Caffeine plus haloperidol reduces fatigue in an experimental model of Parkinson's disease - a prospective to A2AR-D2R heterodimer antagonism.

Fatigue is a non-motor symptom of Parkinson's disease (PD). Adenosine 2A receptor (A2AR) and compromised dopamine neurotransmission are linked to fatigue. Studies demonstrate that A2AR antagonism potentiates dopamine transmission via dopamine receptor D2 (D2R). However, the heterodimer form of A2AR-D2R in the striatum prompted questions about the therapeutic targets for PD patients. This study investigates the effects of caffeine (A2AR non-selective antagonist) plus haloperidol (D2R selective antagonist) treatment in the fatigue induced by the reserpine model of PD. Reserpinized mice showed impaired motor control in the open field test (p < 0.05) and fatigue in the grip strength meter test (p < 0.05). L-DOPA and caffeine plus haloperidol similarly increased motor control (p < 0.05) and mitigated fatigue (p < 0.05). Our results support the A2AR-D2R heterodimer participation in the central fatigue of PD, and highlight the potential of A2AR-D2R antagonism in the management of PD.

Rehabilitation Improves Persistent Symptoms of COVID-19: A Nonrandomized, Controlled, Open Study in Brazil.

OBJECTIVE: This study aimed to investigate the effects of an 8-wk face-to-face rehabilitation program on subjects with persistent symptoms of COVID-19 compared with a remote monitoring group. DESIGN: This is clinical, nonrandomized, controlled, and open study. The face-to-face supervised rehabilitation lasted eight consecutive weeks, twice a week. The remote monitoring group received health guidance. The allocation was carried out by preference because of the emergency period without vaccination during the pandemic. Fatigue, dyspnea (Pulmonary Functional Status and Dyspnea Questionnaire), and exercise capacity (Incremental Shuttle Walk Test) were the primary outcome measures. Lung function, functional status (Post-COVID-19 Functional Status), symptoms of anxiety and depression (Hospital Anxiety and Depression Scale), attention (d2-R), memory (Rey's Auditory-Verbal Learning Test), handgrip strength, and knee extensor strength were secondary outcome measures. RESULTS: Thirty-seven subjects (24.3% hospitalized) completed the baseline and final assessment, rehabilitation ( n = 22, 40.8 [SD, 10.0] yrs, 54.5% female), or remote guidance ( n = 15, 45.4 [SD, 10.5] yrs, 40% female). Both groups showed improved fatigue and exercise capacity. Exercise rehabilitation improved dyspnea, anxiety, attention, and short-term memory. CONCLUSIONS: Rehabilitation is essential for dyspnea in subjects with persistent symptoms of COVID-19 while fatigue naturally reverses.

The striatum drives the ergogenic effects of caffeine.

Caffeine is one of the main ergogenic resources used in exercise and sports. Previously, we reported the ergogenic mechanism of caffeine through neuronal A2AR antagonism in the central nervous system [1]. We now demonstrate that the striatum rules the ergogenic effects of caffeine through neuroplasticity changes. Thirty-four Swiss (8-10 weeks, 47 ± 1.5 g) and twenty-four C57BL/6J (8-10 weeks, 23.9 ± 0.4 g) adult male mice were studied behaviorly and electrophysiologically using caffeine and energy metabolism was studied in SH-SY5Y cells. Systemic (15 mg/kg, i.p.) or striatal (bilateral, 15 µg) caffeine was psychostimulant in the open field (p < 0.05) and increased grip efficiency (p < 0.05). Caffeine also shifted long-term depression (LTD) to potentiation (LTP) in striatal slices and increased the mitochondrial mass (p < 0.05) and membrane potential (p < 0.05) in SH-SY5Y dopaminergic cells. Our results demonstrate the role of the striatum in the ergogenic effects of caffeine, with changes in neuroplasticity and mitochondrial metabolism.

Post-viral fatigue in COVID-19: A review of symptom assessment methods, mental, cognitive, and physical impairment.

Coronavirus 2 is responsible for Severe Acute Respiratory Syndrome-Coronavirus-2 (SARS-CoV-2), and the main sequela is persistent fatigue. Post-viral fatigue is common and affects patients with mild, asymptomatic coronavirus disease-2019 (COVID-19). However, the exact mechanisms involved in developing post-COVID-19 fatigue remain unclear. Furthermore, physical and cognitive impairments in these individuals have been widely described. Therefore, this review aims to summarize and propose tools from a multifaceted perspective to assess COVID-19 infection. Herein, we point out the instruments that can be used to assess fatigue in long-term COVID-19: fatigue in a subjective manner or fatigability in an objective manner. For physical and mental fatigue, structured questionnaires were used to assess perceived symptoms, and physical and cognitive performance assessment tests were used to measure fatigability using reduced performance.

The Role of PGC-1α/UCP2 Signaling in the Beneficial Effects of Physical Exercise on the Brain.

In understanding the pathology of neurological diseases, the role played by brain energy metabolism is gaining prominence. Animal models have demonstrated that regular physical exercise improves brain energy metabolism while also providing antidepressant, anxiolytic, antioxidant and neuroprotective functions. This review summarizes the latest evidence on the roles played by peroxisome proliferator-activated receptor gamma (PPAR-γ) coactivator 1-alpha (PGC-1α) and mitochondrial uncoupling protein (UCP) in this scenario. The beneficial effects of exercise seem to depend on crosstalk between muscles and nervous tissue through the increased release of muscle irisin during exercise.

Behavioural, metabolic and neurochemical effects of environmental enrichment in high-fat cholesterol-enriched diet-fed mice.

While chronic high-fat feeding has long been associated with the rising incidence of obesity/type 2 diabetes, recent evidence has established that it is also associated with deficits in hippocampus-dependent memory. In this regard, environmental enrichment (EE) is an animal housing technique composed of increased space, physical activity, and social interactions, which in turn increases sensory, cognitive, motor, and social stimulation. EE leads to improved cerebral health as defined by increased neurogenesis, enhanced learning and memory and resistance to external cerebral insults. In the present study, the impacts of environmental enrichment (EE) on Swiss mice fed a high-fat, cholesterol-enriched diet (HFECD; 20% fat and 1.5% cholesterol) were investigated. Here, we demonstrated that EE, when initiated 4 weeks after the beginning of HFECD in mice, prevents HFECD-induced spatial memory and object recognition impairment, which were tested in T-maze and object recognition tests. Although EE did not affect HFECD-induced weight gain or hypercholesterolaemia, it improved glucose tolerance. On the other hand, EE was unable to mitigate a decrease in brain-derived neurotrophic factor (BDNF) and IL-6 hippocampal levels induced by the HFECD. Overall, while our results reinforce the positive and neuroprotective effects of EE on cognition they do not support a role for EE in preventing the neurochemical changes induced by the HFECD. Based on clinical observations that nondiabetic individuals with mild forms of impaired glucose tolerance have a higher risk of cognitive impairments, one can speculate about the connection between the effects of EE on glucose intolerance and its effects on cognition.