [7,11], neurodegenerative and/or neurodevelopmental disorders, associated with these regions, might be beneficent from the oral administration of TB. Moreover, this study demonstrated that chronic oral administration of TB did not cause any adverse health effects in rats.…”

“…For instance, caffeine and TB can pass through BBB and block cell surface adenosine receptors, which distributed widely throughout cortical regions [97]. TB and caffeine also act as PDE inhibitor that increases in intracellular cAMP level [7,11,97]. Moreover, these reagents are known to affect Ca 2+ release from intracellular stores of the brain [97].…”

Sub-Chronic Consumption of Dark Chocolate Enhances Cognitive Function and Releases Nerve Growth Factors: A Parallel-Group Randomized Trial

“…Theobromine is the primary methylxanthine found in products made from cacao (Theobroma cacao) [12]. We previously reported that theobromine acts as a phosphodiesterase inhibitor that increases intracellular cyclic adenosine monophosphate (cAMP) [13,14] levels and permeates through the blood–brain barrier [14,15]. Furthermore, cAMP signaling essentially influences the brain mechanism that mediates neural wiring and cognitive processes [16,17,18].…”