Role of Adenosine A<sub>2A</sub>Receptors in the Central Fatigue of Neurodegenerative Diseases

Alves, Ana Cristina de Bem; Bristot, Viviane José de Oliveira; Limana, Mirieli Denardi; Speck, Ana Elisa; Barros, Leonardo; Solano, Alexandre Francisco; Aguiar, Aderbal S.

doi:10.1089/caff.2019.0009

Cited by 11 publications

(5 citation statements)

References 215 publications

(273 reference statements)

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“…Caffeine also improves performance expectations 70 , cognitive and executive functions 65 , 71 – 73 , and vigor 74 in exercising subjects. The contribution of the CNS-mediated effects on exercise-induced fatigue conceptualizes central fatigue 24 , 28 , 51 , 52 , 68 , 75 . Caffeine reduces saccadic eyes fatigue 24 , 28 ,also, the cortical silence of fatigued ankle muscles 51 , 52 .…”

Section: Discussionmentioning

confidence: 99%

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Aguiar

Speck

Canas

et al. 2020

Sci Rep

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Caffeine is one of the most used ergogenic aid for physical exercise and sports. However, its mechanism of action is still controversial. The adenosinergic hypothesis is promising due to the pharmacology of caffeine, a nonselective antagonist of adenosine A 1 and A 2A receptors. We now investigated A 2A R as a possible ergogenic mechanism through pharmacological and genetic inactivation. Forty-two adult females (20.0 ± 0.2 g) and 40 male mice (23.9 ± 0.4 g) from a global and forebrain A 2A R knockout (KO) colony ran an incremental exercise test with indirect calorimetry (Vȯ 2 and RER). We administered caffeine (15 mg/kg, i.p., nonselective) and SCH 58261 (1 mg/kg, i.p., selective A 2A R antagonist) 15 min before the open field and exercise tests. We also evaluated the estrous cycle and infrared temperature immediately at the end of the exercise test. Caffeine and SCH 58621 were psychostimulant. Moreover, Caffeine and SCH 58621 were ergogenic, that is, they increased Vȯ 2 max, running power, and critical power, showing that A 2A R antagonism is ergogenic. Furthermore, the ergogenic effects of caffeine were abrogated in global and forebrain A 2A R KO mice, showing that the antagonism of A 2A R in forebrain neurons is responsible for the ergogenic action of caffeine. Furthermore, caffeine modified the exercising metabolism in an A 2A R-dependent manner, and A 2A R was paramount for exercise thermoregulation. The natural plant alkaloid caffeine (1,3,7-trimethylxantine) is one of the most common ergogenic substances for physical activity practitioners and athletes 1-10. Caffeine increases endurance 1,8-12 , intermittent 7,13,14 and resistance 4,15 exercise in humans. In rodents, its ergogenic effects are conserved because caffeine increases running time on the treadmill at constant 16,17 and accelerated speeds 18,19. Sports sciences promote nonselective phosphodiesterase (PDE) inhibition 7,8 and increased calcium mobilization 2,7,8 as mechanisms for these ergogenic effects. However, the primary pharmacological effect of caffeine is the nonselective antagonism of adenosine A 1 and A 2A receptors (A 1 R, A 2A R) 20-23. Adenosine can act as an inhibitory modulator of the Central Nervous System (CNS) associated with tiredness and drowsiness 24-29. During exercise, circulating ADP/AMP/adenosine levels increase due to ATP hydrolysis 30,31. However, there is still no substantial evidence on the role of adenosine in exercise-induced fatigue. It is just known that the nonselective A 1 R and A 2A R agonist 5′-(N-ethylcarboxamido)adenosine (NECA), injected into the rat brain, abolishes the ergogenic effects of caffeine 16. Since there is increasing evidence that the adenosine modulation system critically controls allostasis 29 and A 2A R have a crucial role in the ability of caffeine to normalize brain function 30, we hypothesized that caffeine decreases fatigue during exercise through antagonism of A 2A R in the CNS. We combined the use of pharmacology (SCH 58261 and caffeine) and transgenic mice with tissue-selective deletion ...

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Section: Discussionmentioning

confidence: 99%

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Aguiar

Speck

Canas

et al. 2020

Sci Rep

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“…Fatigue is a symptom at rest in many NDs such as AD, PD, MSA, ALS and MS ( Chaudhuri and Behan, 2004 ) ( Alves et al, 2019 ). For instance, fatigue is the most common and disabling symptoms in MS, occurring in 50–83% of patients ( Fiest et al, 2016 ).…”

Section: Resultsmentioning

confidence: 99%

Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases

Tyler

2023

IBRO Neuroscience Reports

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“…Athletes are more resistant to high blood lactate concentrations, pain, and fatigue [2,7]. Psychological factors are associated with this performance, such as improved motivation and experience [4–6,9,57]. Moderate doses of caffeine (3–6 mg/kg) decrease RPE in athletes [4–6,9].…”

Section: Discussionmentioning

confidence: 99%

“…Effort perception is a brain function; neurophysiology involves central fatigue and diminished cortical arousal [58], increased cortical activity during movement in the primary motor and supplementary movement areas [59], and increased activation of the temporal and insular cortex [60]. This evidence retrieves the CNS’s role in the development of central fatigue [24,27,28,33–35,57,61–64]. Here, the effect of caffeine on RPE and EMG reinforces this idea.…”

Section: Discussionmentioning

confidence: 99%

Caffeine decreases neuromuscular fatigue in the lumbar muscles – a randomized blind study

Cardoso

Nery

Gonçalves³

et al. 2020

Preprint

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Background Ergogenic evidence for caffeine is robust in sports and isolated limb tasks. Our objective was to evaluate a possible ergogenic effect on postural muscles, still unknown, through the Biering-Sorensens lumbar extension test. Methods A double-blind, controlled placebo, crossover study. Fifty-one healthy, physically inactive male subjects (18-25 years) with average body mass (BMI 18.5-24.9 kg/m2) were recruited. The subjects received oral caffeine (6 mg/kg) and saline (0.3%) in two cross-evaluations separated by one week. The primary outcome was the time in the Biering-Sorensen test after 1 hour of treatment. The secondary outcomes were peak lumbar extension force, rating of perceived exertion, EMGs median frequency and muscle recruitment of multifidus spinae and transversalis/interne oblique muscles, and cardiovascular variables (heart rate and blood pressure). Results 27 subjects were blindly treated with caffeine and saline. Caffeine was ergogenic during the Biering-Sorensen test. It increased lumbar extension time (d=0.34, P<0.05), but not peak force. The perception of effort decreased with caffeine (d=0.37, P<0.05). Caffeine increased muscle stimulation frequency (P<0.05) and recruitment (η²=0.49, P<0.05) of multifidus spinae. In the transversalis/interne oblique muscles, caffeine increased the median frequency (η² = 0.13, P<0.05) and the distribution of higher frequencies (P<0.05). Caffeine also increased muscle recruitment in the transversalis/interne oblique muscles (η²=0.94, P<0.05). Tachycardia and increased blood pressure at the lumbar test were higher in the caffeine condition (P<0.05). Conclusions Our results show that caffeine is ergogenic for postural muscles. Decreased RPE and improved muscle activity suggest central mechanisms of caffeine. Trial registration UTN U1111-1234-2079.

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Role of Adenosine A_2AReceptors in the Central Fatigue of Neurodegenerative Diseases

Cited by 11 publications

References 215 publications

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases

Caffeine decreases neuromuscular fatigue in the lumbar muscles – a randomized blind study

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Role of Adenosine A2AReceptors in the Central Fatigue of Neurodegenerative Diseases

Cited by 11 publications

References 215 publications

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Neuronal adenosine A2A receptors signal ergogenic effects of caffeine

Pathways to healing: Plants with therapeutic potential for neurodegenerative diseases

Caffeine decreases neuromuscular fatigue in the lumbar muscles – a randomized blind study

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Role of Adenosine A_2AReceptors in the Central Fatigue of Neurodegenerative Diseases